E U i s s
Global perspectives on diabetes Volume 56 – D ecember 2011 s p e c i a l
TYPE 1 DIABETES A very special issue 47
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32 DiabetesVoice 43 Contents
Diabetes View s 4 International Diabetes Federation Promoting diabetes care, prevention and a cure worldwide The global impact Diabetes Voice is published quarterly and is freely available Estimating the worldwide burden of type 1 diabetes 6 Leonor Guariguata online at www.diabetesvoice.org.
Hope springs for young people with type 1 diabetes 9 The production of this Special Issue has been made possible Graham Ogle and Larry Deeb thanks to the support of Sanofi Diabetes. The 3-C Study – strong partnerships to improve care This publication is also available in French, Spanish for people with type 1 diabetes in China 13 and Chinese. Linong Ji and Helen McGuire
Editor-in-Chief: Stephanie A Amiel, UK management, care and prevention Managing Editor: Olivier Jacqmain, [email protected] The key to managing diabetes without tears – the treatment and Editor: Tim Nolan, [email protected] Advisory group: Pablo Aschner (Colombia), teaching programme for flexible insulin therapy in Germany 16 Ruth Colagiuri (Australia), Patricia Fokumlah (Cameroon), Ulrich Alfons Müller Attila József (Hungary), Viswanathan Mohan (India).
Taking the benefits of DAFNE to the UK and beyond 19 Layout and printing: Luc Vandensteene, Ex Nihilo, Belgium, Stephanie A Amiel, Julia Lawton, Simon Heller www.exnihilo.be
Positive results in Australia – OzDAFNE takes up the challenge 22 All correspondence and advertising enquiries should be Dianne Harvey addressed to the Managing Editor:
Never say never – implementing DAFNE in Kuwait 24 International Diabetes Federation, Chaussée de La Hulpe 166, Ebaa Alozairi 1170 Brussels, Belgium Phone: +32-2-5431626 – Fax: +32-2-5385114 – [email protected] Great results for DAFNE Singapore – next stop, South-East Asia 27
Su-Yen Goh and Daphne Gardner
Making progress with immune therapies for type 1 diabetes 29 © International Diabetes Federation, 2010 – All rights reserved. Mark Peakman No part of this publication may be reproduced or transmitted in any form or by any means without the written prior permis- All that glitters is not gold – why we need better trials and reporting 32 Rury R Holman sion of the International Diabetes Federation (IDF). Requests to reproduce or translate IDF publications should be addressed Back to the future: investigating new treatments for type 1 diabetes to the IDF Communications Unit, Chaussée de La Hulpe 166,
using old inexpensive drugs 37 B-1170 Brussels, by fax +32-2-5385114, or by e-mail Denise Faustman and Miriam Davis at [email protected].
The information in this magazine is for information purposes only. causes and effects IDF makes no representations or warranties about the accuracy and reliability of any content in the magazine. Any opinions expressed From victim to protector – what the brain does with hypoglycaemia 40 are those of their authors, and do not necessarily represent the views Stephanie A Amiel of IDF. IDF shall not be liable for any loss or damage in connection with your use of this magazine. Through this magazine, you may Epilepsy in children and adolescents with type 1 diabetes 43 link to third-party websites, which are not under IDF’s control. Edith Schober and Reinhard Holl The inclusion of such links does not imply a recommendation or an endorsement by IDF of any material, information, products and services advertised on third-party websites, and IDF disclaims any diabetes champions liability with regard to your access of such linked websites and use of any products or services advertised there. While some information Breakthrough – the story of Elizabeth Hughes and in Diabetes Voice is about medical issues, it is not medical advice and should not be construed as such. the making of a medical miracle 45
Arthur Ainsberg ISSN: 1437-4064 Cover photo © Wong Sze Yuen - istockphoto.com In the race for a glittering prize – Team Type 1 hits the road 47 Phil Southerland From diabetes education and prevention all the way to sporting
excellence – Italy’s BCD Campaign 49 Massimo Massi-Benedetti
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 3 Diabetes views
the diabetes pandemic that maximizes the resources available to tackle the causes A very special and consequences of the upsurge in type 2 diabetes and prioritizes the needs of people with type 1 diabetes. The diagnosis, treatment and management of non-preventable diabetes require integrated health systems, issue in a delivery of care down to primary care level and supportive policies outside the health sector.
stellar year In terms of our campaign to achieve those long-term objectives, 2011 has been a landmark year for diabetes. In September, I attended for diabetes an historic meeting of world leaders The 5th edition of the IDF Diabetes Atlas, which was launched on at the UN Summit, where they adopted the first ever Political World Diabetes Day, 14 November 2011, presented some daunting Declaration on Non-Communicable Diseases. The standard bearer figures: the estimated number of adults living with diabetes has for diabetes throughout, IDF has been a principal figure in the soared to 366 million – more than 8% of the global adult population NCD Alliance largely responsible for that historic accomplishment – and is projected to rise to 552 million people by 2030 – just in New York. And we are among the ‘NCD revolutionaries’ – as short of 10% of all adults. That means that diabetes is growing at described recently by Richard Horton, Editor of The Lancet – who the extraordinary rate of approximately three new cases every 10 are striving to ensure that the promises made by governments can seconds. The Atlas estimates confirm that diabetes continues to be turned into action for people with diabetes of any type. affect disproportionately the socially disadvantaged and continues to increase especially rapidly in low- and middle-income countries Diabetes needs the reach, the voice and the power to generate – where the health system is already ill equipped to provide care government interest in health-protective policies beyond the health and resources for people with any type of diabetes. sector – and then to actually legislate for them. A broad coalition of aligned groups will be fundamental; inter-sectoral alliance is While type 2 diabetes dominates in sheer numbers, type 1 diabetes a significant recommendation of the 2011 Political Declaration. remains a very special issue. With 70,000 newly diagnosed young IDF provides the platform for that much needed collaboration. people every year, the prevalence of type 1 diabetes is growing IDF engages in ‘triple p partnerships’ (public-private-people) that globally – not just in northern Europe. Those affected have very bring together non-health actors and key stakeholders, including particular needs. The bottom line could not be more crude: unless the private sector where appropriate, and civil society in proactive they are diagnosed quickly and then receive insulin and skilled partnerships to promote and protect health. instruction on how to use it, people with type 1 diabetes die very quickly. That adults and children should be dying every day because As we look forward to a new year and welcome a new springtime they go undiagnosed or do not have access to insulin is deplorable. in the fight against diabetes, we must act as a global community. We are all part of the solution! In various partnerships with other non-profit groups and public and private entities IDF is working to bridge some of the gaps. IDF’s child sponsorship programme, Life for a Child, supports services for children with diabetes and their families in resource- poor communities worldwide. And in collaboration with the International Society for Pediatric and Adolescent Diabetes (ISPAD), IDF has produced the brand new Guideline for Diabetes in Childhood and Adolescence – which covers all diabetes in young people. The desired role of the guideline is not only to assist individual healthcare providers in managing young people with Jean Claude Mbanya is IDF President for diabetes; it aims to improve awareness among governments and state healthcare providers of the essential resources needed for the period 2009 to 2012. He is Professor optimal care. of endocrinology at the University of Yaounde, Cameroon, and Chief of the These activities are vital and our involvement can only increase. But our fight for diabetes will take us further – beyond the diabetes Endocrinology and Metabolic Diseases community. Societies in general must build a concerted response to Unit at the Hospital Central in Yaounde.
4 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Diabetes views
items – which, although they are essential, are not Type 1 diabetes: easy to come by for everyone – to have a high degree of knowledge and enough confidence to apply that knowledge and the emotional security to be able to handle it all. Providing that support takes time – quo vadis? another commodity not always in great supply – and expertise, In this special issue of Diabetes Voice, there is a focus on type from healthcare professionals as well as people with diabetes. 1 diabetes. In tackling the world pandemic of diabetes, and the critical importance of making societal change to arrest the Helping our patients to learn how to manage their life on insulin staggering rise in the prevalence of type 2 diabetes, it is easy for injections is too important to leave to chance or to random, well- the needs of the 10% of people with diabetes who have type 1 meaning interventions of unproven validity. It needs resourcing. On diabetes to be forgotten. Yet incidence of type 1 diabetes is also pages 16 to 28, we look at the globalization of one strategy for helping rising – at 3% per year (see page 6) - and as Professor M'Banya people with type 1 diabetes to live more healthily, using structured points out in his editorial, people with type 1 diabetes worldwide education to help patients use insulin flexibly. The Dusseldorf are still dying because of missed diagnoses or inadequate insulin DAFNE programme can help people with type 1 diabetes achieve supply. The disease particularly affects children: IDF estimates that the glucose targets that reduce the risk of complications, while there are over half a million children with type 1 diabetes currently. reducing hypoglycaemia risks and allowing people to live the life But another danger exists in forgetting that type 1 diabetes can they choose with measurable benefit to quality of life. It is founded in arise at any age and that focusing attention only on children may well-validated principles of insulin action and educational strategies disenfranchise adults living with the disease. Be they children or that work for adults, and has a good evidence base for its efficacy. adults, the needs of the people with type 1 diabetes are different Delivering such programmes requires skilled healthcare professionals from those of the majority of people with diabetes and have to be who understand education as well as physiology and metabolism. be addressed separately. The need for an expert multidisciplinary team has never been As exemplified by this special issue, IDF has not forgotten the stronger. Developing such programmes for children and adolescents, 10%. At our international meeting in Dubai, IDF presented data who require different educational approaches, has been slow but is on type 1 diabetes in China from a collaboration that started in evolving. Many throughout the diabetes community will be keeping July, in partnership with the Chinese Diabetes Society and insulin an eye out for future developments. I have no doubt that the editors manufacturers Sanofi Aventis, sponsors of this issue of Diabetes of this special issue would like to hear of successes in this area! Voice. We are excited that this issue of Diabetes Voice is published in Mandarin. Access to good therapy for people with type 1 diabetes should not be a lottery. Nor should it be dependent upon charitable works It is now 90 years since the discovery of insulin. One of the and humanitarian organizations. Health organizations, in trying to remarkable things about the insulin story is how quickly it moved reduce costs by re-structuring services for people with other forms from bench to bedside – one might be forgiven for wondering of diabetes, must not allow the support needed by people with type how it would have fared in today’s regulatory environment! It one to be the baby that gets thrown out with the bath-water! is sobering to reflect that the first recipient of insulin – Leonard Thompson – died of pneumonia in the era before the discovery of antibiotics. On page 45, Thea Cooper and Arthur Ainsberg review the history of the discovery of insulin from the perspective of one of the people whose life it saved – touching also on the limitations of insulin as a therapy. Since Elizabeth Hughes received her first insulin injection, we have learned much about how to use insulin most appropriately – now we need to learn how to transfer that information to our colleagues – and to our patients. And we need the funding to do it effectively.
As with any long-term condition, and certainly as with other forms of diabetes, the best – indeed the only – person who can properly manage the disease is the person who lives with it, day by day, month by month, year by year. It is the role of the healthcare professional to Professor Sir K George M M Alberti equip the patient (and often their family) with the tools to do this. This is much more than a prescription for insulin and blood glucose Chairman of Diabetes UK and monitoring equipment. Good outcomes also need the users of these Past-President of IDF
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 5 Diabetes views Estimating the worldwide burden of type 1 diabetes
Leonor Guariguata
Regional trends Providing an accurate estimate of the number of children with type 1 An estimated 24% of all children with diabetes is an essential component of planning health policy, assessing type 1 diabetes live in the European the quality of care and driving research. There is good evidence that region, where the most reliable and the incidence of type 1 diabetes among children is increasing in many up-to-date estimates of the burden of parts of the world. The International Diabetes Federation’s Diabetes diabetes are available. Two large in- th Atlas, 5 edition, estimates that increase to be 3% per year. The ternational collaborative projects, the cause of this rise is unknown, although it may be linked to a number Diabetes Mondiale study (DiaMond) of factors. Studies have found associations with older mothers, early and the Europe and Diabetes study exposure to dietary components, such as cow’s milk, and a reduction (EURODIAB) have been instrumental in the frequency of early infections. Many of these factors can be in monitoring developments in the in- linked to socioeconomic development and changes in environments. cidence of type 1 diabetes in children, However, there are important geographic differences in the trends, providing us with some of the best evi- which may reflect underlying differences in ethnicity, exposure to dence on trends and prevalence for any potential risk factors and the capacity of health systems to identify region. These studies have shown that and record people diagnosed with type 1 diabetes. Leonor Guariguata the rate of new cases in many countries 2 reports on the global status of type 1 diabetes in children and looks is highest among younger children. at some the key issues behind the latest figures. In many countries, the rate of newly diagnosed Type 1 diabetes is one of the most com- that the incidence is rising rapidly, es- type 1 diabetes mon endocrine and metabolic condi- pecially among the youngest children.2-4 tions among children. According to the Type 1 diabetes is increasing steeply is highest among latest edition of the Diabetes Atlas, an in some central and eastern European younger children. estimated 490,100 children below the countries, where the disease remains less age of 15 years are living with type 1 common than in other regions.5 If these There are a number of clinical implica- diabetes.1 A further 77,800 children un- trends continue, it is inevitable that the tions for this overall drop in the ages der the age of 15 are expected to develop total prevalence of people with type 1 at which young people are being diag- the disease in 2011 and there is evidence diabetes will increase in coming years. nosed with type 1 diabetes. Diagnosis
6 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 THE GLOBAL IMPACT
in a young child may be delayed or be dying from a lack of insulin before and quality care. A study by the missed because of subtle and mislead- they are identified. One study in Sudan International Insulin Foundation, the ing symptoms. In many cases, it can be showed a mortality rate of 42.6 deaths Rapid Assessment Protocol for Insulin impossible for a child to be stabilized per 100,000 children with type 1 diabe- Access, conducted in five countries (Mali, and begin receiving care outside hospi- tes.6 This is compared to 0.63 deaths per Mozambique, Nicaragua, Vietnam, and tal – which, in many parts of the world, 100,000 children with type 1 diabetes Zambia), found several barriers to access presents a serious barrier to seeing a in the USA.7 It is almost impossible to to good care, including a lack of avail- qualified health professional. Moreover, determine the true incidence and prev- ability of quality insulin, syringes, and younger children with diabetes may be alence in these regions; special efforts monitoring devices.9 These barriers pose more likely than their older peers to must be made to record and report on a direct threat to children with type 1 present with ketoacidosis at the time of this problem. Regardless, even in studies diabetes, who must rely on caregivers to diagnosis and may face more years of from high-income countries, children help manage their disease and obtain the hyperglycaemia with increased risk of with type 1 diabetes had at least twice materials necessary to keep them alive. complications. These combined factors the mortality rate of children without place a significant burden on health sys- the disease.8 A number of other factors can have a tems and may increase the costs of care. strong influence on estimates of type 1 Even in high-income diabetes. For older children moving into Europe is followed closely by South- countries, children with adolescence, distinguishing between East Asia, with 23% of the world’s young type 1 diabetes died at type 1 diabetes and type 2 diabetes be- people with type 1 diabetes, and North comes more difficult; problems of mis- America and the Caribbean, with 19%. twice the rate of children classification can hamper efforts to es- However, the lack of data in other parts without the disease. timate accurately the status of diabetes. of the world makes it difficult to estimate Type 2 diabetes is emerging as a serious the true burden. In sub-Saharan Africa Mortality problem for adolescents worldwide. As a and many low-resource countries, diag- This early mortality is almost certainly result, children who present with type 2 nosis may be missed and children may linked to a severe lack of access to insulin diabetes, a disease traditionally associated
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 7 THE GLOBAL IMPACT
with adults, may be misclassified as hav- based diabetes registries, which record life of people with type 1 diabetes, in- ing type 1 diabetes. Similarly, as glo- newly diagnosed people with diabetes. cluding, perhaps especially, the children bal trends in obesity also increase in These numbers are then used to esti- with diabetes and their families through children and adolescents, some young mate the prevalence of type 1 diabetes improved access to medicines, social people who are obese but present with in children. support and diabetes education. With type 1 diabetes may be misclassified as type 1 diabetes on the rise in many parts having type 2 diabetes because of the The Atlas reports type 1 diabetes esti- of the world, resources must be devel- latter’s strong links with obesity.10 mates only for children between 0 and oped to meet the needs of this growing 14 years – and no older – because the population. Generating the figures majority of studies include this informa- All the estimates and figures produced tion. There are few studies estimating Leonor Guariguata by IDF and published in the Diabetes the burden of type 1 diabetes among Leonor Guariguata is biostatistician at the International Diabetes Federation. Atlas are based on studies carried out young people aged between 15 and 19, in regions and countries. For the 5th and even fewer capturing estimates for References edition, a total 88 studies were used to type 1 diabetes in adults. However, there 1 International Diabetes Federation. generate the estimates for diabetes in is some indication that in high-income Diabetes Atlas, 5th ed. IDF. Brussels, 2011. children. The majority of those stud- countries, between 10% and 15% of all 2 Tuomilehto J, Virtala E, Karvonen M, et al. ies were carried out in Europe, North diabetes is attributable to type 1 diabetes, Increase in incidence of insulin-dependent America and South-East Asia. There while the estimate is likely to be lower diabetes mellitus among children in Finland. are serious gaps in the availability of in low- and middle-income countries. Int J Epidemiol 1995; 24: 984-92. studies from sub-Saharan Africa and 3 Gardner SG, Bingley PJ, Sawtell PA, et al. parts of the Western Pacific, which in- The way forward Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford fluences the figures for those regions. Despite gaps in the evidence and the region: time trend analysis. The Bart’s Oxford The quality and reliability of studies can need for more high-quality studies, it Study Group. BMJ 1997; 315: 713-7. vary greatly depending on the meth- is clear that type 1 diabetes is a serious 4 Dahlquist G, Mustonen L. Analysis of 20 ods used and the representation of the health priority all over the world. It is years of prospective registration of childhood population. Most of the studies used for essential to map the disease in order to onset diabetes time trends and birth cohort effects. Swedish Childhood Diabetes Study global estimates draw on population- set priorities for care and improve the Group. Acta Paediatr 2000; 89: 1231-7.
5 EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000; 355: 873-6.
6 Elamin A, Altahir H, Ismail B, Tuvemo T. Clinical pattern of childhood type 1 (insulin-dependent) diabetes mellitus in the Sudan. Diabetologia 1992; 35: 645-8.
7 Nishimura R, LaPorte RE, Dorman JS, et al. Mortality Trends in Type 1 Diabetes: The Allegheny County (Pennsylvania) Registry 1965-1999. Diabetes Care 2001; 24: 823-7.
8 International Diabetes Federation. Diabetes Atlas, 3rd ed. IDF. Brussels, 2007.
9 Beran D, Yudkin JS, de Courten M. Access to care for patients with insulin-requiring diabetes in developing countries: case studies of Mozambique and Zambia. Diabetes Care 2005; 28: 2136-40.
10 Rosenbloom AL, Silverstein JH, Amemiya S, et al. Type 2 diabetes mellitus in the child and adolescent. Pediatric Diabetes 2008; 9: 512-26.
8 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 THE GLOBAL IMPACT Hope springs for young people with type 1 diabetes
Graham Ogle and Larry Deeb
The IDF Diabetes Atlas, In the developed world, the outlook for cure, such as islet cell transplantation. 5th edition, estimates that a child with type 1 diabetes has changed Nowadays, many people live with type 1 worldwide 495,100 children dramatically over the 90 years since in- diabetes for 60 or 70 years, or more, below 15 years of age are living sulin was discovered. The diagnosis used and long-term studies of adults who to be a death sentence, with life expect- developed diabetes during childhood with diabetes. Added to this ancy measured in months. As reported show steady reductions in mortality number would be as many or elsewhere in this issue, there have been rates with time, with the likelihood that more young people aged between steady advances since then, including: this will continue to improve.1 15 and 25 years. Together with longer-acting animal insulin, blood More than a quarter adults with type 1 diabetes, these glucose self-monitoring, HbA1c testing, 1 million plus children and young understanding of complications and the of a million children people face the challenge of living importance of blood glucose control, with type 1 diabetes appreciation of the role of different diets with a complex, life-threatening and exercise regimens, human insulin, – 50% of the global chronic disease, but in widely diabetes education and empowerment population – live in the different circumstances. The (including associations of people with developing world. authors reflect on the latest diabetes and diabetes camps), the multi- figures from around the world disciplinary team, analogue insulins and Examination of the Diabetes Atlas fig- for type 1 diabetes in young insulin pump therapy. In parallel with ures reveals interesting details. Incidence people, describe some of the this, scientific understanding of immu- varies markedly around the world and, nological and pathological mechanisms on average, is increasing at between 3% challenges to providing universal and determination of best-practice care and 4% per year.2,3 Of the estimated care and treatment, and deliver have occurred. 495,100 children with type 1 diabetes, good news about some positive around 230,000 (some 46%) live in trends in the developing world. Extensive research is underway into developed countries – the European all dimensions of type 1 diabetes, with nations, USA and Canada, Australia, much attention focused on closing the New Zealand, Japan, Singapore, Saudi loop between blood glucose measure- Arabia, and other high-income nations. ment and insulin delivery, prediction The remaining 260,000 children with and prevention, and possibilities for a diabetes live in middle- and low-income
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 9 THE GLOBAL IMPACT
countries. India is estimated to have (particularly in Africa) – presumably with available resources. However, there 97,700 and China 8,700 (reflecting the due to high mortality rates. In others are number of countries, particularly in stark difference in measured incidence (for instance in Central America), the sub-Saharan Africa but also in Asia and between these two countries). Africa has incidence may be considerably higher the Americas, where such care is only an estimated 36,000 cases. than the few studies (often relatively available to wealthy families. old) would suggest. These estimates are the best that can be Lack of access to, and the high cost made with the available data. However, Lack of access to of, insulin and other supplies, limited there are, by necessity, many extrapola- insulin, limited medical health professional expertise concern- tions where there are gaps in the data; ing childhood diabetes, lack of diabetes expertise and education, 129 of the 202 countries listed have no education, geographic isolation and ex- incidence data. For a number of others, and extreme poverty treme poverty can result in very poor the data are relatively old and deter- combined lead to very outcomes – starting with frequent mis- mined from a region or city rather than diagnosis at disease onset so the child the whole country. poor outcomes. dies untreated; then a high risk of early Children in high-income countries have death from hypoglycaemia or ketoaci- Even when the rate of incidence is access to comprehensive care – the most dosis; and for those who survive, very known, prevalence is very difficult up-to-date and complete range of health poor blood glucose control. Such sus- to calculate in poor countries, as few technologies that can be offered to peo- tained poor control leads to impaired have a complete registry or any pub- ple with diabetes with the aim of achiev- quality of life – many children drop out lished information on mortality rates. ing best possible outcomes. In many of school, cannot find employment or Direct experience of the IDF Life for middle-income countries and some a marriage partner and develop severe a Child programme suggests that the low-income countries, quality care is complications (such as loss of vision, Atlas may markedly overestimate the also achieved - through well-designed end-stage renal failure and severe neu- existing numbers in some countries cost-effective approaches consistent ropathy) in their 20s or even earlier.
10 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 THE GLOBAL IMPACT
In the last 10 years, however, progress have no specialty diabetes nurse edu- in major world languages. A range of has been made in some low-income cators. Skills and settings to educate other initiatives is also underway: the countries concerning access to insulin families and young people affected by International Society for Pediatric for children and adolescents. Various diabetes are lacking, and often there and Adolescent Diabetes (ISPAD) is factors are helping this trend: economic are no education materials available. conducting training and developing growth in some countries, more market Diversity of languages and educational guidelines; the Changing Diabetes in competition, the availability of reduced levels compound the challenges. Children programme is assisting diabe- prices to developing nations in certain tes centres in a number of countries; and circumstances and the impact of Life for However, we can report with pleasure the International Insulin Foundation is a Child and other programmes (which that the situation is changing. The dia- working to improve access to supplies. receive and deploy donated supplies). betes landscape is being transformed by There is an increasing emphasis on the dedicated efforts of local champi- training paediatric endocrinologists, in- There is an alarming ons – doctors and non-medical people cluding the successful ISPAD/European trend in at least a few determined to make childhood diabetes Society of Paediatric Endocrinology countries towards a focus – combined with support from School in Nairobi, Kenya. the international diabetes community purchasing analogue (health professionals, developed-coun- Very much more remains to be done. and other expensive try associations, industry). However, due to the coordinated col- insulin preparations. We can report with laborative efforts of the international diabetes community to effect change, a However, many children do not receive pleasure that the watershed has been reached for care of enough insulin and have insecure, inter- situation is changing; childhood diabetes worldwide. mittent access, particularly in outlying a watershed has and rural areas of developing countries, Graham Ogle and Larry Deeb and in developing countries that have been reached for Graham Ogle is a paediatric endocrinologist. not yet been able to develop a diabetes care of childhood He is General Manager of the IDF Life for a service. Child programme and Director of Health and diabetes worldwide. Social Services at HOPE worldwide (Australia). Larry Deeb is Clinical Professor of Pediatrics Self-monitoring of blood glucose is also For instance in Mali, the intervention at the University of Florida and Clinical beyond the reach of many thousands of of Santé Diabète and the Government Professor of Behavioral Medicine at Florida State University, USA. He is also the chair children and adolescents with diabe- health services, with support from the of the IDF Task Force for Insulin, Test Strips, and other Diabetes Supplies. tes, as neither their government health Life for a Child Program, has led to system nor their own family’s finances dramatic improvements in survival. In can afford to buy test strips – which, Mali in 2007, only 14 young people aged References paradoxically, are more expensive than below 23 years were known to the dia- 1 Secrest AM, Becker DJ, Kelsey SF, et al. All-cause mortality trends in a large population-based insulin. Transnational solutions are ur- betes community. With the provision cohort with long-standing childhood-onset type 1 diabetes. Diabetes Care 2010; 33: 2573-9. gently needed in this area. Further chal- of adequate insulin, test strips, HbA1c
lenges occur in the availability of HbA1c testing equipment and other supplies, 2 DIAMOND Project Group. Incidence and testing and screening for complications, this number has risen to more than 140 trends of childhood Type 1 diabetes worldwide such as for microalbuminuria. – most of the increase being new cases. 1990-1999. Diabet Med 2006; 23: 857-66. Mortality rates are now low. Similarly, 3 Patterson CC, Dahlquist GG, Gyurus E, et al. Equal to the problem of access to in- in Rwanda, there are improvements in Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted sulin and other supplies is the lack of care4 and sharp increases in numbers. newcases 2005-20: a multicentre prospective available diabetes education in many registration study. Lancet 2009; 373: 2027-33. countries. Few physicians are familiar Life for a Child is supporting diabetes 4 Marshall SL, Sharma, V, Ogle G, Orchard T. with childhood diabetes, and children services in 36 countries and has de- Improvements of Glucose Control Seen in are often treated by adult internists or veloped a website for childhood and Children with Type 1 Diabetes in Rwanda, Africa. Diabetes 2011; 60(Suppl1): Abstract 1165-P, A320. general practitioners. Many countries adolescent diabetes education resources
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 11 Diabetes view from the field
Despite these efforts, many unmet needs CDS facing down r e m a i n . Discrimination against people with type 1 diabetes is still common, challenges to for instance. People with type 1 diabetes face great difficulties accessing higher education and employment. improved care This social unfairness not only has a negative impact on personal lives, it hinders disease management. For example, in order to hide their condition, many students and employees with type 1 for type 1 diabetes never test blood glucose and inject insulin at school or the work place, making intensive glucose control impossible.
Special care for people with type 1 diabetes is available only in the diabetes large clinical centres located in major cities. The type 1 diabetes China is experiencing an increase in the number of people with management capabilities of primary and secondary healthcare type 1 diabetes. New cases as well as improved life expectancy centres are still very limited. Even in the larger clinics, standards of among people with established diabetes are behind the rising care for type 1 diabetes have not been well implemented throughout. prevalence. The incidence of type 1 diabetes among children has Moreover, the way in which people with type 1 diabetes are identified been put at 0.59 per 100,000 people per year. Although this is far remains an area for serious attention. There are multiple reports of lower than in some other regions, such as northern Europe, our misdiagnoses of type 1 diabetes leading to fatalities. numbers are huge because China has such a large population – in excess of 1.3 billion. The personal financial burden of disease management is high. For example, throughout most of the country, glucose test strips and The Chinese Diabetes Society (CDS) is dedicated to improving disposable insulin pen lancets are not reimbursed. As a result, diabetes care for people with type 1 diabetes through education people with type 1 diabetes reportedly are using the disposable and good clinical practice. CDS members have organized a national needles for several days. programme to train medical professionals in the management of type 1 diabetes. The CDS Guideline for diagnosis and treatment of CDS is fully committed to ongoing efforts to promote standards of diabetic ketoacidosis in childhood type 1 diabetes and Consensus of care and education to improve the life of young people with type insulin treatment in childhood type 1 diabetes were developed in 1 diabetes. We will continue to work closely with the government 2009 and 2010, respectively. and other sectors of society to improve quality of life and welfare of all people with the condition in China. CDS has made education one of its priorities. A CDS task-force, which was founded in 2003, focuses on enhancing and extending training for diabetes educators and certifying those who are qualified. Educators play more and more important roles in diabetes management, especially in improving people’s ability to follow professional diabetes management advice.
Beijing Children’s Hospital is a good example. In the past five years, the educator at that hospital designed a structured course covering contents from fundamental survival skills to advanced self-management. Following structured education, blood glucose control has improved dramatically among young people with diabetes at the centre. Many tertiary care centres in large cities organize summer camps for children with type 1 diabetes and their parents, Linong Ji, Director of the Department of providing activities that teach kids with type 1 diabetes and their Endocrinology and Metabolism Peking parents how to cope with the disease, and giving the children the confidence they need to fight the disease, safe in the knowledge University People’s Hospital and President that they are not alone. of the Chinese Diabetes Society
12 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 THE GLOBAL IMPACT The 3-C Study – strong partnerships to improve care for people with type 1 diabetes in China
Helen McGuire and Linong Ji
In March 2010, investigators On World Diabetes Day this year, Incidence was highest in children aged from the Chinese Diabetes 14 November 2011, the 5th edition of between 10 and 14 years of age, and there Society (CDS) published a the International Diabetes Federation was no statistically significant gender- Diabetes Atlas was released containing based difference in the rate. study that captured headlines the estimate that 8,700 children under in the popular as well as the 14 years of age in China have type 1 Opportunities exist to medical media around the diabetes – an incidence rate of 0.6 per achieve earlier diagnosis world. It estimated that the 1 100,000 per year. Although the preva- and strengthen number of people with diabetes lence and incidence rates are relatively in China had risen in excess low in China, the number of people with secondary prevention of 92 million. With the release type 1 diabetes represents more than efforts in China. half the total number of young people of those findings, China took with type 1 diabetes in the Western Recent studies in China on clinical pres- over from India the dubious Pacific Region. entation and outcomes of people with mantle of diabetes capital of the type 1 diabetes suggest that opportuni- world. The authors look at the In 2000, a large study was conducted ties exist to achieve earlier diagnosis epidemiological contribution of over several countries including China and strengthen secondary prevention type 1 diabetes to the national that looked at trends in the incidence and efforts. A 2007 study found that chil- prevalence of type 1 diabetes in children dren under 18 years of age in China and global figures, and present 14 and under.2 Within China, the high- had generally poorer outcomes than a major new study aimed est incidence was found in the region of the average values of young people in 11 ultimately at improving care for Wuhan (4.6 per 100,000 per year) and countries in the Western Pacific Region people with the disease in China. lowest in Zunyi (0.1 per 100000 per year). (Figure).3 Severe hypoglycaemia was
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 13 THE GLOBAL IMPACT
the exception, with a regional aver- and CDS was contacted to determine project in China. An academic research age of 74 events per 100 patient years their interest. A Member Association organization in China was contracted compared with 39 events per person of IDF founded in 1991, CDS conducts to assist with implementation in Beijing years in China. A more recent study, various public education programmes, and Shantou. carried out in Shenyang found that 41% epidemiological surveys and research in of children with type 1 diabetes present China. The mission of CDS is to prevent The potential strength of partnerships with ketoacidosis and that the average and treat diabetes and provide infor- became clear as the IDF team worked duration of symptoms before going to mation to help educate people living closely with healthcare professionals hospital was 24.5 days.4 with diabetes, their families, healthcare and investigators in China to launch professionals and the public about this the project. CDS brought together a Type 1 diabetes in China is an important disease. Led by IDF and with CDS col- network of 19 committed hospitals and area for research due to the paucity of laboration and Sanofi support, the tri- primary health centres to participate available data. Moreover, investigat- party partnership was formed. in the project. These include: Peking ing type 1 diabetes has the potential University People's Hospital, Military to influence the changing healthcare The network of Hospital, Peking Union Hospital, Beijing environment in China to improve care participating healthcare Children's Hospital, Peking University and clinical outcomes for people with First Hospital, Peking University Third the disease throughout the country. facilities is a testament Hospital, Beijing Haidian Hospital, the of the power of effective Luhe Teaching Hospital of the Capital IDF is active in building the global partnerships. Medical University, Pinggu Hospital, diabetes evidence base and advocat- Zhanlan Road Community Health ing for improved care for people with To advance the project design, the IDF Service Centre, the Second Hospital diabetes. An umbrella organization of specialist team, Helen McGuire, David of Tongzhou district, Pinggu Town more than 200 national diabetes associa- Whiting and Katia Skarbek travelled Community Health Service Centre, tions around the world, IDF represents to China on several occasions to meet Pingguoyuan Community Health the interests of the growing number of with stakeholders and refine the proto- Service Centre, the First Affiliated people with diabetes and those at risk. col to match local realities. Professors Hospital of Shantou University Medical Leading the global diabetes community Linong Ji (in Beijing) and Weng (in College, the Second Affiliated Hospital since 1950, IDF’s mission is to promote Shantou) represented CDS, and, along of Shantou University Medical College, diabetes care, prevention and a cure with IDF, led the establishment of the Chaonan Minsheng Hospital, Chenghai worldwide. IDF collaborates with its Member Associations to support their efforts to advance their strategic priori- ties and transfer knowledge from one region of the world to another.
In 2009, IDF conceived a project to as- Figure: Outcomes in children with type 1 diabetes under 18 years of age in China vs 11 countries in the sess the current status of care, including 3 the costs involved in coverage for people Western Pacific Region with type 1 diabetes, in order to influ- China ence change and ultimately improve WPR outcomes for people with diabetes. IDF 9.5% 8.8% and Sanofi agreed to work together to HbA 1c 13.0% realize a timely and innovative type 1 2.5% Microalbuminuria 23.9% diabetes research project. 21.6% Hypertension China was identified as the appropri- ate country to launch such a project
14 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 THE GLOBAL IMPACT
Huaqiao Hospital, Chaonan Longtian Health Service Centre, Chenghai Dongli Health Service Centre. This comprehen- sive network of committed healthcare facilities is a testament of the power of effective partnerships. This global-to-local partnership represents an important model for advancing diabetes care worldwide. Training session for study investigators in Shantou In July 2011, the 3-C Study: Coverage, Cost and Care of Type 1 Diabetes in China5 was launched in Beijing at a press conference featuring Jean Claude Identify the scale of government in- questions about the disease unanswered, Mbanya, IDF President, Linong Ji, CDS vestment needed to improve health- such collaborations are vital. We must President and Riccardo Perfetti, Vice care coverage speak with a common voice if we are President of Global Medical Affairs, Define the burden of disease in terms going to make a real difference. Diabetes Division, Sanofi. The global- of clinical outcomes to-local partnership achieved in this Describe the educational and care ex- Helen McGuire and Linong Ji project represents an important model periences of people with type 1 dia- Helen McGuire is Senior Diabetes for advancing diabetes care worldwide: betes compared with selected clinical Education and Health Systems National member associations provide practice guidelines Specialist at IDF and a member of the IDF team leading the 3-C Study. in-country expertise and networking Describe the information processes Linong Ji is Director of the Department IDF provides the global perspective associated with diabetes care and edu- of Endocrinology and Metabolism at and facilitates knowledge transfer from cation. Peking University People’s Hospital, Beijing, People’s Republic of China. one region of the world to another Industry makes a positive contribu- This is the first research initiative to References tion to the advancement of care by study a chronic disease from a range 1 International Diabetes Federation. Diabetes Atlas 5th edition. IDF. Brussels, 2011. supporting organizations to develop of angles. The model established and and implement projects without in- experience gained in this study will be 2 Yang Z, Wang K, Li T, et al. Childhood diabetes in China. Enormous variation by place and terference from the funder. invaluable in studying other chronic ethnic group. Diabetes Care 1998; 21: 525-9. conditions, such as type 2 diabetes. The The 3-C Study will provide data to in- gaps identified between what should be 3 Craig ME, Jones TW, Silink M, Ping YJ. Diabetes care, glycemic control, and form policy and decisions on the ad- happening in type 1 diabetes care and complications in children with type 1 diabetes vancement of treatment of type 1 dia- day-to-day reality will lay the founda- from Asia and the Western Pacific Region. J Diabetes Complications 2007; 21: 280-7. betes in China. Its key objectives are tions for future translational research as follows: into the implementation of care stand- 4 Xin Y, Yang M, Chen XJ, et al. Clinical features Describe coverage, cost and care for ards for people with type 1 diabetes in at the onset of childhood type 1 diabetes mellitus in Shenyang, China. type 1 diabetes China. J Paediatr Child Health 2010; 46: 171-5. Estimate the number of people with 5 McGuire H, Kissimova-Skarbek K, type 1 diabetes The tri-party partnership led by IDF has Whiting D, Ji L. The 3C Study: Coverage Estimate the economic burden from achieved a culturally relevant and scal- cost and care of type 1diabetes in China – type 1 diabetes and financial barriers able project. With 366 million people in Study Design and Implementation. Diab Res Clin Pract 2011; Doi:10.1016. to care the world living with diabetes and many
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 15 MANAGEMENT, CARE AND PREVENTION The key to managing diabetes without tears – the treatment and teaching programme for flexible insulin therapy in Germany
Ulrich Alfons Müller
Successful implementation of structured It was the paediatrician, Karl Stolte, who, using pre-meal education programmes that teach people with type urine tests to target insulin dose adjustment, first provided 1 diabetes to use insulin flexibly around normal people affected by diabetes with education to adapt their 1 lifestyle behaviours is the subject of this and insulin regimen to be able to eat normally. His idea to increase the dose of soluble (regular) insulin to allow the following four articles in this special issue. dietary freedom came in 1928, when a birthday cake was Programmes such as the UK's Dose Adjustment brought to a hospital ward for a child without diabetes and for Normal Eating (DAFNE), in which the person shared with eight children with the disease. His work and affected by type 1 diabetes is central to all his conviction that “people with diabetes should not eat disease management decisions, are the object of like laboratory animals, which day after day get food cal- a number of projects in different countries. While culated down to the gram” were rejected by most German such programmes are increasingly regarded paediatricians and diabetologists at the time – and until as the state-of-the-art deployment of diabetes as late as the 1980s! resources, their origins lay in Germany early The first diabetes teaching unit in a European country was in the last century. Ulrich Müller looks back at founded by Jean Philippe Assal at the University Hospital the birth and initially arrested development of in Geneva, Switzerland, in 1970. A paradigmatic change flexible insulin therapy programmes, describes was underway in theories about diabetes therapy. ‘Patient the approach itself and demonstrates what education’, which took the form of obedience training, makes it an optimum therapeutic approach. was replaced by an approach based on empathy, empow-
16 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION
erment and autonomy. In 1979, the Diabetes Education for intensified insulin therapy was rolled out to nearly all Study Group of the European Association for the Study of the specialist hospitals in Germany. The precondition for Diabetes was founded. Its major goal was to make skills successful implementation countrywide was the provision of and knowledge training for effective disease management training for physicians, nurses and dietitians. To date, more an integral part of any affected person’s diabetes therapy. than 3,000 people, primarily nurses and dietitians, have un- The emphasis for people with type 1 diabetes was on a dertaken the 12-week course to become a diabetes educator. five-day inpatient treatment and teaching programme in groups of 6 to 10 people. Over the years, about 200 departments of internal medicine have agreed to implement continuous quality assurance A paradigmatic change was underway measures. These include re-examining a random sample of in theories about diabetes therapy. patients 12 to 15 months after they have taken part in the programme. Significant reductions have been seen in key A structured programme – development and evaluation endpoints in a sample of 9,583 people with type 1 diabetes.6 Between 1980 and 1990, Michael Berger and his team at They showed for the first time that the inverse association
the University of Düsseldorf developed the original Geneva between HbA1c and severe hypoglycaemia was not inevitable programme for general use in Germany. The overarching during intensive insulin therapy. Before the intervention, the objective was to provide education, skills training and incidence of severe hypoglycaemia was three times higher
motivation that could enable people with diabetes to take in the lowest compared with the highest quartile of HbA1c, over aspects of their therapy, and manage their diabetes whereas the risk was almost identical (but lower) across
with growing autonomy from healthcare professionals and HbA1c ranges during the year after the DTTP. medical institutions. The resulting dose-adjustment for normal eating course, with a 12-unit curriculum, covers The programme was effective even in people with frequent a range of issues: from understanding diabetes and the episodes of severe hypoglycaemia or ketoacidosis.6 Although way insulin works, to understanding food quality and its quality of life was not measured in the German programme, interactions with insulin and managing on holiday (see Box). there is good evidence from the British DAFNE study7 and other trials that participants benefit psychologically from In striking contrast to the DCCT, enjoying dietary freedom. In a recent trial, there were strong
improvements in HbA1c were not associated with an increased risk of severe hypoglycaemia. BOX: The 12-unit curriculum
During the early 1980s, the programme was based on in- Pathophysiology, insulin and injection tensified insulin therapy and ushered in the loosening of Blood glucose self-monitoring, diet and previously rigid rules for nutrition and daily schedules. Over hypoglycaemia the decades since then, the five-day programme has been Basic diabetes information translated into general hospitals throughout Germany, and Reducing insulin doses has maintained its efficacy – significant reductions in HbA1c values, ketoacidosis, hospitalizations and sick leave.2 This Increasing insulin doses and ketoacidosis success has been repeated in a number of other European Physical activity countries.3,4,5 In striking contrast to the Diabetes Control and HbA 1c, complications, smoking and follow-up Complications Trial (DCCT), those improvements in HbA 1c Nutrition training and carbohydrate counting values were at no time associated with an increased risk of Insulin pumps, contraception and pregnancy severe hypoglycaemia – quite the contrary: the incidence was halved. Travelling and holidays Correcting blood glucose Implementing the German system Social issues During the 1990s, the treatment and teaching programme
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 17 MANAGEMENT, CARE AND PREVENTION
indicators that differences in the quality of diabetes care that Ulrich Alfons Müller are caused by social inequalities disappear after treatment Professor Müller leads the Working Group on Endocrinology and Metabolic 8 and education. Diseases in the Department of Internal Medicine III at the University Hospital Jena, Germany. The Disease Management Programme In 2004, the Disease Management Programme for Diabetes was introduced into the German healthcare system, and structured diabetes education was an integral part of the Programme. As a result, people have the right to access diabetes education. Remuneration for the education pro- grammes is EUR 600 per person per course. In one of the biggest German states, North Rhine-Westphalia, 18,441 people (65% of the of the type 1 diabetes population) reg- istered in the Disease Management Programme in 2009.9 There is good evidence that participants benefit psychologically from enjoying dietary freedom.
Diabetes education – what we can learn! There are some fundamental principles underpinning our vision for structured education programmes for people with References long-term conditions like type 1 diabetes – or indeed type 2 1 Stolte K, Wolff J. Die Behandlung der kindlichen Zuckerkrankheit bei diabetes. These should allow the healthcare professional to frei gewählter Kost. Ergebn Inn Med Kinderheilk 1939; 56: 154-93.
help the patient to identify his or her personal problems and 2 Jörgens V, Grüßer M, Bott U, et al. Effective and safe issues with diabetes or hypertension, and their treatment. translation of intensified insulin therapy to general internal We must keep in mind that it is the ‘empowered’ patient who medicine departments. Diabetologia 1993; 36: 99-105. defines his or her own treatment goals and takes decisions 3 Starostina EG, Antsiferov M, Galstyan GR, et al. Effectiveness and cost- relating to the treatment of diabetes or hypertension; our benefit analysis of intensive treatment and teaching programmes for Type 1 (insulin dependent) diabetes mellitus in Moscow - blood glucose role as healthcare professionals is to inform and facilitate versus urine glucose self-monitoring. Diabetologia 1994; 37: 170-6.
(provide the necessary tools). 4 Pieber TR, Schattenberg S, Brunner A, et al. Evaluation of a structured outpatient group education programm for intensive The principles we developed in the type 1 diabetes pro- insulin therapy. Diabetes Care 1995; 18: 625-30. gramme can be adopted to deliver specific strategies for 5 DAFNE Study Group. Training in flexible, intensive insulin management to people with type 2 diabetes – and within that group, for enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 2002; 325: 746. those who are on insulin and those who are not. Physicians 6 Sämann A, Mühlhauser I, Bender R, et al. Glycaemic control and and nurses and other healthcare professionals need training severe hypoglycaemia following training in flexible, intensive insulin to deliver the programmes. therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia 2005; 48: 1965-70. Our role as healthcare 7 Speight J, Amiel SA, Bradley C, et al. Long-term biomedical and psychosocial professionals is to inform and outcomes following DAFNE (Dose Adjustment For Normal Eating) structured education to promote intensive insulin therapy in adults with sub-optimally provide the necessary tools. controlled Type 1 diabetes. Diabetes Res Clin Pract 2010; 89: 22-9. 8 Bäz L, Müller N, Beluchin E, et al. Differences in the quality of diabetes care Increasingly, computer programs and sophisticated technical caused by social inequalities disappear after treatment and education in a devices are offered to manage diabetes. But we should all tertiary care centre. Diabet Med 2011. doi: 10.1111/j.1464-5491.2011.03455.x be aware that while the use of electronic records facilitates 9 Hagen B, Altenhofen L, Blaschy S, et al. Qualitätssicherungsbericht 2008 evaluation of the programme, those technologies could Disease-Management-Programme in Nordrhein www.kvno.de/downloads/qualbe_dmp08.pdf never replace a fully trained diabetes educator.
18 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION Taking the benefits of DAFNE to the UK and beyond
Stephanie A Amiel, Julia Lawton, Simon Heller
Two English diabetologists were among an international audience while Normal Eating (DAFNE) programme Michael Berger told it to throw away the diet from the therapeutic approach in England. A group of dietitians, spe- to type 1 diabetes. That caught their attention. Berger was describing was cialist nurses and doctors translated a treatment programme that improved diabetes control in real terms. the German teaching aids and received In contrast to the Diabetes Control and Complications Trial (DCCT), training in the principles of the pro- then still running, this was a programme that delivered lower average gramme and in the art and science of delivering education to adults. There blood glucose concentrations and HbA and reduced the risk of severe 1c were some challenges and we had to hypoglycaemia. The DCCT seemed to show that this was not possible: the abandon some long-held beliefs of our lower the HbA , the lower the risk of vascular complications but with a 1c own: dietitians were concerned about much higher risk of hypoglycaemia. Just over a year later, teams from reducing the emphasis on healthy eat- King’s College Hospital London, Sheffield University and North Tyneside ing; doctors worried about abandoning Hospital, all in the UK, visited Dusseldorf, Germany, to find out what the prescription of regular food intake Professor Berger’s team was doing. and the classic meal-snack-meal-snack pattern we believed was necessary to minimize hypoglycaemia risk, and the As Ulrich Müller has described in the the support of the German team, we need to inject soluble (regular) insu- previous article, education underpinned brought their Treatment and Teaching lin 30 minutes before eating in doses the Dusseldorf approach. The UK Programme for Flexible Insulin Therapy decided by the doctor. But we made a teams observed a five-day programme to the UK. decision early on that we should follow of structured education in flexible in- the evidence: the German programme sulin therapy, which aimed to transfer Taking DAFNE to England worked and we should not change it. the healthcare professionals’ knowledge It took a grant from the charity Diabetes Compared to the German diet, the UK and skills in insulin therapy to the in- UK and more than a year of hard work diet is much higher in carbohydrates, so sulin user. Greatly impressed, and with to set up the Dose Adjustment for we needed to revise the DAFNE food
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 19 MANAGEMENT, CARE AND PREVENTION
models and images. Professor Berger’s
team supported us throughout and ob- Essential components of a structured 7 served our first course. education programme UK findings added to Person-centred philosophy evidence from across A structured curriculum Europe and Latin Trained educators America to show that A quality assurance programme DAFNE is effective. Audited outcomes
The rest is history. The Diabetes UK- funded trial of DAFNE demonstrated
clinically relevant reductions in HbA1c at both six months and one year after courses, with other improvements in cardiovascular risk and no rise in se- audit in order to ensure that any changes in bringing people with type 1 diabe- vere hypoglycaemia.1 These findings result only in improvements. tes together to meet, learn and share contributed to the growing evidence experiences. This impression has been base from Germany and other countries There are problems of course. Old hab- reinforced by research being under- and regions, including Austria, Latin its die hard, and constant vigilance is taken in the UK, funded by the National America and Eastern Europe, to show required to ensure that all DAFNE Institute of Health Research (NIHR). that the programme is effective. The courses remain true to the DAFNE The researchers found that the group improvements in diabetes control were principles. Newer insulins offer poten- approach enhances learning, helps to found to be cost-effective.2 Importantly, tial benefits but we do not yet have the overcome feelings of isolation and ena- DAFNE was the first programme to data on how best to incorporate them bles people to compare their experiences measure improvements in quality of life. into the DAFNE regimens. We made of applying DAFNE principles, support- The UK Department of Health funded some obvious mistakes that, with hind- ing more nervous people to ‘take the the implementation of DAFNE to over sight, were rather obvious – the absence leap’ or making dose adjustments that 70 diabetes centres in England, while of a continuing education programme have worked for others.3 Support from many more UK centres deliver variants for the graduates of the DAFNE courses empathic educators, avoiding direct in- on the Assal-Berger curriculum. being a very obvious one that we are struction but referring to DAFNE rules, now addressing. is also important. In the UK, DAFNE is unique in hav- The group approach ing a health care professional training Meanwhile, the DAFNE insulin regi- programme, a published evidence base enhances learning, men, which is by no means unique, for its efficacy, a peer-review system to helps to overcome gets as close to physiology as possible ensure quality of teaching, a nation- with conventional insulins: twice-daily wide audit programme and a quality feelings of isolation injections of low-dose intermediate- assurance programme to maintain the and enables people acting insulins to provide the basal in- consistency of teaching. An annual to compare their sulin that controls endogenous glucose meeting of educators and doctors from production; pre-meal doses of fast- all the UK centres (and often visitors experiences. acting insulin that are adjusted every from elsewhere) reviews progress and Keys to success meal to match carbohydrate content considers new research. The curriculum We do not know precisely what it is – modified if indicated by a pre-meal evolves but we try only to modify the about the DAFNE-type programmes blood test – injected before eating; and programme in ways that either already that deliver benefit. As Ebaa Alozairi algorithms for dose adjustment that have an evidence base or that we can points out in her article, the key lies start with known physiology and are
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adjusted in predictable ways for each research is why some of the biomedical Stephanie A Amiel, Julia user, based on his or her own responses outcomes of the programme are less well Lawton, Simon Heller in pre-meal and pre-bed blood testing. sustained than the psychological and Stephanie A Amiel is the RD Lawrence Professor 5 quality-of-life benefits and why biomed- of Diabetic Medicine at King's College London, We do know that both users and educa- ical outcomes vary between countries. UK. Professor Amiel is Editor-in-Chief of Diabetes Voice and was chair of the DAFNE tors find value in the way the course UK Executive Committee from 2001 to 2011. includes and also extends beyond im- Making DAFNE work worldwide Julia Lawton is a Senior Research Fellow in the proved biomedical outcomes. DAFNE Most importantly, the research pro- Public Health Sciences section of the Centre for Population Health Sciences at the Medical School aims to put the person with diabetes in gramme is listening to what people of the University of Edinburgh, Scotland. control and it appears to achieve this with diabetes have to say. To date, we Simon Heller is Professor of Clinical for most users. Maintaining the qual- have found that most people were glad Diabetes at Sheffield University (UK) and Chief Investigator of the National Institute ity of the courses as the programme to have been able to 'do DAFNE', and of Health Research Programme, ‘Improving expands requires effort and resources remain keen on and committed to sus- management of Type 1 diabetes in the UK: the – in terms of time and people as well taining its approach. There is clear de- DAFNE programme as a research test-bed’. as money. For users, sustaining in the mand for ongoing support from health References long term the benefits derived from professionals who are trained in an 1 DAFNE Study Group. Training in flexible, intensive insulin management to enable DAFNE courses can be a challenge and approach that is responsive to people’s dietary freedom in people with type 1 diabetes: much effort is going in to understand- personal circumstances – suggesting dose adjustment for normal eating (DAFNE) ing how we can support them to make that one-to-one, rather than group, randomised controlled trial. BMJ 2002; 325: 746. this happen. follow-up, and being able to ask for 2 Shearer A, Bagust A, Sanderson D, et al. Cost-effectiveness of flexible intensive help as and when needed, may be most insulin management to enable dietary The course graduates are the main mov- appreciated.6 A national database is freedom in people with Type 1 diabetes in ers in this: UK DAFNE graduates have being maintained also, which collects the UK. Diabet Med 2004; 21: 460-7. created their own website and developed information not just to ensure that the 3 Lawton J, Rankin D. How do structured an application to support carbohydrate programmes are delivering benefit but education programmes work? An ethnographic investigation of the dose adjustment for normal counting, which has been made freely also to facilitate research into which eating (DAFNE) programme for type 1 diabetes available. The UK programme has pro- approaches and strategies are effective patients in the UK. Soc Sci Med 2010; 71: 486-93. vided training to healthcare professionals and which are not. 4 Rogers H, Turner E, Thompson G, et al. Hub- in other countries. It has developed a and-spoke model for a 5-day structured patient education programme for people with Type 1 model in which larger centres can sup- That ongoing research and a growing diabetes. Diabet Med 2009; 26: 915-20. port smaller ones to obtain DAFNE with number of committed and enthusiastic 5 The DAFNE Study Group (2010). Long-term the engagement of all the professional healthcare professionals and people with biomedical and psychosocial outcomes following teams involved.4 Meanwhile, the NIHR type 1 diabetes are working to establish, DAFNE (Dose Adjustment For Normal Eating) structured education to promote intensive insulin programme, which is being coordinated extend and improve DAFNE’s diabetes therapy in adults with sub-optimally controlled in Sheffield (UK), is exploring alterna- education web. Their endeavour needs Type 1 diabetes. Diab Res Clin Pract 2010; 89: 22-9.
tive forms of course delivery and ways resources and support but, as these 6 Rankin D, Cooke DD, Clark M, et al; UK of helping course graduates to sustain or pages hope to show, DAFNE is already NIHR DAFNE Study Group. How and why do patients with Type 1 diabetes sustain their improve on their outcomes. One area to flourishing internationally. use of flexible intensive insulin therapy? A qualitative longitudinal investigation of patients' self-management practices following attendance at a Dose Adjustment for Normal Eating UK DAFNE graduates have (DAFNE) course. Diabet Med 2011; 28: 532-8. 7 Diabetes UK, UK Department of Health, UK National Diabetes Support Team. How created their own website and to Assess Structured Diabetes Education: An improvement toolkit for commissioners and local developed an application to diabetes communities. www.diabetes.org.uk/ Professionals/Publications-reports-and-resources/ support carbohydrate counting. Reports-statistics-and-case-studies/Reports/ Structured-Education-Self-Assessment-Toolkit/
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 21 MANAGEMENT, CARE AND PREVENTION Positive results in Australia – OzDAFNE takes up the challenge
Dianne Harvey
Australian diabetes healthcare OzDAFNE has grown since its mod- an Australian database. Finally, we re- professionals in Melbourne est early stages, from the four origi- placed the UK DAFNE ‘Jaffa cake’ (bus- learned about the DAFNE nal OzDAFNE centres to 20 centres cuit) logo with a picture of a traditional programme for people with type 1 countrywide, and the programme has Australian sweet – the Lamington. provided training for centres in New diabetes in 2004, during a visit OzDAFNE has been to the International Diabetes Zealand and Singapore. An OzDAFNE collaborative was formed to link all Institute there by Stephanie integrated into Australian centres, provide governance Amiel. Rather like the UK teams community health for DAFNE at the national level and a few years earlier, a team maintain links with UK DAFNE. The centres, private of nine health professionals national coordinating centre, Diabetes practice and Diabetes from four Australian centres Australia-Victoria, is partnered with Australia associations. undertook DAFNE training in the Mater Health Services in Brisbane to UK that year. Prior to this, there oversee the training and peer review of With modifications to the resources were no evidence-based group new and existing centres, and contribute complete, our focus shifted towards programmes providing structured to research. increasing the number of OzDAFNE education for people with type 1 centres in order to provide better ac- in Australia. After the training One of the first and most important cess to courses for people with type 1 period, the Australians returned challenges in introducing DAFNE to diabetes around the country. In the home and ran their first courses: an Australian audience was the devel- UK, DAFNE is normally run by hos- in early 2005, OzDAFNE was born. opment of ‘Australianized’ resources. pitals in a clinical setting. However, Changes to the curriculum and hand- major hospitals in Australia have strug- book were minor but included, for ex- gled to incorporate DAFNE into their ample, regulatory guidelines around busy clinical environments within driving. The carbohydrate counting limited budgets. Although some hos- booklet was modified to allow for typi- pital clinics have managed to do so, cal Australian foods and snacks, and the the OzDAFNE programme has also carbohydrate values were sourced from been integrated into a variety of other
22 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION
healthcare settings, such as commu- tributes towards national ad- nity health centres, private practices ministration, training and and Diabetes Australia associations. quality assurance costs. As these non-clinical settings lack Ongoing dedicated fund- direct access to general practitioners ing is needed to maintain and endocrinologists, a formal doctor’s finance for the OzDAFNE consent process, including an insulin programme at the national order form, was devised to allow the level, and to assist indi- OzDAFNE educators to function. vidual centres to sustain it. Rebates from private health Different strokes… insurance companies are be- We also needed a different model for ing investigated as a potential quality assurance. Australia is a vast source of funding. country, so attempting to implement 75% of DAFNE educators from all over the UK DAFNE model of external Educators often Australia and New Zealand attended peer review without adequate funding comment that the our inaugural OzDAFNE professional to support the travel and accommo- DAFNE training was development day in Melbourne. dation required was problematic. As a result, a modified quality assurance the best professional Despite the many challenges involved programme has been implemented that development they have in implementation in Australia, the is based mainly on internal peer review, ever experienced. outcomes of the course participants with external checks and administration described above speak volumes for carried out by the national coordinat- … producing similar benefits DAFNE’s efficacy and the potential ing centre. We are currently working Despite the particular challenges in- benefits of its expansion. Those positive towards a model in which there is a lead volved in bringing DAFNE to Australia, results and the passion of the OzDAFNE OzDAFNE centre in every state that the OzDAFNE outcomes are quite simi- educators support the maintenance of takes responsibility for state training lar to those shown in Germany and the the courses and the implementation of and quality assurance measures. UK. An audit of OzDAFNE data on clin- the programme throughout Australia. ical outcomes included 145 people (pre- The absence of dedicated funding for DAFNE and 12 months post-DAFNE) OzDAFNE affects our quality assurance with type 1 diabetes who participated in programme and impacts on the adop- courses at seven Australian diabetes cen- tion of OzDAFNE by new centres – as tres between February 2005 and March well as ongoing provision of DAFNE 2007. A year after taking part in DAFNE, courses in existing centres. Currently, our participants had better blood glucose
individual OzDAFNE centres self-fund control (average HbA1c fell from 8.2% their services through a variety of ad hoc to 7.8%), reduced incidence of severe Dianne Harvey methods and activities and participant hypoglycaemia, slightly reduced weight Dianne Harvey is dietitian and contributions. For example, a number of (average weight dropped from 75.1 kg to OzDAFNE coordinator, Australia. community health centres have secured 74.2 kg) and reduced anxiety, depression funding for OzDAFNE through chronic and diabetes-related distress.1 disease and self-management funding programmes; and one private practice OzDAFNE educators report enthusiasm model relies on pharmaceutical indus- for the DAFNE programme and often References try support. The National Diabetes and comment that the DAFNE training was 1 McIntyre HD, Knight BA, Harvey DM, Supply Scheme provides the majority the best professional development they et al. Dose adjustment for normal eating of funds to Diabetes Australia-Victoria have ever experienced. This enthusi- (DAFNE) – an audit of outcomes in Australia. MJA 2010; 11: 637-40. as the coordinating centre. This con- asm was evident in June 2011, when
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 23 MANAGEMENT, CARE AND PREVENTION Never say never – implementing DAFNE in Kuwait
Ebaa Alozairi
There is overwhelming evidence that There is lack of diabetes educators and dietitians in Kuwait, and resources vary according to geography. Some diabetes improving HbA1c reduces the risk of long- term complications and improves quality teams offer a substantial amount of education but this is delivered largely on a one-to-one basis and many hospitals of life. In Kuwait, however, few people with lack facilities. Many dietitians in Kuwait either follow the diabetes reach their target levels and, as North American methods – either an insulin-to-carbohy- a consequence, remain at risk of diabetes drate ratio of 1:15 or varying the ratio according to total complications. Healthcare professionals ask daily dose. Both of these present mathematical challenges the people in their care to test their blood to people with diabetes, who often need to use a calculator glucose three or four times a day. Yet in to work out the correct dose. many regions, very few people with diabetes While I was in the UK receiving clinical diabetes and en- have received education on how to adjust docrine training a few years ago, I travelled to the Joslin their insulin according to their blood glucose Diabetes Center, Boston, USA, with a Fulbright grant. The results. Unless appropriate education and Joslin offered an impressive variety of high-quality courses skills training are provided, blood glucose for people with diabetes. I observed many people who had outcomes will not be affected – however travelled long distances across borders to attend sessions. much encouragement is offered. Ebaa Strikingly though, none of the courses had undergone ran- Alozairi describes successful efforts to bring domized controlled trials or had external quality assurance. to Kuwait an educational and therapeutic Back in the UK, I undertook training to become a DAFNE approach based on dose adjustment, the doctor. I was impressed by that programme too: it seemed recent achievements and current progress highly practical – the use of 10 g rather than 15 g carbohy- of DAFNE trainers and graduates, and plans drate portions on which to base insulin, making it easier for expansion throughout the Middle East. for people with diabetes to do the necessary maths. Firmly based on empowerment, the programme was methodo- logically sound, not unduly prescriptive and highly valued by the participants. I went on to complete the quality as- surance training offered by the UK programme. My idea
24 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION
was to transfer the DAFNE model to Kuwait, where I was sessions were held in the morning, like in the UK. However, convinced it would bring considerable benefits to people we encountered difficulties recruiting, as participants gen- with diabetes and the Ministry of Health. erally were not able to take time off from work. Moreover, many people did not want to disclose their diabetes in the Founded on empowerment, workplace due to the strong sense of stigma related to having DAFNE is methodologically sound, the condition. So the sessions were moved to an afternoon and evening timetable, which was welcomed by participants. not unduly prescriptive and highly valued by participants. During the pilot study, all participants expressed their satis- faction – equipped, in many cases, for the first time, with the Initially, I was concerned that the model might not work in skills they needed to manage their own diabetes. Many course Kuwait mainly due to cultural differences: patient empower- participants with type 2 diabetes, which is very prevalent in ment is not standard practice for Middle Eastern doctors Kuwait, were happy to meet others with less-common type 1 and people with diabetes in many cases prefer to depend on diabetes, which generated a positive discussion. their healthcare professional for guidance. The change from a prescriptive approach to patient-centred care is difficult to Never say never! implement and can be confusing from the patient's perspec- Having completed our pilot, the team presented preliminary tive. The UK team agreed to support the pilot programme findings and a plan to extend DAFNE nationwide to the us throughout its implementation in Kuwait. Kuwait Diabetes Society. Despite our positive results, some senior members objected to the idea of group education. In 2009, two dietitians from the Al Amiri hospital made They regarded people in Kuwait as very discreet and would a structured observational visit to the UK and completed be unwilling to discuss their diabetes in a group. So despite DAFNE training. Back in Kuwait, the DAFNE materials were our findings, the model was not altogether welcomed. Also, translated into Arabic and adapted to Kuwaiti culture. With some professionals were not happy that DAFNE educa- support from the head of the diabetes unit at Al Amiri, we tors were adjusting insulin dosages instead of the relevant were able to pilot DAFNE. physician. However, the positive experiences of people with diabetes engaged in DAFNE and our never-say-die attitude Initially, two courses were conducted for groups of women drove the educators on to continue delivering DAFNE – and men separately; a third course was mixed gender. The first albeit in only one hospital.
Participants expressed their satisfaction – equipped for the first time with the skills they needed to manage their own diabetes.
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 25 MANAGEMENT, CARE AND PREVENTION
Having successfully presented our findings to the new- improved HbA1c. Most strikingly, some graduates want ly appointed Director General of the Dasman Diabetes refresher courses, proposing that they be able to follow
Institute, the DAFNE programme was recognized as the their HbA1c as a group. national course for type 1 diabetes. To be held at the Dasman Institute, it the course is open to people from all regions of DAFNE is now part of the compulsory training for doctors the country. All people with type 1 diabetes are welcomed during the Diabetes and Endocrinology degree programme to register and the referral is open to all doctors living and in Kuwait. working in Kuwait. What do DAFNE graduates say? The DAFNE project was launched at the Dasman Institute It is encouraging to read the universally positive feed- in November 2010. The structured teaching programme is back from people who have completed a DAFNE course delivered to groups of between six and eight participants un- in Kuwait. A few of the graduates, without any prompting, der the supervision of DAFNE-trained educators. Healthcare wrote an article in English and Arabic, which was published professionals are invited to attend as observers but with a in a number of newspapers, describing their very positive ex- maximum of two per course. Most of the training is built perience. Another participant paid for all course members to around group work, sharing and comparing experiences with dine together and refused offers of payment from his peers, other participants. However, there are opportunities for each saying that he was “relatively new to my diabetes journey person to speak to DAFNE educators individually. Acceptance and for the first time I feel normal”. The positive feedback has been remarkably good; a number of DAFNE graduates here is stronger even that that I had observed in UK. have requested that the course be extended to two weeks! Future plans To date, eight courses have been completed in 10 months. A Currently, all the various psychological questionnaires and
special one-day Ramadan course recently gave participants biochemical data (weight, hypoglycaemic events, HbA1C) the opportunity to practise estimating the carbohydrate are collected both at baseline and at follow-up, and cross- content of particular complex foods that are eaten mainly cultural differences will be examined. A Ramadan-specific during Ramadan. trial will be carried out next year. People with type 1 dia- betes and healthcare professionals from the Middle East The DAFNE Kuwait collaborative has established strong are welcomed to attend DAFNE Kuwait to observe the links with the UK, keeping the UK DAFNE group informed positive impacts. at all stages, to ensure consistent standards of delivery. With supports from UK DAFNE and the Dasman Diabetes Institute, Kuwait has been made the training centre for the Middle East region. We are delighted to provide training to any centre wishing to adopt this very effective programme.
Acceptance has been remarkably good; a number of DAFNE graduates have requested that the course be extended to two weeks! Ebaa Alozairi Ebaa Alozairi is Assistant Professor at Kuwait University, Positive outcomes nutrition specialist on the American Board of Physician, a consultant in Diabetes and Endocrinology and lead To date, 45 people with diabetes have completed the DAFNE DAFNE clinician in Kuwait ([email protected]). course. None have required admission to hospital because Acknowledgments of their blood glucose. There has been a marked reduction The author would like to thank Simon Heller and DAFNE in rates of hypoglycaemia; most people are requiring fewer UK, the Kuwait DAFNE educators, the Dasman Diabetes visits to the healthcare professionals and consuming less Institute, the Head of the Diabetes Unit at Al Amiri Hospital, DAFNE graduates and healthcare professionals in Kuwait. than half of their pre-course insulin dosages. Many have
26 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION Great results for DAFNE Singapore – next stop, South-East Asia
Su-Yen Goh and Daphne Gardner
Upon returning to Singapore, the newly programme is able to establish its own In November 2010, a pio- christened SgDAFNE team adapted the independent collaborative. neering team comprising materials shared by OzDAFNE and de- a nurse educator, a dieti- veloped a culturally relevant SgDAFNE DAFNE was a paradigm tian and an endocrinolo- programme, including a modified car- shift for people who bohydrate portion booklet for use in gist from Singapore Gen- were not attuned Singapore and the rest of South-East eral Hospital completed a Asia. To the best of our knowledge, to the concept of DAFNE course and post- ours is the first centre in Asia to of- empowerment. course educator training in fer DAFNE, and we are growing and Australia, at the OzDAFNE developing. With two courses given in Many challenges have surfaced during centre, Diabetes Australia- 2011, and at least three more scheduled the development and implementation of Victoria. This was the first for 2012, we also provide healthcare SgDAFNE. Prior to DAFNE, there were professional DAFNE awareness events/ no structured or standardized education step in a process that suc- sessions, such as on World Diabetes and self-management programmes for cessfully took the DAFNE Day this year. people with type 1 diabetes in Singapore. model Singapore. The This was a paradigm shift for most Clinical Leads for the Sin- The inaugural course for SgDAFNE people, some of whom functioned in gapore initiative describe in April 2011 was conducted under a rather paternalistic and hierarchical the experience so far and the watchful eye of an auditor from doctor-patient relationship and were look to the future and con- Diabetes Australia, and OzDAFNE not attuned to the concept of empow- have included us in the OzDAFNE erment. The programme demands a tinental development of collaborative. We are committed to higher intensity of self-monitoring of their growing programme. contributing to the OzDAFNE data- blood glucose compared with routine base until such time as the SgDAFNE care; purchases of glucometer and test
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 27 MANAGEMENT, CARE AND PREVENTION
strips are out-of-pocket expenses with in sauces and gravies) or estimate accu- sensitive (requiring 1:1 rather than 1.5:1 no insurance reimbursement or gov- rately portion sizes. Many Singaporeans or 2:1 ratios) than previously thought. ernment healthcare financing available. tend to be ‘grazers’, snacking throughout The issue of over-insulinization before Some people previously had never done the day rather than eating a full meal at entering the programme has also sur- blood ketone testing, as the cost is pro- regular times. faced; to the delight of participants and hibitive – up to USD 4 per test strip. the SgDAFNE team alike, some people The very act of Although the DAFNE curriculum have had dose reductions of between equips people with the ability to cal- 25% and 40%. injecting insulin in culate and dose for snacks, difficulties public was a daunting arose in terms of interpreting pre-meal SgDAFNE has been an exciting journey barrier for some. glucose concentrations and insulin for all involved and we look forward to stacking. The very act of injecting insu- extending the programme island-wide Another major task was develop- lin in public, as well as weighing foods, and throughout South-East Asia. ing the carbohydrate counting mate- was a daunting barrier for some. rial for the local context. The dietetics team laboured long and hard, and were To the delight of thrilled to produce our own SgDAFNE all involved, some carbohydrate portion booklet in the first Su-Yen Goh and Daphne Gardner quarter of 2011. In adapting the diabe- people have had dose Su-Yen Goh and Daphne Gardner are the Clinical Leads for SgDAFNE tes education material, we had to take reductions of between at Singapore General Hospital. into consideration the socio-cultural 25% and 40%. contexts of food and diabetes: many Acknowledgement SgDAFNE was supported by an Singaporeans dine out for most meals of With two groups of graduates, the unrestricted educational grant from the day, and it was often challenging to SgDAFNE team has also found that sanofi-aventis Singapore with additional support from Abbott Diagnostics. calculate hidden carbohydrates (such as the local people may be more insulin
28 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION Making progress with immune therapies for type 1 diabetes
Mark Peakman
Thirty-five years on from the In the mid-1970s, autoantibodies that models in which new therapies can be demonstration that type 1 diabetes bind to targets in cells in the islets of tested, has led to a period of intense has an autoimmune basis, we have Langerhans were described in the scien- activity as these advances are translated. learned an enormous amount tific literature. They have since become Clinical trial consortia, such as Type 1 about the disease. We know its established as a major biomarker for Diabetes TrialNet and the Immune genetic basis (immune genes), type 1 diabetes, both at diagnosis and Tolerance Network, linking centres with in the preclinical prodrome. We have expertise in the field to do collaborative its pathological basis (immune since learned that the disease results research, have been pivotal in promot- cells) and we would expect to from autoimmune destruction of the ing the acceptance of study designs that be converting this insight into insulin-secreting beta cells in the is- focus on, and are adequately powered therapeutic advances (immune- lets, a process involving the T and B to detect, the preservation of beta-cell based). Certainly, the field of lymphocytes and dendritic cells of the function (measured as the C-peptide immunotherapy for type 1 diabetes immune system (Figure). response to a challenge) in new-onset is very active. Here, Mark Peakman type 1 diabetes, typically measured at reviews the progress being made Focusing on the beta cells six, 12 and 24 months after the intro- and scans the horizon for the most The disease arises on a distinctive ge- duction of the novel therapy. likely future breakthroughs. netic background, in which variants of genes that regulate immune responses Stimulated C peptide has proved an ac- are the predominant feature. This un- ceptable surrogate for any beneficial ef- derstanding, allied with a range of thera- fects of therapy in preserving remaining peutics (many arising from the field of beta cells, which would be expected to transplantation), a better understand- have an impact on glycaemic control if ing of how immunological tolerance is sufficient endogenous insulin production maintained and lost, and several animal remains. A further emerging principle
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 29 MANAGEMENT, CARE AND PREVENTION
with the drug Abatacept (an inhibitor cytokines of T-cell co-stimulation) also can be 3. Via blood beneficial, and an earlier report had in- T B h dicated that depletion of B lymphocytes T REG using Rituximab has clear, but transient benefits. Thus, a small arsenal of agents α CTL is being identified. Importantly, safety β cells Th CTL and feasibility in the setting of new- DC 1. Islet onset disease is becoming established, along with the precedent of enrolling B adolescents and children into these DC studies – important, as new-onset type 1
2. Pancreatic diabetes is common in this age group. lymph node Antigen-specific immunotherapy
The insulin-secreting beta cells of the pancreatic islet express proteins (shown in white) The second approach is termed antigen- that are picked up by dendritic cells (shown in pink) and activate T and B and cytotoxic specific immunotherapy (ASI). It is well lymphocytes (green, yellow and blue) to destroy the beta cells, releasing cytokines as established that induction and restora- they do. Regulatory T cells shown in black can damp down the process. tion of immune tolerance is achieved by administering the very target (au- toantigen) against which the destructive autoimmune response is directed. This may seem counter-intuitive and likely is that trials are more likely to be able to studies have indicated beneficial effects to ramp up the autoimmunity; but if the show benefit if studies are started soon on C-peptide decline. autoantigen is given under appropriate after diagnosis; 100 days from initial conditions, it seems to work, at least in presentation to the first administration Follow-up studies have even shown the model systems. of the study drug is now the norm. potential for a prolonged effect, with preservation of C peptide for several There are different ASI strategies. Using What kind of therapeutic strategies years in some people. Unfortunately, short antigenic peptides representing are emerging? the data emerging from subsequent sequences (epitopes) recognized by T There are currently two main compet- Phase III studies ending in 2011 were lymphocytes – known as peptide im- ing solutions being developed which mixed, although this may be attribut- munotherapy (PIT) – is in Phase I-III target components of the immune sys- able to the study design. Otelixizumab development in clinical allergy and tem. The first is immune modulation via (GlaxoSmithKline/Tolerx, Inc) was re- such strategies as biologics that target T ported to have failed Phase III trials in lymphocytes, B lymphocytes, co-stimu- March 2011. The anti-CD3 antibody latory molecules and cytokine pathways, Teplizumab, developed by Macrogenics Strategies for halting immune among others (see Figure). This is ‘non- and Eli Lilly, also did not meet endpoints damage to beta cells specific immunotherapy’ is designed in a Phase III trial in type 1 diabetes but to act systemically, making no attempt published data indicates that C peptide Immune suppression with drugs that inhibit T lymphocyte function to target only the minority of T lym- was nonetheless preserved. Immune modulation that pro- phocytes that cause beta-cell damage. motes a better immune system The lead compounds here have been two It is to be hoped that these drugs will un- balance monoclonal antibodies directed against dergo continued development to try and Strategies to specifically promote the CD3 protein on the surface of T identify optimal conditions for their use. immune regulation in islets cells. Although it is not exactly clear how Another Phase II trial suggests that in- Combinations of the above anti-CD3 therapy works, two Phase II terfering in pathways of T-cell activation
30 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION
other autoimmune diseases. PIT has several advantages: highly efficient target delivery; avoidance of antibody development; relatively inexpensive syn- thesis costs; and the fact that the dose is not limited by the biological effects of the parent molecule. In Phase I studies in our centre, it appears safe and well tolerated. Future studies will be needed to evaluate its full potential and the best setting for its deployment.
Alternatively, whole proteins from the beta cell have been used. The lead here is insulin, given orally to first-degree relatives without diabetes who already have islet cell autoantibodies. A clinical study conducted by TrialNet is based on sub-study data that suggest that first- What does the future hold for type 1 modes of action. The advantages of such degree relatives who have high titres diabetes therapeutic strategies? a strategy include minimizing the toxici- of anti-insulin autoantibodies might Can sense be made of these ebbs and ties and realizing the synergies that en- expect particular benefit from this ap- flows of positive and negative clinical hance and prolong efficacy. The degree to proach in terms of reduced progression trial data? There is a picture emerging which non-specific immunotherapy and to clinical disease. Giving insulin by that non-specific, biologic-based thera- antigen-specific therapy are combined mouth has no metabolic effect at the pies are effective when given close to may need to be different according to dose used but takes advantage of the diagnosis, whereas antigen-specific im- the stage of disease, for lower risk in the natural immunological phenomenon munotherapy is not – probably because pre-diabetes setting and higher potency that ingested protein antigens are well it operates sub-optimally in such an ac- in newly diagnosed people. tolerated by the immune system. The tive inflammatory setting. Encouraging study will report in one or two years data from oral insulin studies suggest and, it is hoped, will provide better un- that building tolerance against beta-cell Mark Peakman derstanding of the mechanisms of oral autoantigens may be useful if given early Mark Peakman is Professor of Clinical immunological tolerance in humans. and for prolonged periods. Moreover, its Immunology at King's College London, School of Medicine, UK.. excellent safety profile means that ad- The other advanced drug in the ASI ministration in at-risk groups is feasible. Further reading area was the whole beta-cell protein/ Future developments for ASI will centre Staeva-Vieira T, Peakman M, von Herrath M. Translational mini-review series on type 1 diabetes: autoantigen GAD65 (glutamic acid de- on maximizing this potential, probably Immune-based therapeutic approaches for type 1 carboxylase isoform 65 kDa; Diamyd® using multiple antigens or better delivery diabetes. Clin Exp Immunol 2007; 148: 17-31. GAD65). Although promising results systems. New therapeutic modalities at Peakman M, von Herrath M. Antigen-specific immunotherapy for type 1 diabetes: maximizing (preservation of insulin reserve) were very early stages of evaluation include at- the potential. Diabetes 2003; 59: 2087-93. reported in a post-hoc analysis of a sub- tempts to bolster immune regulation us- Matthews JB, Staeva TP, Bernstein PL, et al. set of cases treated with GAD65-alum ing the approach of adoptive cell transfer. Developing combination immunotherapies for type 1 diabetes: recommendations prime and boost in 2008, a repeat con- from the ITN-JDRF Type 1 Diabetes ducted by TrialNet reported no benefit It seems probable that, like many com- Combination Therapy Assessment Group. in 2011. Full reporting of the results of plex human disorders of unknown aeti- Clin Exp Immunol 2010; 160: 176-84. www.diabetestrialnet.org a Phase III study are expected, although ology, type 1 diabetes ultimately may be www.immunetolerance.org preliminary reports suggest no preserva- controlled via a therapeutic approach that www.jdrf.org tion of C-peptide preservation. combines multiple agents with different
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 31 MANAGEMENT, CARE AND PREVENTION All that glitters is not gold – why we need bet ter trials and reporti ng
Rury R Holman
In an age of increasing global information overload, it is becoming progressively more difficult to discern real health and safety signals, or potentially beneficial possibilities, from background noise. The explosion in exploratory analyses of emerging large-scale medical record databases and registries has helped to highlight many potential issues of interest. But establishing the reality of such uncontrolled ‘findings’ can be challenging. A major concern is that apparent associations, which are identified by these often opportunistic analyses, are frequently reported by the media and others as potential ‘medical breakthroughs’ or as possible ‘safety concerns’ for existing therapies. Remarkably, such reports often give equal (or greater) prominence to unsubstantiated exploratory findings than they do to robust results from properly designed and conducted trials. As a result, these reports can raise hopes or fears inappropriately in the population at large. In addition, the almost daily publication of frequently conflicting findings diminishes public faith in scientific pronouncements and may preclude people taking note of proven results that could be crucial to their future health.
32 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 MANAGEMENT, CARE AND PREVENTION
An evidence-based approach to medi- cine has been adopted; it is recognized that intuition, unsystematic clinical experience and pathophysiological All that glitters is not gold – rationale are insufficient grounds for clinical decision making. Clinical ob- servations can produce useful insights but are hindered by small sample sizes and the limitations in human processes why we need bet ter for making inferences. Observational studies can provide compelling evidence but inevitably are limited by the possibil- ity that apparent differences are really due to differences in patients’ prognoses trials and reporti ng secondary to the post hoc selection of treatment and control groups. One such example was the observational finding that women who took hormone replace- ment therapy appeared to have a reduced risk of coronary heart disease. A ran- domized controlled trial (RCT), how- ever, showed the reality: that hormone replacement therapy increases rates of thromboembolic events and gallbladder disease.1 (The probable explanation is that early adopters of hormone replace- ment therapy were more likely to have been health-aware women with corre- spondingly healthier lifestyles.) Randomization is too important to leave to chance.
RCTs provide the highest level of evi- dence and remain the gold standard, although they are not always feasible: no one has yet conducted a RCT for para- chutes! All trials attempt to discover ‘the truth’ but can only provide evidence of the truth, not absolute proof. ‘The truth’ would be the answer to a research ques- tion arrived at by conducting a perfectly executed study on everyone with the characteristics of interest. Participants in RCTs receive the interventions at ran- dom to help ensure similarity of char- acteristics both known and unknown
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 33 MANAGEMENT, CARE AND PREVENTION
– such as demographics, genetic make Adminsitration (FDA) the opportunity full impact of treatments – with respect up, lifestyle choices – at the start of the to develop the data infrastructure and to both benefits and risks. comparison. Individuals, groups and scientific tools needed to conduct active the order in which measurements are safety surveillance of medical products The research community has a duty of obtained all can be randomized. within a distributed system of large pri- care to report trials, studies and ‘inciden- vate and public healthcare databases. tal’ findings in context. In particular, a Randomization must be conducted in more rigorous approach for reporting such a way that the allocation of differ- Equally, trials are moving into a new observational findings is needed. In order ent interventions cannot be influenced era, particularly in diabetes. The FDA to help provide guidance for the media by participants or those conducting the has issued industry guidance for the and others when publicizing results from study – randomization is too impor- evaluation of cardiovascular risk in exploratory studies, systematic reviews, tant to leave to chance. Clinical trial new therapies to treat type 2 diabetes.5 meta-analyses and RCTs, journals should design and reporting has improved This requires that as they are assessed consider adding an evidence level rating immeasurably over time, especially for possible licensing, new agents be to relevant publications. Press releases with the widespread adoption of the studied in such a way as to ensure that issued by investigators, sponsors, fund- CONSORT guidelines.2 RCTs seek to their potential to increase cardiovas- ing bodies and journals could do much establish whether different interventions cular risk does not exceed stipulated more to ensure a correct perspective is lead to different outcomes. However, in thresholds. This cardiovascular safety given to media coverage. Ultimately, order for a difference to be a difference, requirement, which has added greatly routine sharing of individual-level data it must make a difference! A numerical to the development costs of new drugs, from completed trials will help to decide difference may be statistically significant has also led to a rapid increase in the what it is that glitters and identify any but if the size of the effect is not clini- number of cardiovascular outcome hidden nuggets, as has been done suc- cally relevant, then it is of little import. trials being performed, with some cessfully with the Cholesterol Treatment 14 studies currently recruiting over Trialists Collaboration and similar col- Since the truth is rarely absolute, many 110,000 participants. These large-scale, laborative efforts. decisions in medicine continue to be simple, mostly double-blind trials made on the balance of probabilities comparing new agents with placebo, and epidemiological data. Observational will increase substantially the amount data can identify signals of potential of clinically relevant information for Rury R Holman good or harm, but cannot assign causal- treating type 2 diabetes. Rury R Holman is the Director of the University of Oxford Diabetes Trials ity. Meta-analyses, however well con- Unit, Honorary Consultant Physician ducted, depend ultimately only on trials The research community and a Senior Investigator at the UK National Institute for Health Research. and studies that have been performed. has a duty of care to If the appropriate trials have not been References report trials, studies conducted, or indeed have not been 1 Hulley S, Grady D, Bush T, et al for the Heart and Estrogen/progestin reported, then the conclusions will be and ‘incidental’ Replacement Study (HERS) Research flawed. Fortunately, procedures for un- findings in context. Group. JAMA 1998; 280: 605-13. dertaking meta-analyses and systematic 2 Altman DG, Schulz KF, Moher D, reviews have become much more robust, However, smarter trials are needed. et al for the CONSORT Group. The Revised CONSORT Statement particularly with the aid of the Cochrane Testing multiple interventions in fac- for Reporting Randomized Trials: Collaboration,3 among others. torial or head-to-head designs would Explanation and Elaboration. Ann be more efficient, more informative Intern Med 2001; 134: 663-94.
Clearly, a more systematic approach is and more cost-effective. While trials 3 ww.cochrane.org needed when assessing rapidly evolv- are likely to be powered based on the 4 www.mini-sentinel.org ing data from a myriad of sources that time to the first primary endpoint, have highly variable provenance. One subsequent events also should be cap- 5 ww.fda.gov/downloads/Drugs/ such example is the Mini-Sentinel pilot,4 tured routinely and evaluated in detail GuidanceComplianceRegulatory Information/Guidances/UCM071627.pdf which is giving the US Food and Drink to maximize our understanding of the
34 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 M ENT VERTISE A D
LIFE_1111016_ILA136_Type1Diabetes pressAD-21x28.indd 2 21/11/11 16:38 LANTUS ® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Lantus 100 U/ml, solution for injection of insulin glargine is available in a vial of 5 & 10 ml, cartridge of 3 ml for the following reusable pens only: Optipen, ClikSTAR Autopen 24 or Tactipen, cartridge of 3 ml for Opticlik, and prefi lled disposable pens of 3 ml for Lantus Optiset & Lantus Solostar. 2. THERAPEUTIC INDICATIONS: Treatment of adults, adolescents and children of 6 years or above with diabetes mellitus, where treatment with
M ENT VERTISE insulin is required. 3. POSOLOGY AND METHOD OF ADMINISTRATION: Lantus should be administered once daily at any time but at the same time each day. The dosage
A D and timing of dose of Lantus should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus can also be given together with orally active antidiabetic agents. In children older than 6 years Lantus should be given in the evening. In children below the age of 6 years, Lantus should only be used under careful medical supervision. When changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Lantus, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted. Close metabolic monitoring is recommended. Administration: Lantus is administered subcutaneously, should not be administered intravenously and must not be mixed with any other insulin or diluted. For administration details see full SmPC. Patients must be educated to use proper injection techniques and insulin label must always be checked before each injection to avoid medication errors between Lantus and other insulins. Renal impairment & hepatic impairment: insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS: Hypersensitivity to the active substance or to any of the excipients. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Lantus is not the insulin of choice for the treatment of diabetic ketoacidosis. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method of manufacture may result in the need for a change in dose. The warning symptoms of hypoglycaemia may be changed, less pronounced or absent in certain risk groups: for all details see the full SmPC. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.6. DRUG INTERACTIONS: Substances that may enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION: No clinical data from clinical trials are available. A moderate amount of data on pregnant women exposed indicates no adverse effects on pregnancy and no malformation nor feto/neonatal toxicity. Lantus may be considered during pregnancy, if necessary. Breastfeeding women may require adjustments in insulin dose and diet. 8. EFFECTS ON ABILITY TO DRIVE: Patients should take precautions to avoid hypoglycaemia whilst driving. 9. UNDESIRABLE EFFECTS: Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Lipohypertrophy may occur at the injection site. Injection site reactions including redness, pain, itching, hives, swelling, or infl ammation. For uncommon & rare adverse events please consult the full SmPC. 10. OVERDOSAGE: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. More severe episodes may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. PHARMACOLOGICAL PROPERTIES: ATC Code: A10A E04. 12. MARKETING AUTHORIZATION HOLDER: Sanofi -Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing Information based on the EU SmPC as of Jan 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
APIDRA® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Apidra 100 U/ml, solution for injection of insuline glulisine is available in a vial of 10 ml, cartridge of 3 ml for reusable devices Optipen, ClikSTAR, Autopen 24 or Tactipen & cartridge for Opticlik, and prefi lled disposable pens of 3ml for Optiset & Solostar. 2.THERAPEUTIC INDICATIONS: Treatment of adults, adolescents and children, 6 years or older with diabetes mellitus, where treatment with insulin is required. 3. POSOLOGY AND METHOD OF ADMINISTRATION: Apidra should be given by subcutaneous injection shortly (0-15 min) before or soon after meals or by continuous subcutaneous pump infusion. Apidra for injection in a vial can be administered intravenously. Apidra should be used in regimens that include an intermediate or long acting insulin or basal insulin analogue and can be used with oral hypoglycaemic agents. The dosage of Apidra should be individually adjusted. For administration details see full SmPC. Patients must be educated to use proper injection techniques and insulin label must always be checked before each injection to avoid medication errors between Apidra and other insulins. Renal impairment & hepatic impairment: insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS: Hypersensitivity to insulin glulisine or to any of the excipients. Hypoglycaemia. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, source and/or method of manufacture may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted. Adjustment of dosage may be necessary if patients undertake increased physical activity or change their usual meal plan. Conditions which may take the early warning symptoms of hypoglycaemia different or less pronounced are detailed in the full SmPC. Contains less than 1 mmol sodium per dose. Contains metacresol. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. 6. DRUG INTERACTIONS: Substances that may enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION: No adequate data are available. Insulin requirements may decrease during the fi rst trimester and generally increase during the second and third trimesters. Breast-feeding mothers may require adjustements in insulin dose and diet. 8. ABILITY TO DRIVE: Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. 9. UNDESIRABLE EFFECTS: Hypoglycaemia is the most frequent undesirable effect of insulin therapy. Injection site reactions and local hypersensitivity reactions. For uncommon & rare adverse events, consult the full SmPC. 10. OVERDOSAGE: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. Severe hypoglycaemic episodes can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously or by glucose given intravenously. 11. PHARMACODYNAMIC PROPERTIES: ATC code: A10AB06. 12. MARKETING AUTHORIZATION HOLDER: Sanofi -Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing Information based on the EU SmPC as of January 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
INSUMAN®* Abbreviated Prescribing Information. 1. Name And Presentation: Insuman® (insulin human) 40 IU/ml or 100 IU/ml is a regular insulin solution (Rapid), or an isophane insulin suspension (Basal) or biphasic isophane insulin suspension (Comb 15-25-30-50) consisting of 15%, 25% , 30%, or 50% dissolved insulin and complementary portion of 85%, 75%. 70%, or 50% crystalline protamine insulin respectively. Insuman® is provided in a vial (5 or 10 ml) or cartridge (3 ml) for use with the reusable devices OptiPen, ClikSTAR, Autopen 24 or Tactipen and cartridge for OptiClik or pre-fi lled disposable pens (3 ml) SoloSTAR and OptiSet. Insuman® is also available as injection vial & cartridge for infusion (Insuman® Infusat 100 IU/ml). 2. Therapeutic Indications: Diabetes mellitus where treatment with insulin is required. Insuman® Rapid is suitable in hyperglycaemic coma & ketoacidosis, as well as for pre-, -intra- and post-operative stabilisation in patients with diabetes mellitus. 3. Posology And Method Of Administration: The dosage and timings should be individually adjusted. Daily doses and timing of administration: there are no fi xed rules for insulin dose regimen. However, the average insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. Insuman® is injected subcutaneously 15 to 20 minutes (Rapid) or 45 to 60 minutes (Basal) or 30 to 45 minutes (Comb 15-25-30) or 20 to 30 minutes (Comb 50) before a meal. Insuman® Rapid for injection in a vial may also be administered intravenously (intensive care conditions). Insuman® Basal and Comb must never be injected intravenously. Insuman® Infusat is used with an external pump, one part of the daily insulin dose is infused continuously (“basal rate”), and the rest is administered in the form of bolus injections before meals. Refer to the infusion pump operating instructions for detailed information. In the treatment of severe hyperglycaemia or ketoacidosis, insulin administration regimen requires close monitoring. Secondary dose adjustment: Improved metabolic control may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, if the patient’s weight or life-style changes. Other circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia. Patients must be educated to use proper injection techniques. For administration details see full SmPC. Hepatic or renal impairment and elderly: insulin requirements may be reduced. 4. Contra-Indications: Hypersensitivity to the active substance or to any of the excipients. Insuman® Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing. Insuman® Basal and Comb must not be administered intravenously and must not be used in infusion pumps or external or implanted insulin pumps. Insuman® Infusat must not be used in peristaltic pumps with silicone tubing. Refer to the technical manual for contraindications relating to the use of insulin pumps. 5. Special Warnings And Precautions For Use: Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method of manufacture may result in the need for a change in dosage. Following transfer from an animal insulin to human insulin, dose regimen reduction may be required. The warning symptoms of hypoglycaemia may be changed, less pronounced or absent in certain risk groups: for all details see the full SmPC. 6. Drug Interactions: Substances that may enhance or reduce the blood-glucose- lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. Pregnancy And Lactation: No clinical data on exposed pregnancies are available. Insulin does not cross the placental barrier. Caution should be exercised when prescribing to pregnant women. No effects on the suckling child are anticipated. Insuman® can be used during breast-feeding. Lactating women may require adjustments in insulin dose and diet. 8. Effects On Ability To Drive: Patients should take precautions to avoid hypoglycaemia whilst driving. 9. Undesirable Effects: Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Oedema, injection site - GLB.DIA.11.11.36 - 11/11 - GLB.DIA.11.11.36 reactions. For uncommon & rare adverse events please consult the full SmPC. 10. Overdosage: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. More severe episodes may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. Pharmacodynamic Properties: ATC code:A10AC01. 12. Marketing Authorization Holder: Sanofi -Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Abbreviated Prescribing Information based on the EU SmPC as of February 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
LIFE_1111016_ILA136_Type1Diabetes pressAD-21x28.indd 3 21/11/11 16:39 MANAGEMENT, CARE AND PREVENTION Back to the future: investigating new treatments for type 1 diabetes using old inexpensive drugs
Denise Faustman and Miriam Davis
"Great disappointments in medicine frequently give rise to great More than 20 years ago, we began study- innovation – so the saying goes – but who expected a 20-year ing islet transplants in people with long- detour?" Denise Faustman and her team were disappointed by standing type 1 diabetes. We hoped to their findings from human islet cell transplantation trials and replenish the pancreas with healthy islet cells and thereby restore normal blood felt compelled to return to the bench for 20 years to understand glucose. To achieve this, we replaced why the trials had been less successful than had been hoped. people’s islet cells with the same cells They first turned to an animal model of type 1 diabetes, which, modified to shield them from rejection just as in people, features an autoimmune assault on the by their own immune system. In type 1 insulin-producing islet cells in the pancreas. The animal model diabetes and other autoimmune dis- provided an opportunity to tease apart the immune system eases, the immune system regards some that triggers the disease. Over the next 10 years, they turned tissues, such as the insulin-secreting islet to studying the blood of large numbers of people with type cells, as foreign, not part of the self, and 1 diabetes, hoping that the promising mouse data could be it erroneously rejects and destroys them. At first, like many other islet transplant replicated in people. Those years-long and human and mouse researchers worldwide, we thought the studies suggested a new trigger for diabetes and, thus, a new transplanted islet cells could be modi- approach to designing a clinical trial to test a vaccine – a vaccine fied to escape the host's dysfunctional we all hope will be an advance in treatment for people with type immune attack when combined with 1 diabetes, and if successful, a remarkably affordable one. immunosuppressive drugs.
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 37 MANAGEMENT, CARE AND PREVENTION
But we did not realize that the diseased with a degree of scepticism. We identi- worldwide research had uncovered the immune system was relentless: it con- fied a major culprit as a type of immune mechanism by which TNF usually does tinued to attack the newly transplanted cell known as a CD8 T lymphocytes not harm normal cells. However, the islet cells even decades after diagnosis of (or CD8 T cells) in mice as well as and mutant defective CD8 T cells in humans the original disease. The autoimmunity humans.1 Other immune cells might and mice with diabetes became suscep- once again affected the transplanted participate, but small, potent CD8 T tible to specific killing, much like way insulin-secreting cells, even when the cells were a primary perpetrator. bacteria but not normal cells of the body host received drugs to prevent kidney are vulnerable to antibiotics.2,3 rejection. We decided to take a step Initially, we thought only people with dia- back and turned to studying betes had these disease-provoking CD8 We tested these findings first in tissue how type 1 diabetes occurs T cells since when we studied identical culture with isolated cells from people and how rogue white twins, only the twin with diabetes had with diabetes, and showed, at albeit in blood cells are pro- CD8 T cells. However, there are many culture, evidence that TNF selectively duced in the first different types of CD8 T cells. In type killed only the auto-reactive T cells.4 So place. 1 diabetes, only a particular subset of we hypothesized that TNF also could be CD8 T cells is defective – the subset that used as a treatment to destroy the abnor- targets specific proteins found almost mal CD8 T cells that caused type 1 dia- exclusively on the surface of islet cells. betes, while sparing healthy cells. Simply The quest to find the abnormality in CD8 put, we hoped that TNF would act like a At T cells lasted nearly a decade. In the late laser-guided missile or an ‘antibiotic for first, we 1990s, we published our findings diabetes’. That was the rationale behind used a well- that the educator cell of CD8 T our first experiments in NOD mice, then known rodent cells was defective and thus later in human blood samples and now model of type 1 diabetes the subset of rogue CD8 in clinical trials.5,6 called the non-obese diabet- T cells might also ic (NOD) mouse. We wanted to have similar pro- learn more about the basic science teins with the underlying type 1 diabetes in the hope of defect.1 finding more targeted ways to treat the disease. At that time, little was known The about the kinds of rogue T cells that protein de- caused type 1 diabetes – except that fects enabled the they provoked a self-reactive and au- abnormal CD8 T cell toimmune disease. Laboratory-based to escape the process of ‘T research using rodents does not attract cell education’ – the process the interest that human clinical trials do of learning to be tolerant to cells but it is the surest means to reveal the belonging to one’s own body. complex disease processes. So as they matured, poorly educat- The unusual suspects: CD8 T lym- ed CD8 T cells attacked the body’s phocytes own islet cells. But it turned out that Our first major breakthrough came in one of the dark clouds we had identi- 1991, when we discovered that a new fied also had a silver lining: the CD8 T type of immune cell was in part respon- cells became exquisitely vulnerable to sible for attacking the islet cells in the death by a normal protein of the immune pancreas – and this immune cell was not system known as tumour necrosis fac- the one most scientists pursued. Indeed, tor or TNF. We knew about TNF from other scientists received our finding many basic science studies; previous
38 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Finding a fast track to the clinic The successes in killing the rogue T cells monitoring people’s blood, we are able In engaging in clinical trials, our over- and showing pancreas regeneration em- to determine whether the TNF is killing arching aim is to develop only new thera- boldened us to conduct experiments with the disease-provoking cells – like seeing pies that are safe and widely affordable. human blood samples. We studied blood an antibiotic kill bacteria in the blood Clinical development is often very slow samples from 675 people with type 1 of an person with an infection. but a short cut can save time and money diabetes and 512 people without diabetes. and ensure that safety is achieved at earlier Using two different methods to measure Real hope for the future stages. Instead of directly administering cell death in people with diabetes, we As we progress with the testing of BCG, TNF, which is not an existing drug and showed that TNF killed a subpopula- we hope to open up possibilities for treat- would require years of validated manu- tion of CD8 cells but did not kill a dif- ing people with long-standing diabetes facturing processes, or testing it for safety ferent population of T cells. The results using a universally affordable drug. Data on live primates, we chose an indirect applied across all six different doses of from our Phase I trial, using only limited method for TNF exposures that showed TNF.4 Furthermore, TNF was effective doses of BCG and regular blood glucose us faster path to the clinic: we adminis- in selectively killing rogue CD8 T cells monitoring, are encouraging. Our aim is tered an agent that induced internal TNF in several other autoimmune diseases. to carry out these trials quickly and cost- production using an 80-year-old vaccine efficiently in order to develop a cheap called Balcillus-Calmette-Guerin (BCG). TNF was effective in generic drug for type 1 diabetes. selectively killing rogue In 2001 and 2003, we published our results showing that the TNF inducer CD8 T cells in several injected into end-stage diabetic animals autoimmune diseases. Denise Faustman and Miriam Davis was capable of selectively killing the de- Denise Faustman is Director of Immunobiology at fective CD8 T cells responsible for killing By this point, we felt ready to plan for a the Massachusetts General Hospital and Harvard Medical School, Immunbiology Laboratories, 5,6 islet cells. The TNF inducer was an human clinical trial with a TNF-inducer. Boston, USA. ([email protected]) old fashion vaccine that was originally Unlike most other diabetes clinical tri- Miriam Davis is a member of the Department developed for protection from tubercu- als, we focused on advanced type 1 dia- of Medicine at Massachusetts General Hospital and Harvard Medical School, losis and treatment of bladder cancer. It betes. Our rationale was that if mice Immunbiology Laboratories, Boston, USA.
was so successful that after 15 weeks the with advanced type 1 diabetes could be animals with diabetes began to produce cured, we could choose people with the References normal blood glucose levels for sustained greatest need for treatment. Moreover, 1 Faustman D, Li X, Lin HY, et al. Linkage of faulty major histocompatibility complex class I to periods of time. For the first time, killing surmounting the toughest challenge autoimmune diabetes. Science 1991; 254: 1756-61. rogue T cells using TNF was followed by would be the most rigorous way to sup- 2 Hayashi T, Faustman D. Defective function brisk islet regeneration. The concept that port our hypothesis that TNF could of the proteasome in autoimmunity: diabetes might be treated by targeted dis- selectively kill the disease-provoking T Involvement of impaired NF-kB activation. ease removal was surprising and pleasing cells. Our choice of BCG, an established Diabetes Tech Ther 2000; 2: 415-28. news, especially since it worked even in generic drug that was already on the 3 Hayashi T, Kodama S, Faustman DL. Reply advanced disease. market, gave us two advantages: BCG’s to 'LMP2 expression and proteasome activity in NOD mice'. Nat Med 2000; 6: 1065-6. safety is very well established; the drug That additional finding was first met with would be inexpensive. 4 Ban L, Zhang J, Wang L, et al. Selective death widespread scepticism. Now, there is near of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc uniform acceptance of worldwide data Our 20-year research programme had Natl Acad Sci USA 2008; 105: 13644-9. accumulated over the past eight years that established so many mechanisms about 5 Ryu S, Kodama S, Ryu K, et al. Reversal the pancreas can show growth well into the drug's effects that we were able to of established autoimmune diabetes adulthood. Our results have been repli- monitor those throughout the trial to by restoration of endogenous beta cell cated in other animal models and in other ensure that BCG was working in the function. J Clin Invest 2001; 108: 63-72. autoimmune diseases and there is enor- manner and with the purpose intended. 6 Kodama S, Kuhtreiber W, Fujimura S, et al. Islet mous and growing interest in the many This approach is known as translational regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302: 1223-7. different ways the pancreas can regenerate. medicine with biomarkers: by closely
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 39 CAUSES AND EFFECTS From victim to protector – what the brain does with hypoglycaemia
Stephanie A Amiel
The human brain depends on glucose to fuel all its functions. Although the brain can use other metabolic substrates, and babies’ brains do, glucose is its normal energy source. As the brain stores very little glucose, its proper function depends on a reliable supply from its circulation. If blood glucose concentrations fall too low, then brain malfunction results. But what is the plasma glucose concentration that is ‘too low’? Stephaine Amiel looks into this surprisingly controversial topic.
40 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 CAUSES AND EFFECTS
We know that the plasma glucose at cretion. The change in the insulin-to- date memories from the preceding day. which symptoms of hypoglycaemia oc- glucagon ratio in the blood leaving the Importantly, those brain regions that are cur is variable, depending heavily on a pancreas and going to the liver imme- active when we are enjoying ourselves person’s recent glycaemic experience, al- diately switches on glucose production are turned off by hypoglycaemia. Once though the evidence suggests that some by the liver cells, limiting the further the hypoglycaemia is treated, brain ar- degree of slowing of brain function is development of the hypoglycaemia. If eas involved in arousal, stimulated by detectable in everyone once plasma this does not work, and circulating glu- the low blood glucose, relax, perhaps glucose concentrations reach about cose continues to fall, a more vigorous explaining why people feel sleepy after 3 mmol/l (54 mg/dl). The American stress response occurs with secretion an episode. Higher brain functions may Diabetes Association has recommended of stress hormones such as adrenaline not be fully re-established for some 40 that we consider any glucose concen- (epinephrine); stimulation of the au- minutes after plasma glucose concentra- tration of less than 4 mmol/l (72 mg/ tonomic nervous system (which acts tions return to normal. dl) as hypoglycaemia;1 the European to increase the liver’s ability to make Medicines Agency less than 3 mmol/l glucose and also adjusts the circulation The protective stress responses to hy- (54 mg/dl),2 elsewhere, less than 3.5 to increase the blood flow to the brain) poglycaemia presumably evolved to mmol/l (65 mg/dl) is considered di- and the release of other hormones to protect brain glucose supplies dur- agnostic of a hypoglycaemic episode. help sustain the liver’s efforts and also ing times of food shortage, or when Universally, however, it is agreed that slow the rate at which muscle and fat muscle was using lots of glucose very people with diabetes using treatments take glucose out of the circulation. rapidly, perhaps as primitive humans that can cause hypoglycaemia should went chasing after lunch (or possibly adjust their treatment regimens to Research using brain imaging tech- escaping from being lunch for someone avoid frequent exposure to concentra- niques have shown that during symp- else). They efficiently protect the brain tions below 4.5 mmol/l (ap- from glucose deprivation proximately 80 mg/dl). It is and make hypoglycaemia certainly important to give The brain is the victim of severe enough to cause cog- people a lower limit to any nitive impairment very rare glucose targets that we might falling plasma glucose and in health. recommend to them – as well as a higher limit! coordinator of the normal For people with diabetes, protective response. however, hypoglycaemia is The brain is not just a victim an all-too-familiar problem. of falling plasma glucose; it Especially in circumstances is also the coordinator of the normal tomatic hypoglycaemia, there is ac- of complete insulin deficiency (type 1 protective response. It is perhaps not tivation of the classical central stress diabetes and late type 2 diabetes), defects surprising that the body’s most impor- pathways (hypothalamus and pituitary), in the above protective responses to a tant glucose sensors are placed in the hunger and appetite centres and also falling plasma glucose concentration al- brain. Glucose-sensing neurones are areas of the brain that are involved in low the development of severe hypogly- found throughout the brain stem and monitoring how the body is behaving.3 caemia. Circulating insulin results from most famously in the hypothalamus. Brain regions involved in aversion are insulin injection, and concentrations do These neurones are activated by changes also stimulated. The brain seems able not fall just because the glucose con- in their glucose supply. When plasma to focus energy on these important centration is falling. Because the cells glucose falls, these neurones initiate and functions, and diverts attention from making glucagon are driven as much coordinate a stress response that tends such functions as memory and bal- by messages from insulin-secreting cells to correct the situation. ance. Research suggests that people do stopping work, as by the low glucose not make a memory for an event that concentration itself, glucagon responses The response starts with a message occurs when they are hypoglycaemic, to hypoglycaemia are also lost. People to the pancreas to shut down insulin and if hypoglycaemia occurs during with diabetes, therefore, depend most on production and increase glucagon se- sleep at night, they might not consoli- the rest of the stress response and, most
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 41 CAUSES AND EFFECTS
importantly, the generation and percep- recurrent exposure to modest hypogly- concerns that severe hypoglycaemia in tion of symptoms of hypoglycaemia: caemia in daily life. Equally, if a person children with diabetes, which can be stress symptoms and feelings of confu- can adjust his or her diabetes therapy complicated by seizures, may result in sion and, importantly, hunger. Eating or to avoid dropping plasma glucose be- impaired performance in some brain drinking readily available carbohydrate low 3 mmol/l (54 mg/dl) too often, or functions tested later on.6 (An article is the best defence against a small hy- for too long, the ability to perceive oc- by Edith Schober and Reinhard Holl on poglycaemia becoming a big one. casional subsequent hypoglycaemias page 43 of this special issue explores the can be restored. Structured education links between diabetes and epilepsy in Hypoglycaemia programmes (such as those described young people.) There is no doubt that unawareness is on pages 16 to 28 of this special issue) we do need to improve on our ability associated with a six- may help about half the participants to help all of our patients with diabetes with hypoglycaemia unawareness to to minimize their risk for this always fold increase in risk of regain awareness and they do reduce distressing and sometimes dangerous severe hypoglycaemia. the amount of severe hypoglycaemia complication of diabetes therapies. very substantially. It is thought that the Sadly, for about a quarter of people failure to perceive the unpleasantness of Stephanie A Amiel with longstanding type 1 diabetes and each hypoglycaemia, as a result of the Stephanie A Amiel is RD Lawrence Professor of an as yet undetermined number with altered response of reward circuitry and Diabetic Medicine, King’s College London (UK). type 2 diabetes, defects develop in these pleasure perception, may block the oth- second-tier responses to hypoglycaemia. er half from changing their behaviour As well as not being able to suppress enough to avoid future hypoglycaemia insulin or enhance glucagon, these – rendering them resistant to the ben- people mount feeble stress responses efits of a purely educational approach.5 that only start at much lower glucose New strategies that help people change concentrations than usual. In this situ- behaviours for more healthy ones are References ation, the stress responses start after being developed. 1 European Medicines Agency, Committee for the cognitive dysfunction has begun, Proprietary Medicinal Products. Note for guidance and the person experiencing the hy- We must improve on the clinical investigation of medicinal products in the treatment of diabetes mellitus. www.ema. poglycaemia does not have the oppor- our ability to help europa.eu/docs/en_GB/document_library/ tunity to make a proper response and Scientific_guideline/2009/09/WC500003262.pdf people with diabetes take carbohydrate before confusion and 2 Workgroup on Hypoglycemia, American reduced consciousness occur. This ‘hy- to minimize their risk Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the poglycaemia unawareness’ is associated for this distressing American Diabetes Association Workgroup on with a six-fold increase in risk of severe Hypoglycemia. Diabetes Care 2005; 28: 1245-9. complication of hypoglycaemia (by definition hypogly- 3 Teh MM, Dunn JT, Choudhary P, et al. caemia that is so severe the person needs diabetes therapies. Evolution and resolution of human brain to be treated by someone else).4 There perfusion responses to the stress of induced hypoglycemia. Neuroimage 2010; 53: 584-93. is failure of activation of the brain’s What of the long-term effects of hy- 4 Schopman JE, Geddes J, Frier BM. Frequency of stress responses, and failure of activa- poglycaemia on the human brain? symptomatic and asymptomatic hypoglycaemia tion of the symptom perception areas Again, neuroimaging and cognitive in Type 1 diabetes: effect of impaired awareness too. Moreover, research suggests that function tests are being deployed to of hypoglycaemia. Diabet Med 2011; 28: 352-5. there is impaired shutdown of the re- determine whether recurrent hypogly- 5 Smith CB, Choudhary P, Pernet A, et al. ward circuitry and pleasure perception. caemia has an impact on brain structure Hypoglycaemia unawareness is associated with reduced adherence to therapeutic decisions in In some victims of unawareness, these and function. The data are reassuring patients with Type 1 diabetes: evidence from a brain regions even may be stimulated! with regard to minor episodes, and clinical audit. Diabetes Care 2009; 32: 1196-8. probably to even severe hypoglycaemia 6 Northam EA, Lin A. Hypoglycaemia in childhood We know that hypoglycaemia unaware- in adults (as long as a full recovery is onset type 1 diabetes--part villain, but not the only one. Pediatr Diabetes 2010; 11: 134-41. ness can be induced and maintained by made at the time) but there are growing
42 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 CAUSES AND EFFECTS Epilepsy in children and adolescents with type 1 diabetes
Edith Schober and Reinhard Holl
Seizures provoked by Epilepsy is a common chronic neu- of diabetes had preceded the onset of hypoglycaemia are relatively rological condition, which affects the epilepsy by several years. frequent in people with type 1 nervous system. Also referred to as Epilepsy-related a ‘seizure disorder’, epilepsy involves diabetes. Each year, up to seizures in children 15% of children with type 1 sporadic electrical storms in the brain, diabetes experience a severe which cause sudden mild loss of atten- may be mistaken tion or staring, and/or violent muscle hypoglycaemic episode, or for symptoms of contractions and loss of consciousness, ‘hypo’, with seizures – often as a known as grand mal seizures. There hypoglycaemia. result of administering too much are several types of epilepsy, each with Recent studies in children have showed insulin. But seizures also can different causes, symptoms and treat- conflicting results. An Italian centre re- occur during diabetic ketoacidosis ments. Idiopathic generalized epilepsy is ported a higher prevalence of epilepsy in – when not enough insulin a group of disorders that tends to mani- adolescents with diabetes compared to has been taken. These acute fest itself in young people between early young people without diabetes. Again, complications often constitute childhood and adolescence but which diabetes had been diagnosed in these an obstacle to diagnosis of can develop in later life. The prevalence young people on average 2.8 years be- 3 epilepsy in people, especially of idiopathic generalized epilepsy varies fore epilepsy. On the other hand, an children and adolescents, with according to age. A peak prevalence of Australian study found no increase in diabetes. The authors of this 1.1% occurs in adults over 50 years of risk for epilepsy in children and adoles- age; in children and adolescents, the cents with diabetes.4 article look at some of the links prevalence of epilepsy ranges between between epilepsy and type 1 0.2% and 0.4%.1 In many cases, epilepsy-related seizures in diabetes and report on a number children may be mistaken for the symp- of interesting findings from There is a recognized association be- toms of hypoglycaemia. Consequently, their recent study involving tween diabetes and idiopathic general- the diagnosis of epilepsy in children with a large number of European ized epilepsy. In a UK study, a group diabetes is often delayed or underesti- children with type 1 diabetes. of adults with epilepsy were found to mated. Generally, a diagnosis of epilepsy have a four-fold higher prevalence of is based on at least two unprovoked sei- type 1 diabetes compared to the general zures – not resulting from an external population.2 In that group, diagnosis cause, such as injury or consumption of
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 43 CAUSES AND EFFECTS
frequency of epileptic seizures in chil- risk compared to children with type 1 dren and adolescents with diabetes than diabetes alone. The causes of this as- expected: twice as high as in children sociation are unclear. It could it be that without diabetes. There was no differ- people with repeated episodes of ke- ence between boys and girls. toacidosis are more prone to epilepsy. We found a significantly Education to prevent complications higher frequency of Close observation by parents of a child epileptic seizures with diabetes and epilepsy could enable them to anticipate the symptoms of in children and metabolic disturbances, allowing earlier adolescents with diagnosis of (still mild) ketoacidosis. In diabetes than expected. reality, however, we found that rates of mild as well as severe ketoacidosis were Some interesting findings higher in the children with both dis- It was interesting to note that the chil- eases. Children, their families and their dren with both diabetes and epilepsy healthcare providers need to be aware were younger at onset of diabetes than of this increased risk and should receive the children with diabetes alone. The adequate and appropriate education to be reason for the increased frequency of able to detect and prevent ketoacidosis. epilepsy in children with type 1 diabetes is unknown and deserves further inves- tigation. However, previous studies have Edith Schober and Reinhard Holl shown that both severe hypoglycaemia Edith Schober is paediatric diabetologists in the and ketoacidosis can lead to abnormali- Department of Paediatrics and Adolescent Medicine, Division of Paediatric Pulmology, Allergology and prescribed medications or other drugs – ties in an electroencephalogram (test to Endocrinology, Medical University Vienna, Austria. in a person with normal blood glucose detect problems in the electrical activity Reinhard Holl is paediatric diabetologist and levels (above 3.9 mmol/l) and with an of the brain) in children with diabetes. epidemiologist at the Institute of Epidemiology and Medical Biometry, University of Ulm, Germany. interval greater than 24 hours between the seizures. Although monitoring blood Given the risk of acute complications References glucose is recommended when seizures or posed by both diseases, parents of chil- 1 Martinez C, Sullivan T, Hauser WA. Prevalence loss of consciousness occur in a child with dren with epilepsy and diabetes might be of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res 2009; 87: 137-43. diabetes, parents might not carry out a expected to prevent convulsions in their glucose test in such a frightening situation. child by attempting to avert hypoglycae- 2 McCorry D, Nicolson A, Smith D, et al. mia using less insulin – with the conse- An Association between Type 1 Diabetes and Idiopathic Generalized Epilepsy. It could it be that people quence of higher overall blood glucose Ann Neurol 2006; 59: 204-6. levels. However, among the children with with repeated episodes 3 Mancardi MM, Striano P, Giannattasio A, et both diseases, HbA1c levels and insu- al. Type 1 diabetes and epilepsy: More than a of ketoacidosis are lin dosage-to-body weight ratios were casual association? Epilepsia 2010; 51: 319-322. similar to those in the children without more prone to epilepsy. 4 O’Connell MA, Harvey AS, Mackay MT, epilepsy and we saw no difference in the Cameron FJ. Does epilepsy occur more frequently We had the opportunity to analyze type of treatment – pump or injections. in children with Type 1 diabetes? J Paediatr Child Health 2008; 44: 586-9. the association between diabetes and epilepsy in a large group (45,847) of An interesting and unexplained result of 5 Schober E, Otto KP, Dost A, et al for the our study was a significantly increased German/Austrian DPV Initiative and the BMBF young people with type 1 diabetes aged competence network diabetes. Association between 0.1 and 20 years from Germany risk for diabetic ketoacidosis in children of epilepsy and type 1 diabetes in children and Austria as part of the DPV initia- and adolescents with type 1 diabetes and and adolescents. Is there an increased risk for DKA? Journal of Pediatrics (in press). tive.5 We found a significantly higher epilepsy. They appear to be at twice the
44 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Diabetes champions Breakthrough – the story of Elizabeth Hughes and the making of a medical miracle
Arthur Ainsberg
Since its discovery in 1921, insulin has methods would allow Banting to test become the most widely prescribed drug accurately the effects of his treatment. in history. Many of the world’s estimated Though cautious, Macleod granted him 366 million people with diabetes rely a research lab and assigned Best as his on this life-saving treatment. Although assistant. Neither Banting nor Best for millions administration of the drug was a premier scientist or researcher. has become a normal part of life, its Banting had been a mediocre student discovery by four men at the University at the University of Toronto’s Medical of Toronto – Frederick Banting, Charles School and served as a medic in World Best, John James Rickard Macleod, War I. Best was a college student hoping James Collip – was anything but ordi- for experience in a research lab. Of the many medical innovations nary. They endured countless setbacks, seen in the 20th century, few disappointments and betrayals – even At the same time, an adolescent girl were so pivotal as the discovery a fistfight! – before they discovered would be relying on the success of these of insulin for the treatment for an effective extract. Their discovery two unlikely heroes. Elizabeth Hughes diabetes. A newly published transformed the life of nearly every- was the youngest daughter of one of the book, Breakthrough, tells the one around them, including their own. USA’s most famous politicians at that story of a young girl who should time, Charles Evans Hughes. In 1920, Frederick Banting presented have died as a child but survived his idea for a diabetes treatment to John To this day, her father remains the only to see seven grandchildren, James Rickard Macleod at the University man in American history to have served and the drug that, for millions of Toronto. Banting believed that by ty- as New York Governor, US Secretary worldwide, has turned a death ing off part of a dog’s pancreas, its tissues of State, Associate Justice and Chief sentence into something more would degenerate and allow him to iso- Justice of the Supreme Court. In 1919, like a chronic irritation. A portion late a secretion that people with diabetes 11-year-old Elizabeth was diagnosed of the book’s proceeds is going to needed to survive. Although the process with ‘juvenile’ diabetes, now known as IDF’s Life for a Child Programme. had been tried before, the recent ad- type 1 diabetes. Her prognosis looked The authors tell us more. vent of sophisticated glucose monitoring grim. Before insulin, children with type 1
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 45 Diabetes champions
diabetes survived an average of 11 turned her down. Insulin was simply too months after diagnosis; from 1900 to experimental and too scarce. The lives of Elizabeth Hughes 1919, half of all people with diabetes Three months after Frederick died within two years. To meet the demand for mass manu- Banting injected her with insulin, Elizabeth Hughes left Toronto to be- facturing, the Toronto team entered gin a new life. It had been her dream Elizabeth’s parents turned to Frederick into a partnership with Eli Lilly and to live as a normal girl, and insulin Allen, known then as a premier diabe- Company – a radical idea at the time. allowed her to live that dream – as long as she kept her diabetes a se- tes expert. Allen’s ‘starvation diet’ was However, insulin remained an unstable, cret. That was no mean feat, given one of the more effective treatments to experimental drug. People with diabetes the demands of diabetes manage- prolong the short life of a person with continued to die. ment, and this was long before the conveniences of glucose monitors diabetes. Before diabetes, Elizabeth’s and disposable syringes. Yet through recommended daily caloric intake Elizabeth Hughes was to be one of exceptional determination and dis- was 2,200 calories; on the Allen diet, the lucky ones. On 15 August 1922, cipline, she succeeded in living the she sometimes dipped as low as 400. Elizabeth, sat in Banting’s office in extraordinary, ordinary life that she had longed for during her agonizing, Incredibly, Elizabeth adhered perfectly Toronto, became one of the first people pre-insulin years of starvation. to Allen’s diet, never wavering in her to receive an insulin injection. Though Just as remarkable as Elizabeth belief that if she could just stay alive long initial supplies were sparse and danger- Hughes’s ‘disappearance’ in 1922, enough, a breakthrough would occur ous, potentially deadly even, Elizabeth was the way that she re-emerged, that would save her from this disease. flourished. She gained weight quickly after some 43,000 injections of insu- lin, 58 years later. This is recounted and grew taller, changes she described in Michael Bliss’s book, The Discovery If Elizabeth could just as “unspeakably wonderful”. of Insulin. Bliss, understandably, assumed that Elizabeth was dead stay alive long enough, and wrote to Elizabeth’s husband, From the first failed experiment to its a breakthrough would William Gossett, hoping to obtain worldwide launch, insulin was devel- some information about her later occur that would save oped in two years. Today, a new drug years. Imagine his surprise when the reply came from Elizabeth herself! her from this disease. takes approximately 12 years and USD 1 billion to reach the end user (patient) – She was distressed that Bliss had found her and agreed to talk only As Elizabeth wasted away, progress was after successfully completing a series of after he promised to provide her with being made in Toronto. Banting and government and regulatory reviews. But an alias in his book. Even her own Best’s new extract, which they named insulin is not a cure. It does not prevent children did not know of her diabetes insulin, kept a dog with diabetes alive for or eradicate diabetes nor does it pre- until they were 18 years old. 20 days. Researchers around the world vent the development of disabling and Among people with diabetes today, began to take notice. With this new suc- life-threatening complications. Insulin- there are varying opinions about how public or private one should be in cess, Macleod was finally convinced dependent people with diabetes need the quotidian management of dia- that Banting’s and Best’s discovery was to take great care in monitoring and betes. Some advocate injections at worthy of a research team. managing their health. the dinner table; others adhere to a policy of privacy. Such debates were impossible before insulin. Whether The beginning of 1922 would pass in a As we approach the 90th anniversary or not one agrees with Elizabeth’s whirlwind. Researchers lost the ability of the discovery of insulin, it is impor- choice, one cannot help but appre- ciate her remarkable life – or one to make an effective extract; Banting, be- tant to reflect on the importance of the might say lives. lieving others were trying to take credit drug and how much treatment options for his work, temporarily withdrew from have changed since its inception. After Thea Cooper the research team and began drink- centuries of ill-advised and even danger- ing heavily; Elizabeth Hughes’ weight ous recommendations, insulin was the Arthur Ainsberg dropped to 19.5 kg (43 lb). Her mother, first truly effective treatment for people Arthur Ainsberg , with Thea Cooper, is desperate for help, wrote to Banting living with type 1 diabetes. It did not the co-author of Breakthrough - Elizabeth Hughes, the discovery of insulin, and asking him to treat her daughter. As briefly delay an untimely, horrific death; the making of a medical miracle. he did with all other requests, Banting it helped people to live normal, full lives.
46 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Diabetes champions In the race for a glittering prize – Team Type 1 hits the road
Phil Southerland
Many people are shocked when I say that my diabetes is a gift – or that I would not take a cure if it were offered to me. But that is the truth. Diabetes is my life; I would not trade it for the world. Because of diabetes, I am healthier today than I would have been without the disease. Because of diabetes I live an incredible life – beyond my dreams – as the founder and chief executive officer of Team Type 1, a USA-based professional cycling team. Because of diabetes, I am able to play a part in helping to make life better for millions of people around the world. At Team Type 1, our goal is to show people that not only can people live their dreams with diabetes, but that diabetes combined with the resources and diligence it takes to manage the condition properly can be a path to achieving success in all aspects of life.
Team Type 1 was conceived and es- made a sporting bet: at the end of the tablished because of my friend, Joe school day, the higher blood sugar pays Eldridge. When we met in college, Joe for dinner. Joe bought me a lot of burritos was not managing his diabetes well at that semester! But one day, the burritos all. To encourage him to do better, we stopped coming and Joe said, "Thank you
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 47 Diabetes champions
for saving my life." That was the ‘game children or a room full of government tion in Macedoina will have, for the first changer’ for me. officials, many audiences find it very time, free access to insulin and test strips. hard to believe that I was diagnosed 29 It is not a huge population but as a wise Joe told me I was his hero; as far as I was complication-free years ago and that our man once said, even the longest journey concerned, he was the hero: he had taken athletes with type 1 diabetes are compet- must begin with a single step. And for control of his diabetes and his life. I grew ing and winning in world-class events. 2,500 people with diabetes, that journey up without a diabetes role model; diabetes "But you look normal", people say. And now has very a different look to it. had always seemed to me like a disease I reply that that is because we are normal with no heroes. But I knew that Joe could – when we have the tools and education Diabetes is not a sickness; be a powerful inspiration. We both liked we need to control our disease we are. diabetes is a lifestyle. cycling and I thought the bike could be a great platform to reach and motivate Diabetes advocates at the top of their We are bringing a powerful message that young people. Maybe we could provide game we hope will be the global game changer a few diabetes heroes… Team Type 1 has a crucial role to play – for people with diabetes, people without in advocating for the rights of people diabetes, whole communities, employers, Prejudice and ignorance with diabetes. In the USA, people with politicians and policy makers and media forces many people diabetes have access to the supplies and and diabetes stakeholders everywhere: if medication we need, enabling us to live you have the right medicine, test strips and around the world a healthy productive life without limita- a decent meter and you know how to use are forced to hide tions – a basic human right. But that is them properly, diabetes is not a sickness; their diabetes. not the case for the millions of people diabetes is a lifestyle. worldwide who do not have access to Team Type 1 – we work to inspire life-saving supplies. What is more, in Eyes on the prize A global sports organization was born out many countries, outmoded and offensive The recent UN summit was a step in the of that idea. Team Type 1-SANOFI has a discriminatory policies and widespread right direction but much work remains to world-class athletic programme with ap- diabetes unawareness conspire to prevent be done. By continuing to offer an exam- proximately 100 cyclists, runners and tria- people with the condition from attending ple, pushing the boundaries of possibility thletes – more than 60 with type 1 diabetes school or having a job or even having a with diabetes and promoting education and more than 20 with type 2 diabetes – all life partner. No wonder so many people and empowerment, we intend to keep competing at the highest levels in their around the world hide their diabetes – the diabetes advocacy pedals turning, to sports. We work to inspire. We train and they are forced to. maintain the momentum of IDF’s cam- compete against some of the best athletes paign for recognition of diabetes and on the planet to demonstrate to our peers other NCDs at the very highest levels. everywhere that they can achieve their In arenas of sporting excellence and at dreams if they can manage their condi- diabetes meetings and events world- tion and control their blood glucose, and wide, Team Type 1 is fighting to take to encourage others to take up physical the stigma out of diabetes and adding exercise to prevent type 2 diabetes. our voice to the global movement that is effectively pressuring governments to I travel widely with Team Type 1 and take real steps to improve the lives of their have met people striving to live with citizens with diabetes. During a recent diabetes in such countries, who, before trip to Macedonia, where I gave a pres- meeting our athletes, have little hope entation in the lead-up to the September for the future. When they see what our 2011 UN High-Level Meeting on NCDs, athletes have achieved and tell me of their representatives of the Ministry of Health Phil Southerland newfound optimism, I feel a strong emo- requested a meeting at which they agreed Phil Southerland is founder and CEO tion that is difficult to measure or even to fund essential diabetes supplies. As a of Team Type 1. He is also an IDF Blue Circle Champion. describe. Whether I talk to a group of result, the entire type 1 diabetes popula-
48 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 Diabetes champions From diabetes education and prevention all the way to sporting excellence – Italy’s BCD Campaign
Massimo Massi-Benedetti
Great strides have been made in our collective The BCD Campaign is promoted by the International Diabetes understanding of the benefits of well-managed Federation along with Italy’s professional diabetes organi- diabetes and controlled blood glucose, and the zations, the Association of Diabetologists (AMD) and the Italian Diabetology Association (SID), and groups represent- key role in these that is played by physical activity. ing people with diabetes, the Italian Diabetes Association Yet slow progress has been made translating this (FAND-AID) and the Italian Association for Sports and knowledge into effective lifestyle education to Diabetes (ANIAD). The Campaign is supported by the Italian engender healthful behaviour on a large scale. Association of Paediatric Endocrinology and Diabetology and Very many young people remain at particularly high the Ministry of Health and financed by Sanofi Italy. risk from the chronic effects of disabling diabetes The BCD Campaign promotes multiple complications. The threat of huge increases in the partnerships involving a broad range human and economic costs of diabetes demands a concerted response by multiple sectors of society of players in the fight against diabetes. to spot the warning signs and reduce the multiple The Campaign programme is a vehicle for activities that raise health risks associated with this life-long condition. awareness by sharing information on prevention, control and Massimo Massi-Benedetti describes a countrywide treatment of diabetes through lifestyle education – with a special focus on sporting activities. The Campaign promotes initiative in Italy, Campagna Buon Compenso del multiple partnerships involving a broad range of players in Diabete (BCD Campaign), which aims to spread the fight against diabetes: the medical-scientific community, a culture of diabetes prevention through healthy institutions and healthcare professionals, volunteer associa- lifestyle education. tions, sports associations and the media.
December 2011 • Volume 56 • Special Issue 2 DiabetesVoice 49 Diabetes champions
The AC Milan goalkeeper, Christian Abbiati (close up), who took part in several BCD activities. Young campers gather for a hike (main photo).
Since its inception in 2008, the BCD Campaign has reached with diabetes have the opportunity to spend a week at one more than 200,000 people in 80 Italian towns and cities, as of AC Milan’s residential summer camps, where ideal condi- well as major Italian companies and public institutions, carry- tions have been created to guarantee children with diabetes
ing out screening and free tests (blood glucose, HbA1c, blood (selected by Italian Association of Paediatric Endocrinology pressure, BMI) to assess people’s cardiometabolic risks, and and Diabetology) the opportunity to train safely every day providing them with educational materials. To date, some alongside children without diabetes. 14,000 visits have been conducted, involving 600 institu- tions, and 170,000 brochures distributed. More than 2,700 As you would expect from the best summer camps anywhere, press articles and citations have given the BCD Campaign the Milan camps provided a comprehensive range of sporting a visibility equivalent to nearly 360 million media contacts. and leisure activities, as well as a social programme to fuel the People with diabetes can participate in any sporting activities, bonding process among the children and promote empathy even at the very highest levels. and self-confidence. The initiative has proved popular among the medical community and fami- The Campaign supports a range of sporting projects that lies, and has become a top hit on the carry a key message: when diabetes is managed well, it is Internet. Within days of the camps not an obstacle; people with diabetes can participate in any opening, the family members of chil- sporting activities, even at the very highest levels. A new BCD dren with diabetes began exchanging project, Diabetes and Sports, aims to turn this message into comments and writing blogs. Their reality for young people with diabetes in Italy. The project general impression was very positive. is the fruit of partnerships with the elite endurance sports outfit, Team Type 1 and the football club, AC Milan, via their Foundation. (An article on page 47 by the Team’s founder, Massimo Massi-Benedetti Phil Southerland describes the origins aims and activities of Massimo Massi-Benedetti is Chair of the IDF Science Task Force. Team Type 1). Thanks to these collaborations, 70 children
50 DiabetesVoice December 2011 • Volume 56 • Special Issue 2 M ENT VERTISE A D
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