Insulin Discovery : The First Centenary Celebration Symposium

By Insulin Discovery : The First Centenary Celebration Symposium

This commemorative volume published on the occasion of the Symposium on “Discovery of Insulin: The First Centenary Celebration” is dedicated to the memory of Dr. J.P. Bose.

28.08.1894 – 18.02.1970

The Indian Physician who first established the first Diabetic Clinic in whole of Asia in the year 1923 at the School of Tropical Medicine, Calcutta. And he was also the first physician in the country to have used insulin for the first time in a patient with diabetes, in the British dominated India much before her independence. Dr. J.P. Bose did his MB (1919) from the University of Calcutta. He was the Officer-in-charge, Diabetes Research Centre, School of Tropical Medicine, Kolkata. Dr. Bose authored a “Handbook on Diabetes Mellitus and Its Modern Treatment” which ran four editions and multiple publications and monographs in various medical journals on diabetes.

Our respectful homage to this great soul on the centenary celebration of insulin, the wonder molecule for the treatment of diabetes. Insulin Discovery : The First Centenary Celebration Symposium

Contents

1. President's Address 1

Dr. Salil Kumar Pal

2. Secretary's Address 2

Dr. Sarmishtha Mukhopadhyay

3. Editor's Address 3

Dr. Kaushik Pandit

4. A Tale of Discovery of Insulin 4

Dr. Mounam Chattopadhyay, Dr. Pranab Kumar Sahana

5. Journey of insulin 8

Dr. Avivar Awasthi, Dr. Anirban Sinha

6. Economics of Insulin 11

Dr. Soumik Goswami

7. 360 degree Basic Overview of Insulin: From the Gene to 14 Stem cells to Receptor to Signalling in Health and Disease

Dr. Sreenath Ravindranath

8. Insulin Therapy in Renally Challenged Patients 19

Dr Arijit Singha, Dr Rana Bhattacharjee

9. Insulin Therapy in Liver Disease 25

Dr. Sunetra Mondal

10. Insulin in Elderly 34

Dr. Avivar Awasthi, Dr. Animesh Maiti

All photographs used in this volume is under the kind courtesy of the Thomas Fisher Rare Book Library, University of Toronto Insulin Discovery : The First Centenary Celebration Symposium

President's Address

Together with my colleagues and friends, on the occasion of Insulin Discovery Day, I wish you a very warm welcome. It is my pleasure to address you on this platform.

Let me start by saying that it is honor and privilege to be the President of DAIWB. I am deeply grateful to my Distinguished members, Executives and Office staff for their commitments. It is a matter of pride for me to be able to be on the forefront of such a dedicated and inspiring group of people.

With the continuous support and guidance of the members I am confident that we can overcome the impending challenges of the Covid pandemic.

DAIWB is celebrating 101 years of Insulin discovery. Needless to say, this discovery has allowed us to treat diabetes for the first time in the History of Medicine. For nearly 4 decades, from 1921, insulin was our go-to form of therapy and remains ubiquitous today.

Sedentary lifestyle is responsible for obesity in younger generation, thus causing an increased susceptibility to type 2 diabetes. Fortunately, in the last two decades we have gained a better understanding of the pathophysiology of Type 2 diabetes and witnessed tremendous advancements in its management.

Apart from that, we have a large chunk of the population in the undiagnosed stage diabetes or in the pre-diabetic state. So, we have to take responsibility and have a more holistic approach in the management of diabetes, which may be initiated in the stage of prediabetes.

Looking back at the year we've had, no one can deny that it has been one of the most difficult ones seen so far. Nonetheless, the wisdom gained will help us to continue to fight to mitigate the losses caused by this pandemic.

I once again congratulate the DAIWB family for the Insulin Discovery Day Celebration.

I have every confidence that together, we – members, faculty, staff, patients and supporters – will attempt to move the association and our profession forward in the upcoming critical period of the society.

Long live DAIWB

Dr. Salil Kumar Pal President, Diabetic Association of India, West Bengal

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Secretary's Address

On behalf of Diabetic Association of India, West Bengal, my warm greetings to all the distinguished members, endocrinologists, diabetes practitioners, physicians and non-physicians on this auspicious occasion of Insulin discovery Centenary Celebration. I am privileged and honored to get the opportunity to take the charge of secretary of this prestigious organization in this landmark year.

Hundred years ago, Frederick Banting, a young scientist dreamt to save the lives of millions of people suffering from the disease “Diabetes” by extracting the hormone “Insulin”. His dream became reality when Professor J.J.R Macleod provided the infrastructure, young energetic Charles Best became his dedicated work partner and experienced researcher J.B Collip offered his helping hand to guide in a goal directed way. Nobel Prize was awarded two years later, but the voyage didn't stop. The scientists contributed over last hundred years at different point of time to make insulin more physiologic and less immunogenic, more flexible and less painful, more acceptable and less dreadful thus overcoming the apprehension as well as myths related to insulin. The journey which started with syringes, passing through pens, moving towards pills and patches is now tending to end towards artificial pancreas, without losing its relevance for a single day. Beginning of insulin was a revolution by scientists, its continuation made it religion of diabetics and diabetes practitioners, and its futuristic exploration will bring renaissance to impart a best quality of life with diabetes.

Diabetic Association of India, West Bengal celebrates insulin discovery day on 30th July every year very religiously. This year we are in the midst of COVID Pandemic. Unforeseen Pandemic abruptly changed our life style. Pandemic has taken away so many valuable things- growing economy, valuable freedom and priceless lives. But while fighting with the odds and coping up with the new norms, we have learnt and achieved a lot. Now we keep the social distance physically, but maintain the social bondage digitally throughout the nation and even beyond. We are privileged now to have so many national Endocrine faculties participating and celebrating 100 years of Insulin Discovery with us in digital platform. We are honored to have authors even from outside Bengal nurturing our souvenir pages. I express my heartfelt thanks to all faculties and authors of souvenir to make our small but dedicated effort successful. My warm regards for my seniors, colleagues and friends without whose guidance and help this celebration would never become possible. Lastly, I pay my homage to those COVID martyrs who sacrificed their lives as frontline soldiers and inspired us by fighting with only one weapon, the stethoscope.

I strongly believe that Diabetic Association of India, West Bengal will continue this age old tradition of celebration of insulin discovery day for next hundred years too. Quality of life with diabetes will be as good as quality of life without diabetes and that day is not very far…

We shall overcome all the socio-economic, cultural and psychological obstacles to create a diabetes friendly world…

We shall overcome some day….

Stay safe and stay healthy!

Long live Diabetes Association of India, West Bengal

Dr. Sarmishtha Mukhopadhyay Secretary, Diabetic Association of India, West Bengal

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Editor's Address

Dear Reader,

A great event is unfolding almost unseen and unsung within this depressing landscape of COVID-19. The magic molecule of the century or a marvel of the medical research which not only had saved millions of hapless diabetics especially before the entry of the effective and safe oral antihyperglycemics into the scene is completing its century of appearance into the clinical arena. The wonder molecule has also been at the centre stage of not one but six of the Nobel Prize in various categories be it Medicine or Physiology, Chemistry and others. It may not be an exaggeration to say that insulin not only has saved millions of lives but also changed the quality of life by billions of both type 1 and type 2 diabetes for the last century of its existence. We appreciate that while keeping its fundamental skeleton unaltered, the basic research into its molecular structure and altering it to suit the need of the patients of diabetes is one of the significant consequential advance in medicine of this century. We are sure this juggernaut will continue to bring forth newer insulins in a new garb to match the expectations of millions of our patients in near future as well.

It gives us immense pleasure to collate some articles by some members of Diabetic Association of India, West Bengal to have a bird's eye view on the landscape of the developments that have been taking shape in the last one hundred years and a bit of crystal ball gazing. I am sure this would be an important read for all our members from Diabetic Association of India as well as people who would be keen to visit our website where it is located.

Needless to mention, I am really grateful to all the authors of the articles who had toiled hard to produce this seminal piece. I am thankful to the able and dynamic President and Secretary of the organisation to allow me to collate these articles and who have taken this opportunity also to pen a few lines themselves to commemorate this epoch making incidence in the history of progress of modern medical science.

This collection though a drop in the ocean is hopefully inspire the future generations of Physicians to get motivated to excel in their own field and provide further advancements in this field of insulin and beyond.

I pay my homage to the discoverers of this magic molecule, a hormone to say the least at this hour of celebration of the centenary of insulin discovery. Let's all unite for the betterment of our patients and provide better days for them in future.

Long live Diabetic Association of India, West Bengal.

Dr. Kaushik Pandit Editor, Commemorative Volume Member, Diabetic Association of India, West Bengal

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A Tale of Discovery of Insulin

Dr. Mounam Chattopadhyay, Post-Doctoral Trainee Dr. Pranab Kumar Sahana, Associate Professor Department of Endocrinology, NRS Medical College, Kolkata

Discovery of insulin was one of the greatest breakthroughs in the history of medical sciences, which continued to save millions of lives around the world. Before insulin was discovered in 1921, people with diabetes didn't live for long and the most effective treatment was to put patients with diabetes on very strict diets with minimal carbohydrate intake. This could buy patients a few extra years but couldn't save them.

Insulin is the chief anabolic hormone of our body which keeps our blood glucose in control. The name 'insulin' was first coined by Edward Albert Sharpey-Schafer in 1916 for a hypothetical molecule produced by pancreatic islets. Jean de Meyer had already used a similar ward “insuline” for the same substance though in 1909 unaware of the nomenclature by Sharpey-Schafer. The word “insulin” is derived from a Latin word “insula” which means Islet or Island. This refers to the origin of Insulin from b cells of Islets of Langerhans situated in pancreas of most vertebrates.1

There was a long path on the way to the final discovery to insulin chequered by different landmark events and discoveries. It all began when German pathologist and physiologist Paul Langerhans (1847-1888), a then medical student in Berlin, identified clumps of tissues throughout the pancreatic parenchyma under microscope in 1869. They were named as the Islets of Langerhans although little was known about their functions. French pathologist Gustave- Édouard Laguesse (1861-1927) and Archibald Langerhans, son of Paul Langerhans, later surmised that they might secrete some substance which may help in digestion.7 To test this hypothesis to test, two German physicians Oskar Minkowski (1858-1931) and Joseph von Mering (1849-1908), removed the pancreas from a healthy dog in 1889 and to their surprise they found sugars in the dog's urine. Later in 1901 American physician Eugene Lindsay Opie (1873-1971) went on to declare that “Diabetes mellitus when the result of a lesion of the pancreas is caused by destruction of the islands of Langerhans and occurs only when these bodies are in part or wholly destroyed”.8 Over the next few years, between 1906 and 1916, the researchers tried to extract the substance from pancreas but their works remain interrupted by the ongoing World War I. German physician George Ludwig Zuelzer (1870-1949), American Physiologist Ernest Lyman Scott (1877-1966), American Biochemist Israel Kleiner (1885- 1966) and finally a Romanian physiologist Nicolae Paulescu (1869-1931) attempted to inject aqueous pancreatic islet extract in diabetic dogs normalizing their glycosuria or hyperglycaemia to some extent. His findings were laid down in his publication "Research on the Role of the Pancreas in Food Assimilation".9

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By 1920, attempts had been made to extract insulin from ground-up pancreas cells, but they'd all proved unsuccessful. The challenge was to find a way to extract insulin from the pancreas without it being destroyed in the process.

In October 1920, Frederick Banting – a Canadian surgeon – read an article that suggested insulin-producing cells in the pancreas are slower to deteriorate than other pancreas tissue. Banting realised that this might allow for the removal of insulin by breaking down the pancreas in a way that would leave just the cells that produce insulin intact.

But Banting wasn't a scientist and knew he couldn't test his theory alone. On 7 November 1920 he paid a visit to a top professor at the University of Toronto, John Macleod. They put their minds together and began to work on a plan.

Banting (1891-1941) arrived at the conclusion that it was possible to extract the islet secretion successfully as long as there are digestive secretions from the pancreatic acini. As he was a Surgeon, he was already aware of the fact that if somehow the pancreatic ducts could be blocked, it would lead to the atrophy of the pancreas leaving only behind the islets. After that a purified extract could easily be obtained from Islets of Langerhans. Thereafter Banting scribbled a note and kept it to himself which later became famous-“Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosuria.”10 He shared this idea with John James Rickard Macleod (1876-1935), Professor of Physiology, at the University of Toronto. But Macleod was not entirely convinced. He had doubt regarding success of this proposed research plan as Banting had then no research background nor was he updated with the recent research literature. However, he agreed to provide Banting with a laboratory at Toronto to test out his ideas. Two undergraduates were suggested by Macleod for assistance in Banting's research, Charles Herbert Best (1899-1978) and Clarke Noble. But unfortunately Banting required only one of them. So, there was a confusion as to who would be chosen and whom to reject. So, they went for a coin toss. Best won the toss and took charge of the first shift.11

On 17 May 1921 Banting, Best and Macleod first got together to begin their research and set about figuring out how to remove insulin from a dog's pancreas. Finally on 30 July 1921, Banting and Best successfully isolated an extract (which they termed “Isleton”) from the islets of the duct-tied dog. They injected that into a diabetic dog and to their satisfaction blood glucose came down by 40% in just 1 hour. They presented these results to Macleod in the fall of 1921. Macleod suggested the experiments to be repeated with more dogs to confirm the findings further. So he moved Banting and Best to a better equipped laboratory and paid Banting a wage from his research grants so that he can continue the research. The second round of experiments were also satisfactory and Macleod published the findings privately in November in Toronto. As duct-tying dogs were time consuming, Banting tried alternative

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methods e.g. isolating the extract from fetal calf pancreas or adult cow and he remained successful again. They were ready to test it in clinical setting in a human subject. Macleod being highly optimistic suspended all his other research activities and dedicated himself solely in the attempt to purify insulin. Although he invited Canadian Biochemist James Collip (1892-1965) for assistance in this regard, he left the project soon after as Banting and Best were not ready to work with him and considered him an “interloper”.12 On January 11, 1922, Leonard Thompson, a 14-year-old Diabetic boy, was first injected with insulin at Toronto General Hospital. Unfortunately, he suffered severe allergic reaction given the impurity of the extract and further dosing was cancelled. James Collip, a biochemist, joined the group to work on purifying insulin so it would be safe enough to be tested in humans. With his help, a more concentrated and pure form of insulin was developed, this time from the pancreases of cattle Purified ox-pancreas extract was injected as a second dose of insulin on January 23. It was able to eliminate glycosuria without producing any untoward effects. Blood glucose decreased from 520 mg/dl to 120 mg/dl. Glycosuria dropped from 71 to 9 g; ketonuria disappeared.13 Elizabeth Evans Hughes Gossett, one of the first people in the world, to be treated with insulin for her Type 1 Diabetes by Banting as his private patient.14 The first treated patient in US was James D Havens and he was treated at Rochester with insulin imported from Totonto by Dr. John Ralston Williams (1874-1965).15 On the basis of these successes, on 12th December 1921, Banting and Best reported the results of the discovery of insulin to the American Society of Physiology. In November, 1922, Eli Lilly's head chemist, George B. Walden (1895-1982) discovered isoelectric precipitation and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public. Finally in 1923, the Nobel Prize committee acknowledged the extraction of insulin by a team of researchers at the University of Toronto and awarded Nobel Prize to Frederick Grant Banting and John James Rickard Macleod. They were awarded the prize in Physiology or Medicine.16 Banting was disappointed that Best was not mentioned and immediately shared his prize money and credit to Best. Macleod also did the same with Collip. On October 9, 1923, Frederick Banting, Charles Best, and James Collip were granted the patent for “Extract Obtainable from the Mammalian Pancreas or from the

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Related Glands in Fishes, Useful in the Treatment of Diabetes Mellitus, and a Method of Preparing It” or Insulin, U.S Patent No. 1,469,994.The patent was sold to University of Toronto for one dollar only. About the sale of the patent of insulin for $1, Banting reportedly said, “Insulin belongs to the world, not to me.”

In this way, insulin walked a long way from a seedling stage of tied-dog extract to the most purified and clinically appropriate forms of insulin analogues mitigating the devastating consequences of Diabetes Mellitus worldwide and helped in gaining better quality of life and survival of the individuals suffering from the disease.

References:

1. Vecchio I, Tornali C, Bragazzi NL, Martini M (2018-10-23). "The Discovery of Insulin: An Important Milestone in the History of Medicine". Frontiers in Endocrinology. 9: 613. doi:10.3389/fendo.2018.00613. PMC 6205949. PMID 30405529 2. Paulesco NC (August 31, 1921). "Recherche sur le rôle du pancréas dans l'assimilation nutritive". Archives Internationales de Physiologie. 17: 85–109. 3. Banting, Frederick G. (31 October 1920). "Note dated Oct 31/20 from loose leaf notebook 1920/21". University of Toronto Libraries. 4. Wright JR (December 2002). "Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine". CMAJ. 167 (12): 1391–96. PMC 137361. PMID 12473641 5. Rosenfeld L (December 2002). "Insulin: discovery and controversy". Clinical Chemistry. 48 (12): 2270–88. doi:10.1093/clinchem/48.12.2270. PMID 12446492 6. Banting, Frederick G. (Dec 1921 – Jan 1922). "Patient records for Leonard Thompson". University of Toronto Libraries. 7. Banting, Frederick G. (16 August 1922). "Chart for Elizabeth Hughes". University of Toronto Libraries. 8. Woodbury, David Oakes (February 1963). "Please save my son!". University of Toronto Libraries. 9. "The Nobel Prize in Physiology or Medicine 1923". The Nobel Foundation. 10. Stretton AO (October 2002). "The first sequence. Fred Sanger and insulin". Genetics. 162 (2): 527–32. doi:10.1093/genetics/162.2.527. PMC 1462286. PMID 12399368.

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Journey of insulin

Dr. Avivar Awasthi, Post-doctoral Resident Dr. Anirban Sinha, Associate Professor Department of Endocrinology, Medical College, Kolkata

Prior to insulin, the French pharmacist Apollinaire Bouchardat, during the siege of Paris (1870) noticed that there was an improvement in patients with diabetes due to calorie restriction forced by the siege. This sugar-free diet was later popularized as the “Bouchardat's treatment”. Two more diets were popularized in America; the Allen diet was introduced by Frederick Madison Allen, and the “starvation diet” which was introduced by Elliott Proctor Joslin. The discovery of insulin was not as serendipitous as it would seem. Eugene Gley, French physiologist and endocrinologist injected a diabetic pancreatectomized dog with aqueous extract of pancreas. He noted that glycosuria was reduced and symptoms of diabetes significantly improved. Similar experiments were conducted in 1921 by Banting and Best. Zuelzer experimented on pancreatic extracts and termed it as Acomatol. He later published a paper stating that pancreas preparation was suitable for the treatment of diabetes. In 1916, Paulesco concluded that the injection of aqueous solution of pancreatic extract allowed improvement in experimentally induced diabetes. Similar findings were being made in America and Germany at the turn of the 20th century. EL Scott almost came to the discovery of Insulin in 1912, however using alcohol in the pancreatic extract moved him away from the prodigious discovery. The journey of insulin started when Banting hypothesized and starting surgically excising pancreas from dogs. He began working in a lab led by John James Richard MacLeod. His aim was to isolate the hormone secreted by the islets of Langerhans. Aided by two young assistants, Best and Nobel, they extracted pure pancreatic extract from the islets. The Early clinical experiences with insulin experiment dogs started exhibiting signs of hyperglycemia. They started injecting pancreatic extracts of varying compositions to the dogs to assess the outcomes. The teacher and his assistants were joined by James Bertram Collip who further purified the pancreatic extract to produce the “Collip extract”. This extract was injected in a few subjects with type 1 diabetes (T1DM). One notable subject was the 14 years old Leonard Thompson. He was given 7.5 cc of this pancreatic extract in each buttock and there was a 25% decrease in blood glucose. He was later discharged; however, his blood sugars were never well controlled. His daily requirements of the pancreatic extract were 85 units per day.

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In 1936, Hans Christian Hagedorn, BN Jensen, NN Krarup, and J Wodstrup discovered that the duration of action of insulin could be prolonged by addition of protamine. This was further modified by David Ayelmen Scott, who created the first insulin-protamine zinco complex which had a glucose lowering effect upto 48 hours. Standardization of insulin syringes was completed and production was commenced in 1949. Amorphous “lente” insulins were developed in 1952-53. Till 1955, insulin was being extracted and treated with substances to increase its duration of action.

The world was working with a compound whose exact sequence was not known. This changed in 1956 when Frederick Sanger fully sequenced bovine insulin and discovered its exact amino-acid composition. The physical structure on insulin was fully mapped by Dorothy Mary Crowfoot-Hodgkin shortly thereafter. Insulin was successfully synthesized in 1963 in USA. The same year, the first insulin pump was designed. It was the size of a bag-pack.

Like Leonard Thompson in 1922, Sandy Atherton became the first diabetic patient treated with recombinant DNA human insulin 60 years later.

Updike and Hicks implanted a miniature electrical transducer in an animal to monitor glucose continuously. The 1970s harked the introduction of the idea of continuous intra- cutaneous injection of insulin (CSII). Integration of CSII with continuous glucose monitoring (CGM) continued in the subsequent years. The first CGM was FDA approved further down the line in 1999.

The first portable insulin pump, the Autosyringe was developed in 1978. The first needle-free insulin delivery system was introduced a year later. The “basal-bolus” concept of insulin administration and intensive insulin therapy were coined 2 years later.

Insulin was tinkered and modified further and analogue insulins were developed during the 80s and 90s. Insulin pen delivery systems were introduced in 1985. The portable insulin pump MiniMed 506 was released by Medtronic in 1992.

Insulin Lispro was introduced in 1996, while insulin Aspart and Glulisine were released in 2000 and 2004, respectively. Long-acting insulin Detemir was approved in 2005 whereas Insulin Degludec was approved in 2015. The first inhaled insulin, Exubra was approved in 2006, followed by Afrezza in 2014. However, inhaled insulins have not attained the popularity that was expected from such a novel insulin delivery system.

The first artificial pancreas was given FDA approval based on a trial in 124 type 1 diabetics in 2016. The weekly insulin Icodec was introduced in 2020. The second artificial pancreas which was developed by the University of Virginia received FDA approval in 2020. Results of the iLet artificial pancreas single hormone (insulin aspart or lispro) versus dual hormone (insulin,

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dasiglucagon) were published in diabetes care in 2021. There is on-going research into glucose responsive insulin (GRI) also known as smart insulin. There are many candidates for smart insulins which are in various phases of clinical trials. Another landmark discovery was oral insulin. Like smart insulins, there are many candidates for oral insulin that are in various phases of clinical trials.

We have certainly come a long way from ligating the main pancreatic ducts of pancreatectomized animals and extracting islet extracts. The discovery of insulin was a hallmark in medicine which led to the single most dramatic reduction in mortality due to a disease. Before the 1920s diabetic ketoacidosis (DKA) was universally fatal. By the 1930s, the mortality had fallen to 29%, and to less than 10% by the 1950s. Today, the mortality due to DKA is less than 2%.

Cost serves as the biggest limitation for using modern insulin delivery techniques. Hopefully within the coming years, bionic pancreas and oral insulins will be the mainstay of insulin treatment of diabetes.

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Economics of Insulin

Dr. Soumik Goswami, Tutor Department of Endocrinology, NRS Medical College, Kolkata

“Economics is a very dangerous science” – John Maynard Keynes

Irony looms large as we celebrate with much fanfare the centenary of the discovery of insulin. In 1923, the three discoverers sold the patent to manufacture the drug to the University of Toronto for a total of just three Canadian dollars as they felt that it would be unethical to profit from a life-saving discovery. Today, this life-saving drug has become one of the most expensive and unaffordable drugs with prices of insulin variants having tripled in the past decade in many countries, including India.

What began as an ethical venture rather than a commercial one has turned into an out and out economic behemoth. The global insulin drugs market is expected to grow from $25.88 billion in 2020 to $27.2 billion in 2021 at a compound annual growth rate of 5.1%.

However, insulin does not seem to follow the basic principles of economics. While the price of a product usually falls over time as competitors offer better alternatives, or new advances make past breakthroughs less valuable, the same has not happened with insulin. Let us consider an example. The 1990s to early 2000s saw the launch of several mobile phone models and insulin analogues. While mobile phones became more affordable with the availability of newer models, the price of the same insulin analogues have gone up several times even after adjusting for inflation. More importantly, while one can survive without a phone, the same cannot be said for insulin, particularly for those with type 1 diabetes.

Interestingly, the newer insulin analogues which are 4-6 times costlier than conventional human insulins have yet to prove their superior efficacy in glucose reduction and modest reduction in hypoglycaemia, particularly nocturnal hypoglycaemia, remains their major

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documented benefit. Most of this research is industry-funded and from developed countries however. Similarly, pen devices using costlier insulin cartridges when compared to syringe- vial improve ease of use but do not lead to better glycaemic control.

What about the “common man's insulin” – human insulin? Using a conservative estimate of a person using only 30 units of human insulin per day, the yearly cost is about INR 5500/- (including the cost of insulin syringes) which would be worth 15 days of an average Indian's income considering India's per capita income of 1,26,00/- in 2020-2021. A 2016 study evaluating insulin access in public and private health sectors in Bengaluru, India, found that the lowest-paid unskilled worker in the state would pay 1.4 to 9.3?days' wages to purchase monthly supply of insulin, depending on the type and healthcare sector. What adds to the concern further is the apprehension that traditional human insulins might be phased out by pharmaceutical majors as they market newer insulin analogues.

About 25% of patients are known to ration insulin to save costs and there are tragic reports of deaths occurring in individuals with type 1 diabetes. Intriguingly, in India, while domestic insulin makers come under direct price control, companies that import and sell are prescribed a profit margin over the cost of production. Imported insulin is priced 20-30% higher than that produced domestically but since it is a prescription only drug which users do not experiment with, its demand is price inelastic and the consumer is not automatically driven towards the cheaper option. However, multinationals argue that they sell technologically superior products and spend more on research and innovation than domestic players.

There are multiple reasons for the cost being high, one of them being the extremely low market competition in insulin production. Three companies dominate more than 90% of the global as well as Indian insulin market by value and traditionally they raise the price of insulin about 10% each time a new type of insulin clears the third and the final stages towards regulatory approval. Although logic dictates that the absence of patent protection should reduce the price of insulin, patent laws allow the few dominant insulin makers to patent incremental changes to their products thereby evergreening their molecules and making it harder for cheaper generics to enter the market.

To have a balanced view, we need to look at the other side of the story too. Revenue generated by insulin sales for pharmaceutical companies not only cover their own manufacturing and marketing costs but also cover losses on research molecules that never make it to market. In a capitalist economy, private companies would not manufacture and market drugs unless there are financial rewards. Naturally therefore economic rewards rather than patient welfare are drivers of drug research and only a fraction of profits is invested in research and development while the majority fills the coffers of the shareholders.

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If we consider an utopian world where insulin manufacturers direct most of their profits into research, the question remains whether higher prices for existing medicines should fuel innovation that might either never materialize or make the newer insulin even more unaffordable. As an alternate economic solution, research could be socialised to keep the price of life saving medicines within the reach of the common man.

The World Health Organisation (WHO) asks physicians to strike a balance between implementing the best-established standard of care and feasibility in resource-limited settings. WHO is betting on driving down the cost of insulin by encouraging more generic drug makers to enter the market but the results have not yet been salutary.

For patients who cannot afford insulin analogues, making adjustments with their lifestyle makes use of human insulins viable in most. In those who cannot afford even human insulin, the only way out is to rely on hospitals which provide insulin free of cost or at highly subsidised rates. But again, diabetes is different for all, bringing up the need for efficient, affordable and accessible options.

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360 degree Basic Overview of Insulin: From the Gene to Stem cells to Receptor to Signalling in Health and Disease

Dr. Sreenath Ravindranath, Consultant Endocrinologist Caritas Hospital, Thellakom, Kottayam, Kerala

The glucose, lipid, and energy homeostasis of the human body is regulated by insulin signalling, predominantly via action on liver, skeletal muscle, and adipose tissue. As the individual moves from the fed to the fasted state very precise modulation of this pathway is vital for adaption. A proper and coordinated biological response to insulin in different tissues is ensured by the positive and negative modulators acting on different steps of the signalling pathway, as well as the diversity of protein isoform interaction. The insulin/insulin-like growth factor (IGF)-signalling system regulates the storage and release of energy during feeding and fasting and a large portion of somatic growth. Insulin suppresses hepatic gluconeogenesis and promotes glycogen synthesis and storage in liver and muscle, triglyceride synthesis in liver and storage in adipose tissue, and amino acid storage in muscle and thereby plays a significant role in regulation of blood glucose.

The mechanism of action of insulin remained unclear for at least 30 years after the discovery of insulin in 1921. Later in 1950, insulin was found to increase the membrane permeability to glucose, which was then thought to be the basis for its glucose-lowering effect. A membrane receptor for insulin was discovered in 1971 by Jesse R o t h a n d c o l l e a g u e s . V e r y unexpectedly insulin receptor was Photograph of C. H. Best and F. G. Banting ca. 1924 found to be phosphorylated on tyrosine residues in response to insulin binding. Until this discovery tyrosine phosphorylation had been thought of exclusive to oncogenes. This effectively shifted the attention from the cell surface to the intracellular pathways mediating the diverse actions of the receptor. White and Kahn cloned the first of four IR substrate (IRS) proteins. They are a family of adaptor proteins which help to convert the tyrosine phosphorylation signal into a lipid kinase signal by recruiting the catalytic subunit of the enzyme PI3K. The PI3K enzyme generates the triphosphorylated inositol which is required to activate the serine/threonine kinase AKT. The

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riddle of how the tyrosine phosphorylation signal is converted into a serine/threonine phosphorylation signal was solved by the identification of AKT8 as an insulin-activated serine/threonine kinase. Most actions of insulin required the phosphorylation of serine/threonine residues on various substrates. The discovery of AKT clarified the distal steps in insulin signalling, such as the modulation of glucose uptake by glucose transporter type 4 (GLUT4), glycogen synthesis by glycogen synthase kinase 3 (GSK3), protein and fat synthesis by mTOR and gene expression by forkhead family box O (FOXO).

Metabolism, cell growth and differentiation are influenced by insulin action. Virtually all mammalian cells respond to insulin as they possess insulin receptors. The major tissues targeted by insulin's effects on metabolism include: muscle, where insulin promotes glucose uptake and protein synthesis; adipose tissue, where insulin promotes glucose and fatty acid uptake and inhibits lipolysis; the liver, where insulin promotes glucose utilization, suppresses glucose production, and promotes triglyceride synthesis; and neurons, where it promotes anorexigenic and locomotor signals. Macrophages, endothelial cells and insulin-producing pancreatic b-cells are additional insulin target cells with a metabolic function. Some of the key mediators of insulin signalling like PI3K and AKT are activated downstream of other growth factor receptors. Growth factor receptor-bound protein 2 (GRB2) and ERK9 involved in some mitogenic pathways are activated by insulin, creating a network of interacting signalling pathways.

Various isoforms of Akt/protein kinase B (PKB), p70 ribosomal S6 kinase (S6K), serum- and glucocorticoid-induced protein kinase (SGK), as well as several isoforms of protein kinase C (PKC), particularly the atypical PKCs mediate most of the physiological effects of PI3K- generated PIP3. AGC kinase family members share similar structure and mechanisms of activation via phosphorylation of two serine and threonine residues. The phosphorylation and activation of the AGC kinase members regulated by PI3K is mainly done by the major upstream kinase PDK-1 ( 3-phosphoinositide-dependent protein kinase 1). PDK-1 activation is triggered by binding of PDK-1 to membrane bound PIP3. Phosphorylation and activation of AGC protein kinases at serine/threonine residues, such as Thr-308 for Akt is accomplished by PDK-1. However, Akt phosphorylation at Ser-473 is required for full activation, and this is accomplished by the mammalian target of rapamycin complex 2 (mTORC2). Three different isoforms of serine/threonine protein kinases encoded by different genes exist for the Akt/PKB family of proteins .Interaction of these isoforms with PIP3 and recruitment to the plasma membrane is made possible with the PH domain, which all the isoforms possess. Insulin-sensitive tissues most abundantly have Akt2 isoform and it seems to play a predominant role in mediating insulin action on metabolism.

PDK-1 and mTORC2 when activated by Akt lead to the phosphorylation and activation of many downstream targets. The mTORC1 complex is activated as a result of phosphorylation of

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tuberous sclerosis complex protein 2(TSC-2) by Akt. The mTORC1 complex then phosphorylates and inhibits 4E-binding protein 1 (4E-BP1), activates ribosomal protein S6 kinases S6K1 and S6K2 and SREBP1, and leads to the regulation of a network of genes controlling metabolism, protein synthesis, and cell growth. Akt acts on several other substrates involved in insulin action. The TBC1D4, and its homolog TBC1D1, are phosphorylated by Akt and are involved in insulin- and contraction-mediated glucose uptake. The glycogen synthase kinase 3 is phosphorylated and inactivated by Akt, resulting in glycogen synthase activation and glycogen accumulation in liver. The ability of PGC-1a to promote gluconeogenesis and fatty acid oxidation is impaired by the phosphorylation of PGC- 1a. The effect of insulin to inhibit lipolysis in adipocytes and insulin secretion in b cells is mediated by phosphorylation of phosphodiesterase 3B (PDE3B) by Akt resulting in its activation and in a decrease in cyclic AMP levels.

At supraphysiological concentrations, glucose itself is able to alter insulin sensitivity in muscle and fat, as well as decrease insulin secretion from b cells. Adipose tissue and hepatic insulin action is impaired as a result of hyperglycemia induced by decreased glucose transport in skeletal muscle. Insulin resistance is induced through several pathways, which are all believed to be linked to oxidative stress. The flux through the polyol pathway is increased as a result of hyperglycemia which causes JNK activation and increases the hexosamine-biosynthetic pathway. This promotes insulin resistance in adipose tissue, skeletal muscle, liver, and pancreas in part by O-GlcNAcylation of IRS proteins. O-GlcNAcylation of IR also occurs due to hyperglycemia, which impairs receptor dimerization and of Foxo1 leading to increased gluconeogenic gene expression. Hyperglycemia also activates the PKC pathway. By inducing de novo synthesis of DAG through activation of PKC pathway, hyperglycemia causes insulin resistance by forming a multimolecular complex, including receptor of AGE/IRS-1/Src.

The ectopic accumulation of lipids in metabolic syndrome, especially fatty acids (FA), causes insulin resistance via multiple mechanisms. Owing to muscle-specific overexpression of lipoprotein lipase there is increased hydrolysis of circulating triglycerides leading to skeletal muscle insulin resistance. Multiple lipid intermediates have been shown to promote insulin resistance. In obesity elevated circulating free fatty acids (FFA) are observed which induces activation of JNK, IKK, and PKC and IRS-1 Ser-307 phosphorylation. The fatty acid palmitate promotes insulin resistance by inducing endoplasmic reticulum (ER) stress, cytokine production, and activates JNK. All these highlight the crucial interplay of lipids with respect to dietary interventions in insulin signalling . Insulin resistance is also induced by the lipid metabolite DAG . By activating PKC-q and inducing IRS-1 Ser-307 phosphorylation increased muscle DAG (intramyocellular lipid) leads to muscle insulin resistance. In obese and diabetic patients increased plasma concentration of the sphingolipid ceramide is observed and is

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associated with severe insulin resistance. PKC and JNK activation by ceramide induces insulin resistance and, thus, inhibition of ceramide synthesis ameliorates insulin resistance. The alteration of membrane–lipid composition also affects insulin signalling. In type-2 diabetic patients an increase in the saturated-to-unsaturated FA ratio is observed and is thought to reduce membrane fluidity and insulin sensitivity. Moreover, an increase in the phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratio in endoplasmic reticulum leads to the activation of ER stress and is associated with insulin resistance.

The key component which promotes obesity-associated insulin resistance is the chronic low grade inflammatory state associated with obesity. In response to caloric overload adipose tissue expansion occurs and is associated with an increase in immune cell infiltration and a subsequent proinflammatory response. Adipocytes and macrophages are important in this scenario. Both the cell types are capable of secreting proinflammatory cytokines and inducing insulin resistance. Adipocytes secrete chemokine MCP-1 which drives macrophage accumulation into adipose tissues and induces insulin resistance. Increased secretion of cytokines, such as TNF-a, IL1ß, or IL-6, by both immune cells and adipocytes is observed with obesity and induces insulin resistance via multiple mechanisms, including activation of Ser/Thr kinases, decreasing IRS-1, GLUT4, and PPARg expression, or activation of SOCS3 in adipocytes.

As we celebrate the 100th anniversary of the discovery of insulin, the signalling pathways of this important hormone have largely been defined. In the living organism, the integrated signals arising from insulin's pleiotropic actions in multiple tissues cannot be easily reconciled with intrinsic cellular pathways. These signalling pathways contain Photograph of F. G. Banting in his laboratory several points of regulation, signal divergence, and cross talk with other signalling cascades. To mediate the variety of insulin biological responses the complexity of this signalling system is essential. Various phosphatases and inhibitory proteins negatively regulate many steps in insulin signalling. One of the great challenges remaining is deciphering the complexity of insulin-resistance pathogenesis. In most instances insulin resistance is triggered by cellular perturbations, such as lipotoxicity, inflammation, glucotoxicity, mitochondrial dysfunction, and ER stress,

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which lead to deregulation of genes and inhibitory protein modifications, resulting in impaired insulin action. Better understanding of the causes and mechanisms leading to insulin resistance as well as identifying new molecules impacting insulin signalling and new levels of control, will be essential for a more effective treatment of type-2 diabetes and associated diseases.

References: 1. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J. 1922;12:141–146. 2. Freychet P, Roth J, Neville DM., Jr Insulin receptors in the liver: specific binding of (125 I)insulin to the plasma membrane and its relation to insulin bioactivity. Proc Natl Acad Sci USA. 1971;68:1833–1837. 3. Ebina Y, et al. The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985;40:747–758. 4. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96. 5. Cleasby ME, Reinten TA, Cooney GJ, James DE, Kraegen EW. Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Mol Endocrinol. 2007;21:215–228. 6. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;339:172–177. 7. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6:a009191. 8. Weisberg SP, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808. 9. Xu H, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–1830. 10. Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, et al. 2000. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6: 924–928.

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Insulin Therapy in Renally Challenged Patients

Dr Arijit Singha, Post-doctoral Trainee Dr Rana Bhattacharjee, Asst. Professor and In-charge, Hormone Assay Lab. Department of Endocrinology and Metabolism, IPGME&R, Kolkata

Impaired renal function is a reality in a patient with diabetes mellitus. With the global epidemic of diabetes, the incidence of diabetic kidney disease is rising. It accounts for the most common cause of the end-stage renal disease (ESRD) globally1. In a prospective population-based cohort study, Sukkar L et al observed that 22.6% of patients with diabetes develop chronic kidney disease over a median period of 5.7 years. The incidence also increases with older age and associated comorbidities2.

The understanding of kidney disease in diabetes is evolving with a noticeable shift from the classical dogma of 'stages of albuminuria' to a more nuanced heterogeneous process (3,4). There is evidence of an increased incidence of acute kidney injury (AKI) in patients with both type 1 and type 2 diabetes mellitus5,6. It is now realized that like CKD, AKI may be considered as a bona fide complication of diabetes3. The pathophysiology of renal impairment is multifactorial and complex. Once hyperglycemia develops, there are structural changes to glomerulus (hypertrophy, nodular sclerosis) and extra-glomerular (interstitial fibrosis, arteriolar hyalinization, tubular changes) areas of the kidney leading to slow but progressive decline in GFR even with optimized glycemic control7. Non-diabetic kidney diseases can also affect people with diabetes. Managing blood glucose levels in DKD is Photograph of Banting with dog ca. 1922 difficult. This is a unique condition in which there is a decrease in insulin resistance as well as a delay in insulin clearance8. Furthermore, azotemia, dialysis, and increased susceptibility to sepsis often lead to wide glycemic variability.

Insulin produces the greatest reduction of HbA1C among all antidiabetic agents and is quite indispensable in the armamentarium of the management of DKD. In a search for prescription practices in patients with different stages of CKD in India, insulin is the second most commonly prescribed drug9. As in patients without DKD, insulin administration requires knowledge, expertise, and empathy. It should be remembered that apart from glycemic control, insulin possibly does not have any additional reno-protective effect. However, the theoretical anabolic effect of insulin in this catabolic condition is desirable. There are several 19 Insulin Discovery : The First Centenary Celebration Symposium

issues to be considered about insulin therapy in diabetic kidney disease: lThere is no established guideline in relation to preferred type of insulin, recommended regimen, or titration algorithms. lThere is a paucity of published data lAltered glucose homeostasis and insulin pharmacokinetics is common lIncreased risk of hypoglycemia in many individuals lVery high insulin requirement in some patients lThe frequent presence of diminished visual acuity (cataract, diabetic retinopathy) may hinder the self-administration of insulin.

Thus, insulin therapy in patients with DKD should be individualized and needs clinical judgments. Insulin resistance and glucose homeostasis in DKD Insulin resistance prevails in patients with DKD. There is an inverse correlation between HOMA-IR and eGFR10. Importantly, in both type 1 and type 2 diabetes mellitus patients, insulin resistance is associated with increased salt sensitivity, elevated blood pressure, albuminuria, and deterioration of renal function11. Moreover, increased insulin resistance may further contribute to protein catabolism and malnutrition11. The etiology of insulin resistance in DKD is multifactorial and includes several risk factors e.g., physical inactivity, metabolic acidosis, anemia, adipokine derangements, active vitamin D deficiency, oxidative stress, and chronic inflammation. Post-receptor defect and altered GLUT 4 expression may also lead to decreased glucose uptake in skeletal muscle10. The kidney plays a significant role in glucose homeostasis, removing 20% of glucose from the circulation in the fed state. In the fasting state, 20% of the circulatory glucose is contributed by renal gluconeogenesis. Moreover, a significant amount of filtered glucose is reabsorbed by the SGLT2 in the proximal convoluted tubule12. Insulin pharmacokinetics in DKD Endogenous insulin, secreted from pancreatic beta cells, enters the portal circulation and the majority of it (~ 75%) undergoes first-pass metabolism in the liver. The remainder enters the systemic circulation and ~30% of the total circulating insulin is presented to the kidney. In healthy individuals, the renal clearance of insulin is 200 ml/min13. It is estimated that the kidney removes 6 to 8 U of endogenous insulin per day and little amount (~1%) of filtered insulin appears in the urine14. A decrease in the insulin clearance is observed in patients with eGFR <40 ml/min/1.73m2 and a significant prolongation of the insulin half-life is demonstrable when eGFR falls to <20 ml/min/1.73m213. It should be remembered this sequence of insulin metabolism may not be true in the case of exogenous insulin which is administered subcutaneously or intravenously. As there is no fast- pass metabolism in the liver, kidneys are exposed to a higher concentration of insulin and

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most of the exogenously administered insulin is degraded in the kidney. Therefore, deterioration of the kidney function significantly delays insulin clearance. Once dialysis starts, remarkable improvement in insulin clearance usually occurs15.

Insulin secretion is diminished in patients with chronic kidney disease. High serum parathyroid hormone (PTH) induces increased cytoplasmic calcium concentration in pancreatic beta cells resulting in the closure of the ATP-sensitive K channel. There is also a possible role of active vitamin D deficiency and evidence suggests that the intravenous administration of 1,25 (OH)2 vitamin D3 in patients on maintenance dialysis improves early and late phases of insulin secretion13.

Insulin therapy in patients with CKD The evidence for the use of insulin in diabetes and CKD is limited. Due to insufficient data, improper study design, and systemic bias, the Cochrane review failed to conclude about the superiority of any particular insulin preparation, mode of administration, or dose titration16. However certain observations are important to consider: lThe reduction in insulin requirement is similar in type 1 and insulin-treated type 2 diabetes mellitus17. lShort-acting Insulin analogs have the advantage of rapid absorption, greater meal-time flexibility, and possible reduction in hypoglycemia18. lThere is no significant correlation between the severity of renal dysfunction and pharmacokinetics of insulin aspart. However, insulin lispro and glulisine need dose reduction12. lThere is a significant improvement in fasting plasma glucose, HbA1C, quality of life, and hypoglycemic episodes in patients on glargine compared to NPH insulin19. lReduction of the dose of glargine and detemir up to 27-30% may be required19. lThe ultralong acting pharmacokinetic properties of insulin degludec are preserved. It is also associated with a lower frequency of hypoglycemia compared to glargine or detemir20.

Based on the available literature, common clinical practices in India, a consensus has been reached on the dose adjustment of insulin therapy21. The expert group also suggested the initial total daily dose across the GFR in both type and type 2 diabetes mellitus (Table 1).

GFR (ml/min/1.73m2) % Reduction of total daily dose Insulin dose (Units/Kg/day)

Type 1 DM Type 2 DM

<60 No reduction 1.0 0.5

60-15 25% 0.75 0.3-0.4

<15 50% 0.5 0.25

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Insulin therapy in patients on hemodialysis The majority of ESRD patients on hemodialysis receive insulin therapy to achieve glycemic control. The principles of insulin therapy are the same for dialysis patients as for the general diabetic population. Dialysis is associated with diminished insulin resistance and decreased insulin requirements. It has been shown earlier that approximately one-third of insulin- treated type 2 diabetic patients became insulin-independent after 1 year of hemodialysis. However, hypoglycaemic events tended to be higher than in the predialysis period. Importantly, long-term chronic HD therapy does not affect the glycemic status and the use of high glucose solution in HD sessions is useful to prevent hypoglycemia without affecting HbA1C18. Several different insulin regimens can be used with comparable glycemic control. Examples include twice-daily intermediate-acting insulin with regular insulin before breakfast and before dinner or long-acting insulin with regular insulin two to three times a day before meals. It should be remembered that the insulin dose should be adjusted on the day following hemodialysis. Sobngwi E et. al. observed a 25% reduction in basal insulin requirement the day after dialysis compared to the previous day. However, the dose of bolus insulin remained unchanged22.

Insulin therapy in patients on peritoneal dialysis Intraperitoneal administration of insulin is attractive because it is more physiological. Like endogenous insulin, it enters the portal circulation. It is also associated with lower hyperinsulinemia than subcutaneous insulin. However, higher doses of administered insulin are associated with unfavorable lipid profile, risk of peritonitis and fibroblastic proliferation as well as the development of specific complications such as hepatic subscapular steatonecrosis and malignant omentum syndrome. Hence, the use of intraperitoneal insulin administration has been fallen out of favor, and switching from subcutaneous to the intra- peritoneal route is no longer recommended18.

Insulin therapy in acute-on chronic renal failure in patients with DKD As discussed earlier, patients with diabetes are more prone to develop acute renal failure. It may present as a complication of diabetic ketoacidosis or hyperosmolar non-ketotic coma. Several other risk factors specific to diabetic populations are identified e.g., intravenous contrast use, papillary necrosis complicating urinary tract infections, use of RAAS blocker in atherosclerotic renal arteries, etc. Management of blood glucose in acute renal failure is critical. Insulin requirement may increase or decrease in this situation5. There is no established guideline of insulin therapy in acute renal failure. The patients should be managed as 'critically ill', and treated with intravenous insulin administration and frequent glucose monitoring.

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Blood glucose monitoring in DKD The monitoring of glycemic status should be done in accordance with established standard guidelines. The blood glucose should be monitored frequently (three or times more) in patients with multiple daily insulin injections. The optimal frequency of SMBG is not reported but should be enough to reach sufficient glycemic goals.

Measurement of HbA1C is a standard of care to monitor long-term glycemic control. However, it is less reliable in advanced CKD patients. Other biomarkers such as glycated albumin or fructosamine assay provide no advantage over HbA1C and are thus not recommended. According to the KDIGO guideline, HbA1C targets should be <6.5% to <8% in patients not treated with dialysis. The target should be individualized. For patients with multiple comorbidities, higher HbA1C targets of <7.0% to <8% might be preferred, whereas a lower target of <6.5% may be considered to prevent the onset of complications. HbA1C should be measured two to four times a year depending upon the adequacy of glycemic control4. There is no recommended HbA1C cut-off for patients on dialysis.

A continuous glucose monitoring system provides real-time data on glycemic variability. It is useful to support treatment decisions for patients who have HbA1C values discordant with SMBG or clinical symptoms. It is also recommended when initiating new antihyperglycemic therapy and adjusting current medications to achieve glycemic targets while avoiding hypoglycemic episodes. CGMS has been validated as a reliable and accurate marker of blood glucose in uremic patients on dialysis23.

Conclusion The treatment of diabetes and kidney disease with insulin is a combination of art and science. Altered insulin pharmacokinetics, anorexia, gastroparesis, underlying sepsis, etc. often lead to wide fluctuations in blood glucose. The treatment would aim to optimize blood glucose levels with careful avoidance of hypoglycemia. An individualized approach of glycemic targets is preferable. Finally, well-designed randomized control trials in different stages of chronic kidney disease are needed to establish the best possible insulin regimen.

References 1. Shrishrimal K, Hart P, Michota F. Managing diabetes in hemodialysis patients: observations and recommendations. Cleve Clin J Med. 2009:649-55. doi: 10.3949/ccjm.76a.09054 2. Sukkar L, Kang A, Hockham C, Young T et al. Incidence and Associations of Chronic Kidney Disease in Community Participants With Diabetes: A 5-Year Prospective Analysis of the EXTEND45 Study. Diabetes Care. 2020:982-990. doi: 10.2337/dc19-1803. 3. Advani A. Acute Kidney Injury: A Bona Fide Complication of Diabetes. Diabetes. 2020:2229-2237. doi: 10.2337/db20-0604. 4. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020:S1-S115. doi: 10.1016/j.kint.2020.06.019. 5. Woodrow G, Brownjohn AM, Turney JH. Acute renal failure in patients with type 1 diabetes mellitus. Postgrad Med J 1994;70:192- 4. doi: 10.1136/pgmj.70.821.192. 6. Girman CJ, Kou TD, Brodovicz K et al. Risk of acute renal failure in patients with Type 2 diabetes mellitus. Diabet Med. 2012;29:614-21. doi: 10.1111/j.1464-5491.2011.03498.x.

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7. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021;17:319-334. doi: 10.1038/s41581-021-00393-8. 8. Escott GM, da Silveira LG, Cancelier VDA et al.Monitoring and management of hyperglycemia in patients with advanced diabetic kidney disease. J Diabetes Complications. 2021;35:107774. doi: 10.1016/j.jdiacomp.2020.107774. 9. Prasad N, Yadav AK, Kundu M et al. Prescription practices in patients with mild to moderate chronic kidney disease in India, Kidney International Reports 2021 10. Spoto B, Pisano A, Zoccali C. Insulin resistance in chronic kidney disease: a systematic review. Am J Physiol Renal Physiol. 2016 ;311:F1087-F1108. doi: 10.1152/ajprenal.00340.2016. 11. Karalliedde J, Gnudi L. Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a determinant of diabetic kidney disease. Nephrol Dial Transplant. 2016 ;31:206-13. doi: 10.1093/ndt/gfu405. 12. Gianchandani RY, Neupane S, Iyengar JJ et al. Pathophysiology and management of hypoglycemia in end-stage renal disease patients: a review. Endocr pract. 2017 Mar;23(3):353-362. doi: 10.4158/EP161471.RA. 13. Ritz E, Adamczak M, Wiecek, A. Carbohydrate Metabolism in Kidney Disease and Kidney Failure. Nutritional Management of Renal Disease. 2013;17-30. 10.1016/B978-0-12-391934-2.00002-3. 14. Meyer C, Dostou J, Nadkarni V, Gerich J. Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism. Am J Physiol. 1998 ;275:F915-21. doi: 10.1152/ajprenal.1998.275.6.F915. 15. Rabkin R, Simon NM, Steiner S, Colwell JA. Effect of renal disease on renal uptake and excretion of insulin in man. N Engl J Med. 1970;282:182-7. doi: 10.1056/NEJM197001222820402. 16. Lo C, Toyama T, Wang Y et al. Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. Cochrane Database Syst Rev. 2018 24;9:CD011798. doi: 10.1002/14651858.CD011798.pub2. 17. Biesenbach G, Raml A, Schmekal B et al. Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin- treated Type 2 diabetic patients. Diabet Med. 2003 ;20:642-5. doi: 10.1046/j.1464-5491.2003.01025.x. 18. Iglesias P, Díez JJ. Insulin therapy in renal disease. Diabetes Obes Metab. 2008;10:811-23. doi: 10.1111/j.1463- 1326.2007.00802.x. 19. Toyoda M, Kimura M, Yamamoto N et al. Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis. J Nephrol. 2012;25:989-95. doi: 10.5301/jn.5000081 20. Kiss I, Arold G, Roepstorff C, Bøttcher SG, Klim S, Haahr H. Insulin degludec: pharmacokinetics in patients with renal impairment. Clin Pharmacokinet. 2014 ;53:175-83. doi: 10.1007/s40262-013-0113-2. 21. Rajput R, Sinha B, Majumdar S et al. Consensus statement on insulin therapy in chronic kidney disease. Diabetes Res Clin Pract. 2017;127:10-20. doi: 10.1016/j.diabres.2017.02.032. 22. Sobngwi E, Enoru S, Ashuntantang G et al. Day-to-day variation of insulin requirements of patients with type 2 diabetes and end- stage renal disease undergoing maintenance hemodialysis. Diabetes Care. 2010;33:1409-12. doi: 10.2337/dc09-2176. 23. Marshall J, Jennings P, Scott A et al.. Glycemic control in diabetic CAPD patients assessed by continuous glucose monitoring system (CGMS). Kidney Int. 2003;64:1480-6. doi: 10.1046/j.1523-1755.2003.00209.x.

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Insulin Therapy In Liver Disease

Sunetra Mondal, Consultant Endocrinologist

Introduction The liver plays a vital role in carbohydrate metabolism. There is a complex interaction between liver dysfunction and diabetes mellitus (DM).Glucose intolerance is seen in up to 80% of patients with chronic liver disease (CLD) and 96% of those with cirrhosis.1-3 The management of diabetes mellitus in patients with liver diseases is challenging and insulin forms the cornerstone of therapy in most patients.

DM and liver diseases There are multiple direct and indirect associations between DM and liver diseases. They share pathophysiologic links and the concurrent presence of both affect cardio-metabolic risks and mortality of each other. Patients with DM are found to have a spectrum of liver diseases ranging from non alcoholic fatty liver diseases, cirrhosis with portal hypertension

Photograph of J. B. Collip, C. H. Best, Mrs. F. N. G. Starr, and F. G. Banting

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sometimes leading to end stage liver disease and hepatocellular carcinoma(HCC).4,5 In patients with hepatic dysfunction related to chronic hepatitis C, T2DM was found to be an independent predictor of complications including ascites, spontaneous bacterial peritonitis, renal dysfunction and HCC.6 An increased prevalence of mortality from CLD and HCC has been reported in patients with DM compared to those without. On the other hand, liver cirrhosis accounted for upto 12.5% of deaths in patients with T2DM.7

1. Diabetic hepatopathy (Liver disease linked to DM): T2DM can worsen NAFLD/NASH or cause diabetic hepatosclerosis and glycogenic hepatopathy.

2. Hepatogenous diabetes (Liver disease causing DM)

3. Etiologies leading to both DM and liver impairment : Hemochromatosis, Hepatitis C virus , autoimmune hepatitis

4. Treatment related : Many of the antihyperglycemic agents cause hepatic impairment whereas treatment directed to liver disorders like glucocorticoids in autoimmune liver diseases or immunosuppressants used post liver transplant can lead to DM.

Hepatogenous diabetes (HD) follows the diagnosis of cirrhosis, in contrast to T2DM in patients with CLD where it precedes the diagnosis of cirrhosis. Microvascular and macrovascular complications in HD are less frequently seen than in T2DM.5 HD may be associated with a higher risk of hypoglycemia than with T2DM with compensated cirrhosis . The risks of adverse events arising from oral hypoglycemic agents like metformin associated lactic acidosis is also higher in HD.5

Role of Insulin in the pathogenesis of liver diseases lDefects in insulin action: Insulin resistance has been identified as a major pathogenetic factor in the pre-cirrhotic stages of CLD. Glucose uptake is reduced in the peripheral tissues but not in splanchnic areas. Insulin resistance (IR) in can lead to adipose tissue dysfunction causing increased production of pro-inflammatory cytokines, decreased anti-inflammatory cytokines, and excessive lipolysis leading to production of free fatty acids (FFA) that are taken up by the liver. Both FFA and inflammatory cytokines cause oxidative stress mediated damage to hepatocytes and and activate fibrogenesis via stellate cells .Hyperinsulinemia can also lead to activation of oncogenic pathways involving STAT3, insulin like growth factor (IGF) and c-JunN-terminal kinase1 (JNK1) pathway.8 Hyperglycemia can also directly promote lipogenesis by directly promoting tricyclic acid (TCA) pathway leading to the generation of acetyl CoA (substrate for both gluconeogenesis and de novo lipogenesis) or indirectly by promoting expression of lipogenic genes like acetyl CoA carboxylase - ACC, fatty acid synthase. Serum insulin levels in HD are significantly higher than in T2DM. However, whether

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hyperinsulinemia is the cause for IR or an adaptive response is yet unknown. Proposed causes for hyperinsulinemia include reduced hepatic clearance of insulin as well as portosystemic shunting .8,9 lb-cell Dysfunction: b-cell dysfunction is also seen in cirrhosis. It can be due to the concurrent injury of liver and pancreatic b-cells by excess FFA, alcohol, iron deposition in NAFLD, alcoholic cirrhosis and hemochromatosis respectively. Hepatitis C virus can impair b-cell function through either direct (toxic) or indirect (autoimmune) effects.11 lA recent study has demonstrated that reduction of insulin secretion rather than insulin sensitivity correlates with severity of the liver disease.12 In decompensated cirrhosis, there might be a direct “toxic” effect on pancreatic islets due to increase in level of substances that undergo hepatic synthesis or degradation.5

Classification of liver impairment

The Child-Pugh score, used to assess the overall prognosis of CLD, is also used to guide the use and dose drugs in patients with CLD ( Table 1 ) .While DM is not included in any of the prognostic classification systems, the presence of DM is known to worsen the outcome of liver disease of any etiology. Insulin is the only antihyperglycemic agent that can be used in all stages of liver disease.

Therapeutic use of Insulin in liver disease a. Pharmacokinetic considerations : The major site for insulin metabolism is the liver which accounts for approximately 40%–50% of endogenous insulin metabolism. A study on exogenous insulin uptake by the human cirrhotic liver found that fractional hepatic extraction of insulin was only 13 ± 5% in cirrhotic patients, which differed significantly from the fractional hepatic extraction found in controls (51 ± 5%; p < 0.001).13 Upto 60% of patients with liver cirrhosis require insulin. b. Comparison to other Anti Hyperglycemic Agents i. Cirrhosis of liver Insulin is the first-line agent in the management of diabetes in chronic liver disease. It can be used in decompensated CLD and can be used in any stage of hepatic impairment. However, long term studies of the efficacy and safety of of different insulin is still lacking. It must be noted that hepatorenal syndrome often coexist with CLD and concomitant renal impairment makes the use of oral hypoglycemic agents further challenging. Many of the oral hypoglycemic agents are metabolized by the liver or have hepatotoxic effects. In moderate or severe CLD (Child Pugh's stage C), none of the available agents except insulin are deemed safe whereas in Child Pugh stage B, it is necessary to avoid certain agents like pioglitazone while high levels of

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caution must be exercised while using most other agents for drug class-specific risks which include hypoglycemia with insulin secretagogues, lactic acidosis with metformin. There is scarcity of data with most other agents in moderate or severe hepatic impairment. ii. NAFLD spectrum disorder While insulin is one of the most effective and safe antihyperglycemic agent , there is evidence to suggest that the use of the oral hypoglycemic agent pioglitazone could cause some histological improvement in patients with NASH and the American Association for the study of liver disease (AASLD) recommends its use in patients with T2DM and NASH.14,15However, pioglitazone is contraindicated if the ALT levels exceed 2.5 times he ULN.5 There is some evidence to suggest that metformin causes some improvement in steatosis and retards progression to HCC but studies found discordant results and metformin is not currently recommended by the AASLD for NASH.15, 16 There is emerging evidence of benefit with GLP1Ra (Liraglutide) and SGLT2i in NASH.17 Insulin while reducing hyperglycemia however lacks any pleiotropic benefit in patients with NASH. iii. Autoimmune hepatitis Glucocorticoids, mostly prednisolone, are indicated in many patients with active autoimmune hepatitis. They cause predominantly postprandial hyperglycemia. While NPH insulin is the preferred insulin in glucocorticoid induced hyperglycemia and matches its time profile of action, those with significant fasting hyperglycemia would benefit most from a basal bolus regimen. iv. Hepatocellular Carcinoma Metformin has been shown to retard progression of HCC. Some chemo-preventive role has been seen with DPP4i, GLP1RA, pioglitazone, SGLT2i and gliclazide. Insulin has theoretical tumor-proliferative actions and a meta-analysis suggests that insulin increases the risk of progression to HCC in patients with hepatitis C virus infection though its effect on HCC progression is not clear.18 v. Hepatitis C virus associated liver disease Hepatitis C causes defects in both insulin action and secretion. Inactivation of GLP-1 through up-regulation of DPP-4 is postulated as a mechanism for insulin resistance in HCV infection which makes DPP4i an interesting therapeutic option in HCV related CLD along with metformin for its anti tumor effects to decrease the risk for HCC.4 In decompensated cases; insulin remains the treatment of choice. vi. Hepatic encephalopathy Metformin and acarbose have shown protective properties against hepatic

28 Insulin Discovery : The First Centenary Celebration Symposium

encephalopathy by inhibiting intestinal glutaminase and reducing ammonia levels respectively.19, 20 However, metformin portends risks of lactic acidosis whereas acarbose has limited efficacy in patients unable to tolerate oral feeds. Insulin remains the safest agent. vii. Acute hepatic impairment Acute onset liver disease is mostly seen in the settings of infections with sepsis, hepatotoxic drugs or poisons. There is concomitant dehydration and renal impairment in many of them, and many have altered consciousness with poor oral intake. There is a very high risk of hypoglycemia due to lack of glycogen reserve as well as impaired gluconeogenesis and the PK/PD alteration of most oral hypoglycemic agents in this setting is unknown, making short acting insulin the safest choice for hyperglycemia. c. Choice of insulin – type , regimen and device Rapid acting analog insulin such as insulin lispro, aspart and glulisine are useful for controlling postprandial hyperglycemia and their pharmacokinetics is not significantly altered as a result of hepatic dysfunction and thus may offer equivalent or improved glycemic control compared to standard insulin, with a lower risk for hypoglycaemia, particularly nocturnal and severe hypoglycemia.

Among the rapid acting analogs, insulin aspart showed no differences in PK in patients with hepatic impairment.21 Among long acting insulin, insulin degludec has an ultra-long effect lasting ~ 42 hours. In a study on 24 individuals with different degrees of hepatic dysfunction, following a single subcutaneous dose of 0.4 U/kg insulin degludec, no differences were observed in area under the 120-h serum insulin degludec concentration–time curve (AUC0-120), Cmaxion, and apparent clearance(CL/F) for individuals with impaired versus normal hepatic function; thus demonstrating a stable pharmacokinetic profile. No differences with respect to drug absorption or clearance in cirrhotic patients and no episode of serious hypoglycemia were observed.22 However, in a case series on efficacy of detemir insulin on patients with NAFLD, very high insulin doses were required, and significant weight gain was problematic.23 The fact that the rapid acting analogs and particularly ultra-rapid acting analogs like FiASP can be given just after meal is of benefit to patients with advanced CLD who have severe nausea and reduced appetite and may dose-adjust the insulin just after their meals depending on their intake.

Prescribing information (PI)s of most insulin including glargine, glulisine, aspart 30/70, degludec, and degludec/ aspart suggest frequent dose adjustments based on blood glucose to minimize hypoglycemia or hyperglycemic excursions in patients with hepatic impairment.3

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Among the different regimen, basal plus or basal bolus regimen consisting of a peak less long acting analog given in the night along with two or three pre-prandial rapid acting analogues seem to be the most reasonable choice in patients with liver disease. In few patients with recurrent hypoglycemia, only pre-prandial rapid acting analogs may be sufficient. For those with severe coagulopathy, care must be taken to reduce the number of pricks for glucose monitoring and number of insulin injections if feasible and pen devices with thinner needles are more prudent to use. There is some evidence of benefit with the use of continuous subcutaneous insulin infusion through portable pump in a small case series of four cirrhotic patients with T2DM who had inadequate blood glucose control with conventional insulin therapy.24 d. Glycemic monitoring and dosing of insulin While insulin therapy is considered as the safest and most effective therapy in patients with liver dysfunction, a number of factors make it difficult to predict insulin dose requirement in patients with liver disease with wide fluctuations in blood glucose levels and episodes of hypoglycemia. Insulin requirement in decompensated liver disease patients may be decreased due to reduced gluconeogenesis and reduced hepatic catabolism of insulin; however, it might be increased to compensate for insulin resistance. Other factors include nausea, anorexia, sarcopenia and use of beta blockers in those with portal hypertension which increase the risk for hypoglycemia and increase chances of hypoglycemic unawareness due to masking of symptoms arising from sympathetic activation. In compensated cirrhosis, the effects of insulin resistance seem to predominate and insulin requirements are usually high whereas in patients with decompensated cirrhosis, requirement is low due to a reduction in hepatic clearance and gluconeogenesis. Overall, insulin requirement in patients with cirrhosis should start at low doses with close monitoring due to the risk of hypoglycemia. e. Diet in CLD and Insulin Diet in patients with CLD usually involves carbohydrate intake of up to 50–70% of daily calorie intake, specially in patients with hepatic encephalopathy in whom it is necessary to keep the protein intake low and often, vegetarian protein is preferred leading to inadvertent intake of excess carbohydrates.3 Patients mostly take small evenly distributed meals throughout the day. Therefore, small doses of rapid-acting insulin analogs prior to meals usually help to control the postprandial surge. Long acting analogues may be indicated for those with fasting hyperglycemia. f. Safety Concerns Hypoglycemia remains the prime concern with the use of insulin in CLD and needs close monitoring with dose adjustments (discussed in section d). Weight gain ranging from 3 to 9 kg has been reported following the initiation of insulin

30 Insulin Discovery : The First Centenary Celebration Symposium

therapy in patients with liver disease.4 Much of it is attributable to fluid retention, intrinsic anabolic properties of insulin, the central effects on appetite and the behavioral changes related to fear of hypoglycemia. This weight gain is predominantly represented by fat mass and is of concern for those with metabolic syndrome as it may further exacerbate the underlying insulin resistance.4,9 Data from observational studies suggest an association between treatment with insulin and hepatocellular carcinoma development in patients with T2DM but further, larger studies are needed.4

Current status in the guidelines Most of the existing guidelines on type 2 Diabetes Mellitus and on liver disease including the ones by the American Diabetes Association (ADA) and consensus guideline by EASLGD highlight the need for insulin therapy in T2DM patients with CLD with frequent dose adjustment and careful glucose monitoring.26, 27 An Indian consensus statement also supports insulin in hepatic decompensation patients with necessary dose adjustments and prefers the use of insulin analogs.3

Table 1 : The Child Pugh system of classification of liver diseases and use of insulin vs other agents

Points 1 2 2

Ascites Absent Slight Moderate

Bilirubin (mg/dl) <2 2-3 >3

Albumin(mg/dl) >3.5 2.8-3.5 <2.8

Prothrombin time in seconds <4 4-6 >6 over control or INR <1.7 1.7-2.3 >2.3

Encephalopathy None Grade 1-2 (Mild to Moderate) Grade 3–4 ( Severe)

Total score 5 – 6 7 – 9 10 Child Pugh class A B C

Whether OHAs and Yes Avoid Pioglitazone and Vildagliptin Avoid most OHAs. GLP1Ra can be used Caution with Metformin, insulin Alpha glucosidase inhibitors secretagogues, SGLT2i may be used if tolerated

Whether Insulin can be Yes Yes Yes, caution for high risk of used hypoglycemia

31 Insulin Discovery : The First Centenary Celebration Symposium

References

1. Blendea MC, Thompson MJ, Malkani S. Diabetes and chronic liver disease: Etiology and pitfalls in monitoring. Clin Diabetes 2010;28:139.

2. Hickman IJ, Macdonald GA. Impact of diabetes on the severity of liver disease. Am J Med 2007;120:829-34.

3. Gangopadhyay KK, Singh P. Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment. Indian J Endocr Metab 2017;21:341-54

4. Ahmadieh H, Azar ST. Liver disease and diabetes: association, pathophysiology, and management. Diabetes Res Clin Pract. 2014 Apr;104(1):53-62. doi: 10.1016/j.diabres.2014.01.003. Epub 2014 Jan 14. PMID: 24485856.

5. Ray S, Pal P. Diabetes and Liver Disease: A Bi-directional Association— Clinical Impact and Management Strategies. Int J Diab 2020;14-30.

6. Kwon SY, Kim SS, Kwon OS, Kwon KA, Chung MG, Park DK, Kim YS, et al. Prognostic significance of glycaemic control in patients with HBV and HCV-related cirrhosis and diabetes mellitus. Diabet Med 2005; 22: 1530-5

7. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999 Mar;29(3):664-9.

8. Dongiovanni, P., Rametta, R., Meroni, M., & Valenti, L. (2015). The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development – a potential therapeutic target? Expert Review of Gastroenterology & Hepatology, 10(2), 229–242. doi:10.1586/17474124.2016.1110018.

9. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol 2009; 15: 280-8.

10. García-Compean D, Jaquez-Quintana JO, Maldonado-Garza H. Hepatogenous diabetes. Current views of an ancient problem. Ann Hepatol 2009; 8: 13-20.

11. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007; 30: 734-43.12. Grancini V, Trombetta M, Lunati ME, et al. Contribution of ß-cell dysfunction and insulin resistance to cirrhosis associated diabetes: role of severity of liver disease.JHepatol.2015;63(6):1484-90.

13. Letiexhe MR, Scheen AJ, Gerard PL, Bastens BH, Pirotte J, Belaiche J, Lefèbvre PJ. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J Clin Endocrinol Metab 1993; 77: 1263-8. 85. Petrides AS. Liver disease and diabetes mellitus. Diabetes Rev 1994; 2: 2-18.

14. Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, Ünalp A, Tonascia J, Nash Crn Research Group. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemporary clinical trials. 2009 Jan 1;30(1):88-96.

15. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-57.

16. Li Y, Liu L, Wang B, Wang JU, Chen D. Metformin in non-alcoholic fatty liver disease: A systematic review and meta analysis. Biomedical reports. 2013 Jan 1;1(1):57-64.

17. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, Abouda G, Aldersley MA, Stocken D. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. The Lancet. 2016 Feb 13;387(10019):679-90.

18. Kawaguchi T, Taniguchi E, Morita Y, Shirachi M, Tateishi I, Nagata E, Sata M. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver International. 2010 Mar;30(3):479-86.

19. Ampuero J, Ranchal I, Nunez D, Díaz-Herrero MD, Maraver M, Campo JA, Rojas A, Camacho I, Figueruela B, Bautista JD, Romero-Gómez M. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One. 2012 Nov 15;7(11):e49279.

20. Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, Magliano PL, Gravina AG, Torella R. A randomized controlled trial of acarbose in hepatic encephalopathy. Clinical Gastroenterology and Hepatology. 2005 Feb 1;3(2):184-91.

21. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005; 60: 469-76.

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22. Kupcova V, Arold G, Roepstorff C, Højbjerre M, Klim S, Haahr H. Insulin degludec: Pharmacokinetic properties in subjects with hepatic impairment. Clin Drug Invest 2014; 34: 127-33.

23. Whyte M, Quaglia A, Hopkins D. Insulin detemir may be less efficacious in patients with nonalcoholic fatty liver disease and hypertriglyceridemia. Clin Case Rep. 2015;4:83–6.

24. Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert opinion on drug metabolism & toxicology. 2014 Jun 1;10(6):839-57.

25. Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12(9): 533-557 [PMID: 33033564 DOI: 10.4254/wjh.v12.i9.533].

26. American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021 Jan 1;44(Supplement 1):S15-33.

27. Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, Aboubakr AA, AbdelMaqsod A, Sedrak H, Assaad SN, Elwakil R, Esmat G. Managing diabetes and liver disease association: Practice guidelines from the Egyptian Association for the Study of Liver and Gastrointestinal Disease (EASLGD). Arab journal of gastroenterology: the official publication of the Pan-Arab Association of Gastroenterology. 2019 Mar;20(1):61-3. Insulin Discovery : The First Centenary Celebration Symposium

Insulin in Elderly

Dr. Avivar Awasthi, Post-doctoral Resident Dr. Animesh Maiti, Associate Professor & Head Dept. of Endocrinology, Medical College, Kolkata

In 2020, the Indian population above 65 years of age was 6.57%1. The prevalence of diabetes in adults in India is 8.9% which translates to about 7,70,05,600 cases as per the International Diabetes Federation2. These statistics bludgeon home a few striking details. There is a significant proportion of elderly population that has diabetes and requires treatment and this will go onto increase in the coming years.

In the era of patient centric tailored approach to treatment of diabetes, the elderly population presents with its own unique challenges; There is extensive variability in clinical presentation of diabetes and diabetic complications, psychosocial environment, and availability of resources. They have more comorbidities and disabilities, and have limited mobility. Some elderly people are active and are medically stable. They can perform self-care and usually have controlled blood sugars. There are others who are not active, or those who have severe disabilities, or those who are neglected. These subsets of people are at risk of hyperglycemia and its complications, as well as hypoglycemia.

The risk of hypoglycemia and its sequelae are more devastating in this population. Photograph of Major F. G. Banting 14_02_1941 Hypoglycemic unawareness is higher in elderly and may be multifactorial in its etiology. Many elderly people have long standing diabetes and have concomitant autonomic dysfunction. Hypertension is a major comorbidity seen in this population. Some hypertensives like betablockers may mask symptoms of hypoglycemia and may pose a higher risk of morbidity and mortality. Furthermore, there may be a subnormal counter-regulatory response to hypoglycemia. Hypoglycemia, particularly nocturnal hypoglycemia may result in increased risk of fall as well as cardiac arrhythmias, myocardial infarction, worsening of heart failure, and sudden cardiac death3. All in all, hypoglycemia leads to a vicious cycle of hypoglycemia, disability, recurrent hypoglycemia, and eventual mortality. Therefore, avoiding hypoglycemia needs to be one of the major treatment goals while treating diabetes in these patients. These

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patients need to be educated regarding recognizing hypoglycemic episodes, and keeping small sweets or simple carbohydrate rich edibles nearby.

Cognition may be affected and cognitive decline in this population is more prevalent4, 5. Joint mobility, especially joint mobility in hands, proves to be an added hurdle when choosing insulin which require well-defined, coordinated fine motor control of the hands.

Frailty is quite common in the geriatric population. Age related loss of muscle bulk is accelerated due to diabetes6. The elderly have higher rates of sarcopenia and even if diagnosed with diabetes in their later years, the fall of muscle bulk is higher than age matched normoglycemic population. These patients are prone to falls and fragility fractures. Sarcopenic patients may have less subcutaneous volume and accidental injections into intramuscular compartments may lead to erratic blood glucose levels. Some of these patients may be bed-bound or may have severe impairment in activities of daily living. These patients are more prone to hypoglycemia, hyperglycemic emergencies, and pressure ulcers. It is important to address these issues and be very lenient with glycemic targets in such cases.

There is a higher prevalence of renal impairment in the elderly population which can be attributed to diabetic nephropathy, renal impairment due to other causes, and age-related decline in GFR. Declining GFR reduces insulin clearance which increases the risk of hypoglycemia. However, all insulin preparations can be used in patients with CKD with moslt no change in dosage [7]. Frequent monitoring is advised in these patients, and if there are risk factors for hypoglycemia or other co-morbidities, the dosage of insulin should be reduced. Patients with eGFR <30 mL/min/1.73m2 often have coexisting delayed gastric emptying. These patients may benefit with use of rapid acting insulin analogues over regular insulin and administering rapid-acting insulin after meals may better approximate the insulin and postprandial blood glucose peaks. Postprandial insulin with a dose-adjusted for number of calories consumed may be helpful in subjects with varying food intake7.

Reduced eyesight is a common problem in elderly. Therefore, carefully explaining the dose of insulin and reinforcing use of prescription glasses is recommended. Use of magnifying glasses may also be encouraged in select cases. Reinforcing proper use of insulin syringes based on units/mL insulin is a must. In cases where patients are using U100 insulin, prescribing odd number units should be avoided if insulin is being given via insulin U100 syringes. Another approach may be counting the number of audible clicks on an insulin pen which can correlate to the dose of insulin required. If the patient is unsure about the dose by counting the clicks, they can reset the insulin pen and start again. The insulin pen delivery system should offer least resistance while dialing up the required insulin dose, and there should neither be any resistance while injecting insulin into the subcutaneous tissue. After administering insulin dose, another audible click indicates that the insulin has been delivered into the subcutaneous tissue. Patients who have small joint arthritis may find it difficult to

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operate an insulin pen and may find it easier to administer insulin via syringe. However, depending on the hand disabilities present, patient preference should always be sought prior to initiating or continuing insulin therapy. If a patient is on an insulin pump, the care-giver needs to assess the basal rate of insulin as well as the rate of bolus insulin given at meal time.

After taking into account all these unique characteristics, the goals of glycemic management must differ based on presence or absence of comorbidities, disabilities, living situation, and availability of resources. Considerations for the above should be made and presented to these people in a gentle, tender, and nuanced way. Doctor-patient communication is vital in these scenarios.

Glycemic targets differ based on patient characteristics. There are strict glycemic targets in patients with no disabilities, few co-morbidities, having a significant life expectancy where the goal is to prevent future microvascular and macrovascular complications (HbA1C <7.5%, average fasting glucose range: 90-130 mg/dL; average bedtime glucose range: 90-150 mg/dL). Patients with multiple chronic comorbidities with mild to moderate cognitive impairment who have impairment in activities of daily living have an intermediate life expectancy. They are at risk for hypoglycemia and falls. In these patients the glycemic targets are lax (HbA1C <8%, average fasting glucose range: 90-150 mg/dL; average bedtime glucose range: 100-180 mg/dL). The last subset of elderly are those who have end-stage chronic illnesses, who may or may not manifest with moderate to severe cognitive impairment. These patients have limited life expectancy and have the highest risk for hypoglycemia and falls. This population benefits the most from very lenient glycemic targets (HbA1C <8.5%, average fasting glucose range: 100-180 mg/dL; average bedtime glucose range: 110-200 mg/dL)[3]. However, it is important to know that HbA1C measurements may have false values, and it is a poor marker of glycemic variability and risk of hypoglycemia8,9. Insulin can be safely used in elderly as long as the route, dosage, and storage are carefully explained. The chosen insulin regimen should avoid being too complex to understand. Basal insulin given along with non- insulin agents is well tolerated.

In a resource poor setting, sometimes the only long-acting insulin available may be NPH insulin, and the only available short acting insulin may be regular insulin. If NPH is being administered, then the least possible dose should be given with gradual up-titration. A pragmatic approach may be to start NPH at 0.1 per kg body weight at night and gradually up- titrate. However, NPH has a higher risk of hypoglycemia as compared to the more expensive peakless basal insulins10.

If long-acting insulins like insulin glargine U100 can be given, it should be given in the morning because postprandial glucose contributes more than fasting glucose to overall hyperglycemia in older adults11. It also reduces the risk of fasting hypoglycemia. Insulin

36 Insulin Discovery : The First Centenary Celebration Symposium

glargine U100 may be initiated at 0.2 units/kg. In a comparative study it was seen that insulin glargine U300 and insulin degludec showed similar levels of glycemic control with lesser glycemic variability and hypoglycemia as compared to insulin glargine U100 (156). The dose of basal insulin should be increased by 2-3 units every 5-7 days until the fasting glucose is in the individualized target range. If 50% of the fasting capillary blood glucose (CBG) values are above the goal, then the basal insulin dose can be increased by 2 units. If >2 fasting CBG values/week are <80 mg/dL then the dose should be reduced by 2 units3.

If the fasting plasma glucose is controlled however the HbA1c is elevated, the basal insulin dose is >0.5 U/kg, or there is a big discrepancy between the fasting and postprandial CBG, a rapid-acting insulin can be added to the largest meal of the day3, 7.

This basal plus approach can be to the basal-bolus regimen as and when required. Mealtime insulin should be discontinued while adding noninsulin agents. Noninsulin agents can be tried if the underlying comorbidities permit, and the mealtime insulin dose is <10 units. However, switching from one to three or four injections per day increases complexity.

Premixed insulin may be started twice a day which may be less complex however it lacks flexibility and may increase the risk of hypoglycemia. Premixed insulin may be composed on a basal (70%) and rapid acting insulin (30%) or an equal distribution of both components (50%: 50%)3.

If cost is not a limiting factor, then there are two more approaches with respect to premixed analogues. One involves long-acting insulin with a rapid acting insulin analogue, another is the use of a long-acting insulin with a GLP1 receptor analogue. Insulin co-formulation with insulin degludec plus insulin aspart (70/30) before the largest meal as a once daily injection3. Fixed doses of GLP-1 receptor agonists (GLP1Ra) and basal insulin, insulin degludec and liraglutide (IDegLira), and insulin glargine and lixisenatide (LixiLan) are present in the market and can be given once daily. The insulin with GLP1Ra combinations are very expensive in our setting, however, there are studies reporting robust HbA1c reductions, less incidences of hypoglycemia, with weight loss13.

Insulin is a vital tool in our armamentarium required for the treatment of diabetes. Unless there is a strong support system for an elderly person, absence of disabilities and cognitive dysfunction, absent or minimal microvascular and macrovascular complications, and a long- life expectancy, the glycemic targets should be very liberal. Insulin therapy should be simple and should be judiciously explained to the patient. There should not be any treatment inertia for initiating insulin in patients with uncontrolled hyperglycemia. Peakless insulins are preferred over insulin NPH for basal insulin coverage. Frequent CBG monitoring should be encouraged. Hypoglycemia should be explained in detail to the patient and how to treat it.

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References: 1. Population ages 65 and above (% of total population) - India | Data. Data.worldbank.org. 2021. Available from: https://data.worldbank.org/indicator/SP.POP.65UP.TO.ZS?locations=IN 2. “Members” Region South Asia. Idf.org. 2021. Available from: https://idf.org/our-network/regions-members/south-east- asia/members/94-india.html 3. Leung E, Wongrakpanich S, Munshi M. Diabetes Management in the Elderly. Diabetes Spectrum. 2018;31(3):245-253. 4. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75.e2 5. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5(1):64–74 6. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinkov´a E, Vandewoude M, Zamboni M; European Working Group on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on sarcopenia in older people. Age Ageing. 2010; 39(4):412–423 7. LeRoith D, Biessels G, Braithwaite S, Casanueva F, Draznin B, Halter J et al. Treatment of Diabetes in Older Adults: An Endocrine Society* Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2019;104(5):1520-1574 8. American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2 in Standards of Medical Care in Diabetes— 2018. Diabetes Care 2018;41(Suppl. 1): S13–S27 9. Munshi MN, Segal AR, Slyne C, Samur AA, Brooks KM, Horton ES. Shortfalls of the use of HbA1C-derived eAG in older adults with diabetes. Diabetes Res Clin Pract 2015;110:60–65 10. Lee P, Chang A, Blaum C, Vlajnic A, Gao L, Halter J. Comparison of Safety and Efficacy of Insulin Glargine and Neutral Protamine Hagedorn Insulin in Older Adults with Type 2 Diabetes Mellitus: Results from a Pooled Analysis. Journal of the American Geriatrics Society. 2012;60(1):51-59. 11. Munshi M, Pandya N, Umpierrez G, DiGenio A, Zhou R, Riddle M. Contributions of Basal and Prandial Hyperglycemia to Total Hyperglycemia in Older and Younger Adults with Type 2 Diabetes Mellitus. Journal of the American Geriatrics Society. 2013;61(4):535-541 12. 156. Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, Pratley RE, Haahr PM, Lange M, Brown-Frandsen K, Moses A, Skibsted S, Kvist K, Buse JB; DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723–73 13. Maiorino MI, Chiodini P, Bellastella G, Capuano A, Esposito K, Giugliano D. Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Care. 2017;40(4):614–624.

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