FEATURE

SEVERE INSULIN RESISTANCE

EIGHT YEARS ON AN UPDATE ON THE NATIONAL SEVERE INSULIN RESISTANCE SERVICE

The National Severe Insulin Resistance Service (NSIRS) was commissioned by NHS England in 2011 to provide diagnostic, therapeutic and educational support for adults and children with known or suspected syndromes of severe insulin resistance (SIR). Clinical Lead Dr Anna Stears and Diabetes Specialist Nurse Charlotte Jenkins Liu discuss the service and present some case studies illustrating the work it does

nsulin resistance can be defi ned abnormal distribution of subcutaneous Specialist therapies, such as high- as an impaired responsiveness fat. Other patients have even rarer strength insulins, insulin pump therapy, to the glucose-lowering response conditions, for example abnormal metreleptin, GLP1-agonists or of insulin. It can be caused by several function of their insulin receptor, due to immunosuppression, may be offered physiological and pathological a genetic mutation, or antibodies against if appropriate. We also offer surveillance Iconditions, the most common being the insulin receptor. The NSIRS does and treatment of hyperlipidaemia, obesity. Patients referred to the NSIRS not provide a service for patients polycystic ovarian syndrome and have rare genetic or acquired conditions whose primary cause of insulin appearance issues. Patients may require causing SIR and around 70% of the resistance is obesity related, as they genetic counselling and we will often patients seen to date have lipodystrophy, are better served by existing obesity see several members of the same

PHOTO: MEDIA STUDIO a group of conditions that leads to the services. family together.

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32-37_Insulin-Resistance_SA5REVISED.indd 32 20/02/2019 10:36 Our case studies have now been reduced significantly Metreleptin therapy (Myalept) has to 1.6mmol/l. recently been granted marketing With the patients’ permission, the authorisation in the EU and NICE is following cases give some real-life What is lipodystrophy? currently reviewing cost-effectiveness examples of these rare conditions Lipodystrophy is a very rare condition data, in order to decide which patients and of the experiences of patients. with a number of genetic or acquired will receive NHS funding for metreleptin Some names have been changed. causes. It can affect the whole body therapy in the UK in the future. It is (generalised) or part of the body (partial). currently only provided in the UK on a Case 1: Insatiable Because women normally have more fat named patient basis through the NSIRS. hunger – introducing tissue than men, these conditions are We will continue to support these metreleptin commonly diagnosed in females during patients going forward, whatever the Karen, (below), 54, (BMI 21.5kg/m²) puberty, although there is an equal outcome of the NICE review of Myalept. with familial partial lipodystrophy Type 2 likelihood of men and women carrying secondary to a mutation in the LMNA the abnormal gene. There are currently Case study 2: Managing gene, was referred to the NSIRS with only a limited number of identified diabetes control or a 15-year history of poorly controlled genetic causes of lipodystrophy and quality of life – or both? diabetes (HbA1c 64mmol/mol) and genetic testing does not always provide hypertrigly-ceridaemia (7.3mmol/l). She a definitive diagnosis. So around 20% was treated with oral antihyperglycaemia of the patients seen in the service, medication and a fibrate. who have the clinical appearance She was often hungry, but was of lipodystrophy, do not yet have making efforts to improve her diet by a precise cause identified. following a low-fat diet, as advised by Lipodystrophy can affect both the NSIRS dietitian. Her HbA1c came the physical and mental health of an down from 64mmol/mol to 46mmol/mol individual. Physically, they may have: with dietary changes. After starting • significant insulin resistance and on metreleptin therapy she reported difficult-to-control diabetes an improvement in her hunger levels. • hypertriglyceridaemia and increased Her blood glucose levels also risk of pancreatitis normalised to HbA1c 42mmol/mol. • polycystic ovary syndrome Meanwhile, her triglyceride levels • non-alcoholic fatty liver disease and cirrhosis • cardiomyopathy. “I commenced leptin therapy about a year ago and this has made a huge difference to my life. My diabetes The impact on mental health usually results and lipid profile have improved results from the difference in appearance immensely to the point where I do not arising from abnormal fat distribution. have to worry about them anymore.” What is leptin? Leptin is a hormone produced by adipocytes which has a central role in energy homeostasis. Normally, a low leptin concentration signals starvation and increases hunger. As a result of the lack of adipose tissue, people with lipodystrophy may be deficient in leptin and therefore develop an insatiable hunger, due to a lack of satiety signals and hypertriglyceridaemia, ectopic liver fat accumulation and hyperglycaemia due to insulin resistance. Leptin replacement injections (metreleptin, Myalept) may be offered to selected patients with lipodystrophy Lynne (above), 51, (BMI 19.5kg/m²) with a low leptin level and metabolic was diagnosed with acquired abnormalities. Metreleptin is used in generalised lipodystrophy, complicated combination with changes in diet and by poorly controlled diabetes, lifestyle, diabetes medication and hypertriglyceridaemia and recurrent lipid-lowering therapies. Patients have pancreatitis. She was referred to the improvements in appetite reduction, NSIRS in 2012. Following intensive triglyceride levels, with improved review and education, and also after diabetes control with reduced commencing metreleptin replacement insulin requirements. therapy, she was requiring up to nine

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SEVERE INSULIN RESISTANCE

subcutaneous injections per day, and Case study 3: Metabolic carbohydrate in the diet and weight a total daily insulin dose of 152 units to surgery reduction. The SIRS specialist dietitians maintain blood glucose levels in target. Barbara (below), 53, has familial partial provide advice, based on each individual’s This caused severe discomfort at her lipodystrophy Type 1 with secondary basal metabolic rate for their gender, age injection sites, due to complete absence diabetes and hepatic steatosis. Despite and weight. If unsuccessful, metabolic of subcutaneous adipose tissue. So extensive input from the NSIRS team, surgery may be suggested. Although the after exceptional funding approval, she continued to struggle with her numbers of patients are small (five RYGB insulin pump therapy was started, weight and diabetes management, and one sleeve gastrectomy), we have using a Medtronic 640g pump with so exceptional funding was requested had some very positive outcomes in 30° angle cannula sets. for a Roux-en-Y gastric bypass (RYGB). patients with partial lipodystrophy1 which Lynne’s pre-pump HbA1c was The application was rejected, so she adds to existing positive case reports 43mmol/mol, but with frequent self-funded the procedure in 2016. in the literature2–6. hypoglycaemia. Since starting pump Her pre-operative BMI was 28kg/m², therapy her HbA1c has remained within and her diabetes was suboptimally Case study 4: How the target range. Her last result was controlled with an HbA1c of 75mmol/ receptive is the insulin 48mmol/mol, with significantly fewer mol on a total daily insulin dose of >150 receptor? episodes of hypoglycaemia, but the units of insulin. Post surgery there was Andrea, 30, (BMI 22.84kg/m²) was effect on her quality of life, due to an improvement in her HbA1c to referred to our service with a six-month reduced pain from injecting large history of newly diagnosed diabetes frequent doses of insulin via a pen, with extremely high insulin requirements. has been the most valuable to her. She also had severe skin pigmentation (acanthosis nigricans), weight loss Insulin pump therapy in ‘non-Type 1’ and severe clinical and biochemical diabetes hyperandrogenism. Three months after In the last three years we have been her diabetes diagnosis she was requiring evaluating insulin pump therapy in hundreds of units of insulin a day, selected patients with lipodystrophy and delivered at 22 to 25 units/hour via an other causes of SIR. As these patients insulin pump, with additional mealtime fall outside the NICE criteria for pump bolus doses of 300 units Humalog U200 therapy, individual funding requests insulin via a KwikPen. She did not use were required. As well as improved the pump overnight due to overnight quality of life, another common theme hypoglycaemia. noted in NSIRS pump users has been Andrea was found to have a high that their total daily insulin requirement titre of anti-insulin receptor antibodies, is significantly lower compared with confirming that she has Type B insulin pre-pump. resistance. This very rare condition There is also a marked drop in insulin is characterised by a rapid onset requirements overnight, and increased of severe hyperglycaemia, severe bolus requirements with carbohydrate hyperinsulinaemia, acanthosis intake. To address this issue, we reduce nigricans, weight loss and often severe the starting doses beyond the initial hyperandrogenism in women. The calculation and reduce the overnight lipid profile is usually normal and the basal from the start. adiponectin is high. Type B insulin Improvements in HbA1c levels have resistance is often associated with been less convincing so far. This may the autoimmune condition systemic be related to factors such as a lack of “The NSIRS team provided…diagnosis and lupus erythematous. highly specialist care (and) support for formal diabetes education, distance obtaining metabolic surgery, which has She was treated with intravenous from the service or simply small given me a second chance to live life…” methyl prednisolone, rituximab and oral numbers of patients (in our service) prednisolone. Four weeks after initiation of started on pumps. Within the service immunosuppressive therapy, Andrea had we now have seven patients using 54mmol/mol and she was able to stop stopped insulin entirely and was taking insulin pumps. insulin treatment. However, the HbA1c metformin only. She will require 1g We plan to ensure that has risen slightly to 60mmol/mol so she rituximab every six months for two years. all patients who have approved funding has increased her oral medication. Her Since her treatment Andrea has for pump therapy in the NSIRS attend BMI has reduced to 17.85kg/m². Her gained weight (BMI 28.44kg/m²), and a carbohydrate awareness workshop. liver MRI shows that her liver fat has is feeling much better. Her last HbA1c We also plan to measure halved and hepatic stiffness has was 32mmol/mol without any diabetes the effect on quality of life of using significantly reduced. treatment. She has been advised to anxiety and depression questionnaire maintain blood glucose monitoring, scores pre and post pump therapy. Reduction in energy intake in around three to four times a week to In time, with increased numbers, the patients with lipodystrophy observe for any deterioration. She may benefits of insulin pump therapy in this One of the most important lipodystrophy require further rituximab infusions if group may become clearer. treatments is the reduction of fat and she shows any signs of relapse.

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Metabolic changes in patients with insulin psychology support specifically receptoropathy compared with more common for the NSIRS. causes of insulin resistance Looking to the future Common Insulin Resistance/ We are looking into addressing the Insulin Receptoropathy Lipodystrophies need for support related to body image issues after patients highlighted this Insulin as an unmet need. We hope to pilot Glucose a support group later in the year to provide: Triglyceride • strategies and mechanisms to deal with unwanted attention HDL Cholesterol and comments • relaxation techniques to reduce Adiponectin anxiety • practical advice for clothing IGFBP-1 • the opportunity to meet other SHBG people with lipodystrophy.

We have delivered a series of talks across England in Liverpool, Leicester, Insulin receptoropathies Not just the physical Durham, London (the Association of Other examples of insulin feelings British Clinical Diabetologists), Warwick receptoropathy are those due to People with chronic conditions have (HEART UK), and at the Cambridge mutations in the insulin receptor for an increased risk of developing mental Insulin Pump course in a bid to raise example those diagnosed in childhood health problems, with around 30% awareness of severe insulin resistance with Donohue Syndrome and Rabson- known to have a mental health syndrome nationally. Presentations in Mendenhall Syndrome and less severely condition. A rare disease increases the south-west are planned for 2019. affected patients who are usually this percentage to around 69%. A Our website is being updated to diagnosed in puberty/adulthood, also review of the clinical notes of NSIRS include links to further information known as Type A resistance. Patients patients showed that 40% of patients about lipodystrophy and other severe with insulin receptoropathies usually with lipodystrophy are prescribed insulin resistance syndromes for have a normal lipid profile and a high antidepressants compared with both patients and healthcare adiponectin, which is the opposite to 10% to 20% in general Type 2 professionals. the metabolic abnormalities in patients diabetes settings7,8. Over the coming year, we will with lipodystrophies and/or the more People with lipodystrophy often also be evaluating proactive cardiac common obesity-related insulin report traumatic experiences, such surveillance for lipodystrophy patients resistance syndromes. as bullying at school or work, abusive due to the increased risk of coronary comments about their appearance artery disease. from strangers or accusations of eating Finally, after identifying a disorders or parental neglect due to disproportionate geographical spread their low BMI. All of this can have a of patients we are now also offering People with significant psychological impact affecting telephone clinics for follow-up lipodystrophy often self-esteem, relationships and self- appointments in a bid to reduce report traumatic management behaviour. In addition, the burden of long journeys. being such a rare condition, there is experiences, such limited awareness or understanding of Referral to the NSRIS as bullying at lipodystrophy and other syndromes of The NSIRS is provided for patients with school or work, severe insulin resistance among some lipodystrophy and/or severe insulin healthcare professionals. This can result resistance. The service is funded by comments about in a lack of trust, or feelings of frustration NHS England and there is no charge to their appearance and anger, especially if affected patients referring clinical commissioning groups from strangers... are given conflicting advice. or hospital Trusts. Improving Access to Psychological The referral criteria are as follows: this can have a Therapies (IAPT) has enabled us to offer • Donohue Syndrome or Rabson psychological better support for mental health issues Mendenhall Syndrome with confirmed (see also article on page 18, this issue). severe hyperinsulinaemia* impact, affecting The psychological wellbeing service is • clinically diagnosed lipodystrophy self-esteem, now available to NSIRS patients on a (generalised or partial) relationships and referral basis, but it does not meet the • unexplained severe insulin resistance needs of everyone in our clinic, as they with: BMI<30kg/m2 (BMI Z score <=+3 self-management are not all local. We are continuing to in children) and acanthosis nigricans behaviour collect data to support funding for and/or severe hyperinsulinaemia*

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32-37_Insulin-Resistance_SA4.indd 36 18/02/2019 12:16 Insulin molecule – causes problems for patients who are resistant

*severe hyperinsulinaemia = fasting If you would like to refer a Acknowledgements insulin>150pM or peak plasma insulin on patient to our service, or if you Thank you to our patients for their oral glucose tolerance testing >1,500pM. would like to discuss a patient willingness to provide their stories In conclusion, syndromes of severe with us, please either email and photographs, and to Media insulin resistance are debilitating and insulinresistanceservice@ Studio for taking the photographs. potentially life-threatening and diagnosis addenbrookes.nhs.uk We are also grateful to our is often delayed. Therapeutic options or phone 01223 768455. colleagues at the National Severe are limited, but are likely to improve. Insulin Resistance Service at Bariatric surgery, metreleptin • Patient support groups: Addenbrookes: Claire Adams, replacement therapy, GLP-1 agonists, Lipodystrophy UK . Catherine Flanagan, Lisa Gaff, Humulin-R U500 insulin and other www.lipodystrophy.co.uk Samantha Gorman, Dr Audrey concentrated insulin formulations, insulin Lipodystrophy UK Facebook Melvin, Professor Sir Stephen pump therapy and/or immunosuppression group. www.facebook.com/ O’Rahilly, Eirini Pizirtzidou, Tracy may be useful in selected patients. Single groups/LipodystrophyUK/ Randall, Professor David Savage, gene causes are increasingly being Changing Faces. Ellie Wilber, Dr Rachel Williams recognised. Specialist referral is advised. www.changingfaces.org.uk and Elaine Withers.

REFERENCES 1 Melvin A, Adams C, Flanagan C gastric bypass: case report and bypass surgery in a patient with et al (2017). Roux-en-Y gastric literature review. Journal of familial partial lipodystrophy. bypass surgery in the Gastrointestinal Surgery 21 (4), Diabetes Care 29 (6), 1380–1382 management of familial partial 739–743 7 Mast R, Rauh S, Groeneveld L et al lipodystrophy Type 1. The Journal 4 Kozusko K, Tsang V, Bottomley W (2017). The use of antidepressants, of Clinical Endocrinology and et al (2015). Clinical and molecular anxiolytics and hypnotics in Metabolism 102 (10), 3616–3620 characterisation of a novel PLIN1 people with Type 2 diabetes and 2 Ciudin A, Baena-Fustegueras J, frameshift mutation identified in patterns associated with use: the Fort J et al (2011). Successful patients with familial partial Hoorn Diabetes Care System treatment for the Dunnigan-type lipodystrophy. Diabetes 64 (1), Cohort. BioMed Research familial partial lipodystrophy with 299–310 International 1–8 Roux-en-Y gastric bypass. Clinical 5 McGrath N and Krishna G (2006). 8 Wang Y, Lopez J, Bolge S et al Endocrinology 75 (3), 403–404 Gastric bypass for insulin (2016). Depression among people 3 Grundfest-Broniatowski S, Yan J, resistance due to lipodystrophy. with Type 2 diabetes mellitus. US Kroh M et al (2017). Successful Obesity Surgery 16 (11), 1542–1544 National Health and Nutrition treatment of an unusual case of 6 Utzschneider K and Trence D Examination Survey (NHANES).

FPLD2: the role of Roux-en-Y (2006). Effectiveness of gastric BMC Psychiatry 16 (1), 88 PHOTO: ADOBE STOCK

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