RSSDI Textbook of Diabetes Mellitus Viswanathan Mohan, Hemraj B Chandalia, Gumpeny Ramachandra Sridhar, Ashok Kumar Das, Sri Venkata Madhu, Paturi Vishnupriya Rao
INDEX
×
Chapter Notes

Save Clear


1HISTORY OF DIABETES
Section Editor: Hemraj B Chandalia2

Landmarks in the History of DiabetesCHATPER 1

Ranjit Unnikrishnan
 
History of Diabetes
Chapter Outline
  • ♦ Diabetes in the Ancient World
  • ♦ Diabetes in the Dark Ages
  • ♦ The Advent of Modern Era
  • ♦ Breakthrough—The 20th Century
  • ♦ The Tiger Changes its Stripes: Transformation in the Natural History of Diabetes and Effect on Complications
  • ♦ Advances in Our Understanding of the Etiopathogenesis of Diabetes
  • ♦ Tight Control or No Tight Control—Changing Paradigms in Diabetes Management
  • ♦ Diabetes Goes Global
 
INTRODUCTION
Diabetes has been known to mankind from times immemorial. In recent decades, it has taken over the title of “captain of the men of death” from tuberculosis and “the great mimic” from syphilis so much so that the diabetologist is now considered the last of the internists, a physician who needs to have intimate knowledge of the working of each organ of the body in order to effectively treat his patient. Side by side with the explosion in prevalence of diabetes, there have been numerous exciting discoveries in the basic science and therapeutics of diabetes which have made the life of people with diabetes much more comfortable than it was even a quarter of a century ago. In this chapter, we will look at some of the milestones in the history of diabetes and acquaint ourselves with some of the outstanding men and women who have contributed to the development of this important branch of medicine over the course of the centuries.
 
DIABETES IN THE ANCIENT WORLD
The first documented evidence of diabetes in human history comes from a remarkable papyrus discovered in Egypt in the 19th century by a German archaeologist named George Ebers, and known ever since as the Ebers papyrus in his honor. This ancient document, which has been dated to 1,552 BC by modern carbon dating techniques, is 110 pages long and contains several formulae and folk remedies in addition to descriptions of various diseases. This papyrus describes a polyuric state, which is likely to have referred to diabetes, but further descriptions are absent.
 
Diabetes in Ancient India
In ancient India, diabetes was known as prameha (pra: excess, meha: urine), a term used to refer to the disease even today in certain Indian languages. It is mentioned in the Chakradatta that Lord Shiva dictated a formulation for the treatment of prameha to his son Lord Ganesha.4
zoom view
Fig. 1.1: Charaka (left); Sushruta performing surgery (right)Source: Life Diabetes Museum; http://www.dlife.com/files/Timeline
zoom view
Flow chart 1.1: Principles of treatment of Madhumeha (diabetes) in Ayurveda (1)
Another view is that Ganesha himself suffered from prameha in view of his predilection for sweets and sedentary lifestyle. This would make him the earliest known diabetic patient in history.1
The Charaka Samhita, dating back to 1,500 BC, describes prameha in great detail. It recognizes 20 types of prameha, which, if not treated, can lead to madhumeha (madhu: honey, meha: urine; literally sweet urine, an unambiguous description of diabetes). It was noted that the disease could be diagnosed by detecting ants congregating around the patient's urine. The hereditary nature of the illness is also described in this ancient text. A similar description is also given in the Sushruta Samhita from the 10th century BC (Fig. 1.1).
The ancient Indian texts also recognized the existence of two distinct types of madhumeha: (1) krisha (lean; corresponding to type 1 diabetes) and (2) sthula (obese; type 2 diabetes). The treatment prescribed for the latter variety was strict diet and plenty of physical exercises (fashionably termed lifestyle modification today) (Flow chart 1.1). Our ancestors also appreciated the fact that the treatment of the krisha variety was difficult, a truism in those pre-insulin days (and indeed even today).
Thus, ancient Indian physicians were acquainted with the classification, etiology and treatment of diabetes as long ago as 1,500 BC. Their texts provide a remarkably accurate picture of the disease; one would be hard-pressed to find a better clinical description of diabetes in any textbook even today.
 
Diabetes Gets its Name
It is generally accepted that the term diabetes, literally meaning “siphon”, was coined by Aretaeus of Cappedocia, in reference to the polyuria characteristic of uncontrolled disease. He likened the disease to a “siphon”, sucking water out of the body through the urine. He considered diabetes to be a rather uncommon disease characterized 5by “melting of flesh and limbs into the urine”. He also noted that established patients did not live long.2
Galen, who practiced in Rome in the second century AD, is considered to be the foremost physician of the Roman world. He considered diabetes to be extremely rare, noting that he had come across only two patients in his entire career. Both Aretaeus and Galen were of the view that diabetes was a result of a defect in the kidney, a view which lingered on for more than 1,500 years. Strangely enough, Hippocrates, considered as the Father of Modern Medicine, was apparently unaware of diabetes, although this could reflect the extreme rarity of the condition in his days.
 
DIABETES IN THE DARK AGES
There was not much progress in the field of diabetes in the Middle Ages, although some Arab and Chinese physicians did make some clinical observations on the disease. The Chinese physician Chen Chhuan and the Persian physician Avicenna described the complications of diabetes in some detail. There is also some evidence to show that diabetes was slowly becoming more common during this period, as evidenced from the frequency with which it appears in physicians′ records throughout Europe.
 
THE ADVENT OF MODERN ERA
The modern era of diabetes can be said to have been inaugurated by Theophastus Bombastus von Honnheim, better known as Paracelsus, who led a revival of scientific medicine in the 16th century AD. He disapproved of the then popular method of “water tasting” to diagnose diabetes and suggested that the urine should be examined chemically instead. Toward this end, he evaporated the urine of a diabetic patient and obtained a white residue, which, for some reason, he mistook for salt. He therefore concluded that diabetes was due to deposition of salt-like material in the kidney and bladder.
The first description of the sweet taste of diabetic urine came from Thomas Willis (of circle of Willis fame), who considered diabetic urine to be as sweet as sugar or honey, but surprisingly failed to come to the conclusion that the sweetness was due to the presence of sugar. Willis also noted that diabetes was becoming increasingly common, possibly on account of the “good fellowship” and “guzzling down of unalloyed wine” so prevalent in his day. The actual presence of sugar in the urine was described by Matthew Dobson in 1772, when he evaporated the urine form two diabetic patients and obtained a white cake that tasted exactly the same as sugar.3
The Scottish physician William Cullen divided polyuria into two types: (1) one with sweet urine, to which he gave the term diabetes mellitus (mellitus: sweet), and (2) the other in which the urine was tasteless, which he termed diabetes insipidus (insipidus: tasteless).
While it was now clear that the urine of diabetic patients contained sugar, it was still not certain where this sugar came from. The English physician John Rollo was of the opinion that the sugar came from the vegetables in the diet. Therefore, he prescribed a strict diet for his patients in which all greens were prohibited and only foods of animal origin were allowed.4 Although patients did show improvement with this diet, its very strictness led many of them to default, leading Rollo to lament on the consequences of deviation. This makes him probably the first person to recognize the problem of non-compliance in diabetic patients. Nevertheless, the low-carbohydrate diet proposed by him remained, in its various iterations, the mainstay of diabetes treatment for more than a century.
The late 18th and early 19th centuries were the “golden ages” of scientific discovery in the physical sciences. Advances in these fields, particularly chemistry, provided physicians with the tools needed to accurately diagnose and monitor diabetes. In 1815, the French chemist Eugene Chevreul showed that the sugar in diabetic urine was glucose, and this was found in the 1830s to be true of the blood of diabetic patients as well. The first method to detect urine glucose was described by Trommer in 1841. This was followed in rapid succession by the tests of Fehling, Roberts and Benedict, which remained the mainstay of diabetes diagnosis until blood glucose estimations became more widely available.
Simultaneously, giant strides were being made in unraveling the pathogenesis of diabetes. Until the 19th century, it was widely believed that the seat of diabetes was the kidney. However, autopsies of diabetes patients failed to show any pathology in the kidneys or in any other organ for that matter. The initial steps in piecing together the puzzle were made by the French physiologist Claude Bernard in the 1840s. Until Bernard's seminal work, it was assumed that only plants could make sugar and that animals could only break down substances made by plants. It was also assumed that the blood of animals contained no sugar except immediately after meals and in conditions like diabetes. However, Bernard found that the blood of animals in the fasted state also contained sugar, even 6if they were not diabetic. He also correctly identified the liver to be the source of glucose in the blood and glycogen to be its immediate precursor. The discovery of the central role of the liver in glucose metabolism led many scientists to postulate that this organ could be responsible for diabetes. However, even these scientists agreed that this could be the case only in the older, fatter patients with diabetes, the so-called “diabete gras”. The cause of diabetes in young thin individuals, “diabete maigre”, remained obscure.
The major breakthrough came in 1889, when the Lithuanian scientist Oscar Minkowski discovered that removal of the pancreas in dogs caused diabetes.5 This focused attention on the pancreas, an organ which had hitherto been considered only as a source of digestive enzymes. Minkowski and his colleague Josef von Mering noted that the condition of the dog was similar to that of a human patient with diabete maigre.
It was, however, still not clear how removal of the pancreas caused diabetes, or in other words, what vital role the pancreas played in normal individuals to prevent the development of diabetes. In 1869, a medical student in Berlin, Paul Langerhans, had identified clusters of cells in the pancreas, distinct from the enzyme producing acinar cells.6 These cells were named the “islets of Langerhans” by Gustave Laguesse, who postulated that they might have something to do with diabetes.7
The late 19th century saw giant strides in endocrinology, the science dealing with the internal secretions of the body. Therefore, it was not surprising that scientists soon started postulating the presence of an internal secretion from the islets of Langerhans, which could prevent the development of glycosuria and diabetes. The hypothetical islet secretion was named “insuline” by the Belgian scientist Jean de Meyer in 1909.8
Thus, by the end of the 19th century, the stepping stones for the next giant stride were in place. The key players in glucose metabolism had been identified—the liver, kidney and most importantly, the pancreas. Unfortunately, therapy for diabetes patients remained rudimentary. Most patients with diabetes were treated with a combination of diets, many of which were of dubious efficacy. One diet which did show some benefit was the Allen regime, introduced by Frederick Allen.9 This involved total elimination of carbohydrate from the diet and its replacement with calories derived from fat. Although this regimen provided patients with a few extra years of life, the quality of life was poor and many died form malnutrition rather than diabetes. Meanwhile, the diagnosis of what is now known as type 1 diabetes continued to be a sentence of death for most patients.
 
BREAKTHROUGH—THE 20TH CENTURY
The story of the discovery of insulin in 1921 is well-known throughout the world. But what is not so widely known is that in the years between 1900 and 1921, at least five scientists came close to isolating the elusive internal secretion of the pancreas. With a little luck, any one of them might have received the recognition and adulation which went to the Canadian group which eventually succeeded in isolating insulin.
In 1905, Eugene Gley, a French scientist, ligated the pancreatic duct of animal and after atrophy of the pancreas, extracted what was left. He found that the extract decreased glycosuria in depancreatized dogs. However, for reasons best known to himself, he did not further pursue this line of investigation and thus missed out on a path breaking discovery. Similarly, in 1903, two Scottish scientists, John Rennie and Thomas Fraser, attempted to relieve glycosuria in human patients by injecting extracts from fish pancreata, a proposition made attractive by the fact that the exocrine and endocrine components of the pancreas are separate in fish. However, the injections produced severe side effects and the experiment was abandoned.
In 1906, the German physician Georg Zuelzer, in association with Minkowski, attempted to alleviate glycosuria in humans by injecting animal pancreas extracts. Again, even though the extracts worked, side effects were so severe that the investigators gave up. Other investigators who came tantalizingly close to piecing together the final pieces of the jigsaw were Ernest Scott and Israel Kleiner.
Later, in 1919, the Romanian scientist Nicholai Paulescu, in an experiment astoundingly similar to the one that would be carried out in Canada 2 years later, described a pancreatic extract that cured symptoms of diabetes in depancreatized dogs.10 Unlike the earlier workers, he followed up on his studies and published a series of papers in 1921, culminating in the grant of a patent for “pancreine” in April 1922. However, he did not have the funds necessary to produce his extract in large quantities and his work was ignored when it came to awarding the Nobel Prize for the discovery of insulin.
Therefore, by the end of the second decade of the 20th century, considerable progress had been made on the isolation of the internal secretion of the pancreas and its role in reducing glycosuria.7
zoom view
Fig. 1.2: Frederick G Banting (right) and Charles H Best (left).Source: University of Toronto. http://link.library.utoronto.ca/insulin/digobject.cfm?Idno=P10103
However, little of this was known to an orthopedic surgeon and part-time physiology lecturer at the Western University, Toronto, Frederick Grant Banting (Fig. 1.2), when he was asked to lecture to some medical students on the physiology of the pancreas. Preparing for his lecture, Banting chanced to come across a report by Moses Barron in which he described a patient whose main pancreatic duct had been blocked by a stone, causing atrophy of the exocrine tissue, leaving only the islets behind and in whom diabetes did not develop. The report powerfully inspired Banting and he spent much of his time thinking about it, until one night, suddenly waking up from sleep, he got out of bed and scribbled on a piece of paper:
“Diabetus. Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate the internal secretion of these to relieve glycosuria”.11
Note that the eventual discoverer of insulin got the spelling of diabetes wrong!
Although Banting's superiors at the Western University were supportive, they were unable to help him further as the institution lacked sufficient facilities and funds. Instead, they referred him to James Macleod (Fig. 1.3), Professor of Physiology at Toronto University, considered to be an authority in carbohydrate metabolism.
Banting and Macleod's first meeting did not go well. Macleod was unimpressed by Banting's rudimentary knowledge of the pancreas and diabetes. However, Banting's perseverance won through and he was able to persuade Macleod to allow him the use of an old disused lab within the facility, along with the services of an assistant. However, it was made clear to Banting that he need expect no salary; indeed, only by selling his car and taking loans from his father and brothers was he able to see the next few months through. For an assistant, he was offered the choice of two medical students—Charles H Best and Clark Noble. The two tossed a coin to see who should work the first half of the summer and Best won. By the time the second half of the summer came around, Best had become so involved in the work that Noble agreed he should continue for the entire duration.
zoom view
Fig. 1.3: John James Rickard Macleod.Source: Bataille M Diabetes and Metabolism 2005;31(1):29-34.
Banting and Best spent the summer of 1921 in their cramped lab, testing out Banting's hypothesis. Banting performed the pancreatectomies and made dogs develop diabetes. Best measured the blood and urinary glucose using the newly developed Benedict-Lewis method. In August 1921, they depancreatized two dogs and treated one with pancreatic extract, leaving the other as control. The control dog died in 4 days while the other survived and did well. However, the process of ligating the pancreatic duct in dogs and waiting for atrophy of the exocrine tissue took close to 7 weeks.8
zoom view
Fig. 1.4: James B Collip.Source: Reference 1 (further reading).
This led Banting to look elsewhere for a source of pancreatic extract. He finally found a steady source from fetal calf pancreata, obtained from the local abattoir. Later he found that he could use adult beef pancreas just as effectively. Banting and Best gave the name “isletin” to the active substance in the extract produced by them; the name “insulin” was suggested by Macleod, harking back to de Meyer's work at the beginning of the century.
Around this time, Macleod suggested the addition of Bert Collip (Fig. 1.4), a biochemist, to the team. Collip was able to purify the crude extracts made by Banting and Best and modify it into a form more suitable for use in human patients. The first patient to receive insulin injections was the teenaged Leonard Thompson on January 11, 1922. Thompson, who at 14 years of age weighed only 29.5 kg, received 15 mL of the “thick brown muck”, following which his blood glucose fell from 440 mg/dL to 320 mg/dL. On January 23, he received a more purified form of the extract prepared by Collip, and this time his glucose levels fell from 520 mg/dL to 120 mg/dL. This case, along with six others, was reported in the Canadian Medical Association Journal in March 1922.12
Some idea of the importance of the discovery of insulin can be gained from the fact that the scientists concerned were awarded the Nobel Prize in 1923, less than 2 years after the event. The prize actually went to Banting and Macleod. Banting decided to share his prize with Best, whereupon Macleod announced that he would share his with Collip. There remains a considerable debate to this day as to who among the four deserves the most credit for the discovery of insulin. What is certain, though, is that the discovery of insulin ranks as one of the most significant medical achievements of modern times, changing the lives of millions of diabetes patients for the better. It is also of interest that no fewer than three further Nobel Prizes have been awarded in the field of insulin physiology in the succeeding years—to Frederick Sanger in 1958 for the discovery of the amino acid sequence of insulin, to Dorothy Hodgkin in 1964 for deciphering the three-dimensional structure of insulin and to Rosalyn Yalow in 1977 for the discovery of the radioimmunoassay technique to measure insulin levels.
 
Perfecting the Miracle Drug— Developments in Insulin Therapy
As described earlier, the insulin extracts prepared by Banting and Best were far from the finished product. Even with the best efforts of Collip, the early batches of insulin varied widely in their potency and purity and were as capable of producing allergic reactions as they were of reducing the blood glucose. The product was also susceptible to rapid deterioration. This unsatisfactory state of affairs, fortunately, did not last long.
In January 1923, three of the discoverers of insulin, Macleod, Banting and Best assigned their patent rights to insulin to the Board of Governors of the University of Toronto for the token sum of one dollar each. The University then entered into a contract with Eli Lilly and Company for the commercial production of insulin. This decision was influenced by the fact that in late 1922, George Walden, Lilly's chief chemist, had discovered the technique of isoelectric precipitation, which enabled the manufacture of insulin with stability and purity up to 100 times more than any of the earlier prepared extracts.
In the meantime, August Krogh, a renowned Danish scientist and Nobel laureate, happened to visit Toronto during his visit to North America to deliver a lecture at Yale University.9
Table 1.1   Landmarks in Therapy of Diabetes. The Modern Era
Year
Landmarks
1921
Discovery of insulin
1922
First clinical use of insulin
1926
Insulin crystallization techniques introduced
1946
NPH insulin developed
1955
The first sulfonylurea (carbutamide) introduced
1956
Lente insulin introduced
1957
Introduction of the first biguanide (phenformin)
1963
First premixed insulin introduced
1978
Subcutaneous insulin infusion pump (Pickup, UK)
1982
Recombinant human insulin approved by US FDA
1995
The first alpha glucosidase inhibitor approved by US FDA
1996
The first rapid-acting insulin analog
1997
The first thiazolidinedione
2000
Edmonton protocol for islet cell transplant
2003
The first long-acting insulin analog approved by US FDA
2005
The first GLP-1 analog
2006
The first DPP-4 inhibitor
(USFDA: United States Food and Drug Administration; GLP-1: Glucagon-like peptide 1; DPP-4: Dipeptidyl peptidase 4)
He met with Banting and Macleod and left with an authorization from the University of Toronto enabling him to introduce insulin into Scandinavia. By late 1923, Nordisk's insulin production had begun in Denmark.
Further developments occurred in rapid succession (Table 1.1). In 1926, Abel succeeded in crystallizing insulin for the first time, enabling further improvements in purity. This, however, came at the expense of a reduction in the duration of action, necessitating up to four injections per day in order to ensure stable control of sugars.13 The problem was solved by Hans Christian Hagedorn, who suggested the addition of protamine (an alkaline protein abundant in fish sperm) in isophane (precisely balanced) proportions to insulin.14 The resultant insulin, termed isophane or neutral protamine Hagedorn (NPH) insulin, was the first intermediate-acting insulin preparation. Meanwhile, chemists at Novo (then separate from Nordisk) solved the same problem by adding zinc crystals to insulin; by changing the size of the crystals, one could alter the duration of action of insulin. Thus were born the lente insulins.
In spite of all this progress, there were still several roadblocks to be overcome. A major issue was that allergic reactions were still common, as were disfiguring lipoatrophy and lipohypertrophy. In 1941, the Swedish physician Jorpes found that one could prevent these allergic reactions by using highly purified insulin obtained by multiple crystallization.15 Further work by Steiner demonstrated that these reactions were due to proinsulin and other “contaminants”, which appeared as two additional peaks on insulin electrophoresis. Further efforts by the major insulin manufacturers led to the development of “clean” insulins (monocomponent, highly purified and single peak) which virtually eliminated the troublesome allergies.
The second major issue was a direct consequence of the exploding epidemic of diabetes. By 1976, 1.5 million Americans were taking insulin, with an year-on-year increment of 5%. It was projected that by the year 1992, the world would run out of insulin to supply all these additional patients, even if the entire beef and pork production of the world were diverted to insulin production. This meant that alternative sources of insulin had to be looked for urgently. Fortunately, due to developments in biotechnology, this crisis point was never reached; instead, by 1983, the first “human” insulin produced from Escherichia coli bacteria was on the market. Within the space of a single decade, it had displaced both porcine and bovine insulin from the European market. In India, animal insulin held out for somewhat longer but is now virtually unavailable.
The third problem was that subcutaneous insulin therapy using conventional insulin, be it of animal or human origin, could not precisely mimic the body's exquisitely controlled insulin secretion pattern. Regular insulin is not true “prandial” insulin; its slow absorption and delayed clearance cause the blood glucose to rise too high after a meal and fall too low before the next. Similarly, none of the conventional intermediate-acting insulins are true “basal” insulins; their action does not last 24 hours and they have a discrete peak of action, leading to nocturnal hypoglycemia when administered at dinner-time or bed-time. The discovery of the amino acid sequence of insulin by Sanger in 1955 stimulated research into developing new varieties (analogs) of insulin, which while retaining the efficacy of conventional insulin, would have more favorable pharmacokinetic profiles.
The first rapid-acting insulin analog to be introduced was insulin lispro in the mid 1990s, which was soon followed by aspart and glulisine. These molecules have rapid onset of action, enabling injection just before a meal, and rapid decay of action, reducing the risk of postabsorptive hypoglycemia.10
The first long-acting (basal) insulin analog was glargine, introduced in 2003. This was followed by insulin detemir in 2006. These analogs have a prolonged and peakless action, enabling once daily administration with reduced risk of hypoglycemia. A very long-acting insulin analog, insulin degludec, is ready to enter the market soon.
Concurrently, with the developments in insulin pharmacology, insulin delivery systems also underwent a sea change. The advent of disposable syringes obviated the need for repeated sterilization and allowed patients more flexibility. The introduction of insulin pens enabled patients to inject themselves more discreetly and with less pain. However, the shortcomings of subcutaneous insulin delivery (even with the newer designer insulins) in mimicking the normal pancreatic secretion of insulin still remained. The first continuous subcutaneous insulin infusion (CSII) pump, introduced by John Pickup in 1978, was an attempt to overcome the limitations of multiple dose insulin injections by providing a constant supply of insulin to the body, supplemented by mealtime boluses of rapid-acting insulin. The first insulin pumps were unwieldy and cumbersome affairs. Advances made over the last three decades have made insulin pumps smaller, smarter and more acceptable to patients than ever before so much that many authorities consider them the insulin delivery mode of choice in individuals with type 1 diabetes, although the cost remains prohibitively high.
 
Completing the Armamentarium—The Development of Oral Antidiabetic Agents
From the mid-19th century onwards, there were sporadic attempts to devise some form of oral pharmacological treatment of diabetes. One of the earliest candidate sources of an antidiabetic medication was goat's rue (Gallega officinalis), which has been mentioned as a folk remedy for diabetes in different cultures over the years. The active principle of this plant, guanidine, was identified in the early years of the 20th century. The first orally active antidiabetic agent, synthalin, was a derivative of guanidine and was introduced in 1926 by the German scientist Frank.16 Unfortunately, this agent was found to be too toxic for clinical use and was soon withdrawn from the market. Moreover, the discovery of insulin at around the same time cooled enthusiasm toward this line of research for a few years thereafter.
In 1937, Ruiz et al. serendipitously discovered the hypoglycemic action of sulfonamide antibacterials while evaluating a new drug for the treatment of enteric fever. These observations were confirmed in 1942 by Marcel Janbon, who reported hypoglycemia and seizures in patients administered this new sulfonamide agent.17 Based on these observations, Auguste Loubatieres was able to establish that this group of drugs caused hypoglycemia through their direct action on pancreatic beta cells.18,19 This marked the beginning of the sulfonylurea era. However, it was not until 1955 that the first agent in this class, carbutamide, was introduced into clinical practice by Franke and Fuchs.20 This was followed in rapid succession by other agents such as tolbutamide, chlorpropamide, glibenclamide, glipizide, gliclazide and glimepiride.
Meanwhile, the guanidine story just refused to die down. In 1957, the first non-toxic guanidine derivative or biguanide, phenformin, was introduced, followed shortly thereafter by metformin.21 These drugs became widely popular during the next decade, but reports of lactic acidosis led to the removal of phenformin from the US market in the 1960s. Metformin, perhaps unfairly, was tarred with the same brush and did not make it to American shores for nearly four decades. It was, however, widely used in the rest of the world. It was only in 1995 that the US market finally opened its doors to metformin, faced with overwhelming evidence on the safety and efficacy of this agent from the rest of the world. Metformin is now the most widely prescribed oral antidiabetic agent worldwide and is the first-line drug for type 2 diabetes according to most of the global algorithms.
A number of new classes of antidiabetic agents were introduced during the 1990s (Table 1.1). Two of these classes, namely the non-sulfonylurea secretagogues (glinides) and the alpha glucosidase inhibitors, are relatively mild agents which have a niche role in the management of type 2 diabetes. The third drug class introduced in the 1990s, the thiazoloidinediones, have, however, had a turbulent history. The introduction of this new class of insulin sensitizers created plenty of excitement, particularly when the initial clinical trial experiences showed encouraging results not only in the treatment but also in the prevention of type 2 diabetes. Indeed, the first agent in this class, troglitazone, had the makings of a wonder drug. Unfortunately, its time in the limelight was limited; within 4 years of its launch, it had been banned due to reports of fatal hepatic toxicity. Troglitazone was never 11marketed in India. The other two drugs in the class, pioglitazone and rosiglitazone, were found to be liver friendly and were widely prescribed over the last two decades. However, in 2007, a meta-analysis showed an increased risk of adverse coronary events in individuals taking rosiglitazone.22 This led to a number of restrictions in the use of this drug, culminating in the Drugs Controller General of India (DCGI) banning rosiglitazone in 2010. With this, pioglitazone is now the only drug left in the class. It is an extremely potent antidiabetic agent, but recent reports of bladder cancer among users of this drug raise concern over its future.23
In the first decade of the 20th century, interest has been focused on a previously neglected aspect of carbohydrate metabolism—the gut-derived hormones or incretins. Incretins are a group of peptide hormones released from the gut in response to a meal, which have myriad actions not only in digestion and metabolism but also in organs far afield. The two main incretin hormones are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both these hormones act on the pancreas, stimulating insulin release from the beta cells and suppressing glucagon release from the alpha cells. They also inhibit gastric emptying and thereby induce satiety. Evidence from experimental animals also suggests that they may induce beta cell regeneration. In vivo, incretins have extremely short half lives since they are rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP-4).
In type 2 diabetes, the levels of both GLP-1 and GIP are low; however, the response to GLP-1 is maintained. This led workers to postulate that increasing the availability of GLP-1 to the cells could help in controlling hyperglycemia in these patients. This has the advantage of producing glucose-dependent insulin secretion, minimizing the chances of hypoglycemia and suppressing glucagon levels, which none of the currently available antidiabetic agents are capable of doing.
The two strategies to improve the availability of GLP-1 to the cells are (1) to administer a GLP-1 analog which is resistant to DPP-4 and (2) to inhibit the enzyme DPP-4 so that the body can make better use of endogenous GLP-1. The incretin mimetics act via the first mechanism whereas the DPP-4 inhibitors (incretin enhancers) utilize the second mechanism.
The first incretin mimetic, exenatide, was developed from a protein derived form the saliva of the Gila Monster, a venomous lizard found in the US and Mexico. This agent is given by subcutaneous injection twice daily and is effective in reducing hyperglycemia as well as body weight. The other GLP-1 agonist available in India is liraglutide, which can be given as a once daily injection. Once weekly exenatide is available in the US but has not been introduced in India at the time of writing.
In contrast to incretin mimetics, DPP-4 inhibitors are orally active agents which provide physiological levels of GLP-1 to the cells. The agents currently available in India are sitagliptin, vildagliptin, saxagliptin and linagliptin. Alogliptin is also available in some countries. These drugs are better tolerated than GLP-1 agonists but are milder and do not produce significant weight loss.
A drug class which has received much interest of late is the sodium glucose transporter 2 (SGLT2) inhibitors. These agents reduce hyperglycemia by promoting glucose loss through the urine and thereby control diabetes as well as produce weight loss. Unfortunately, the development of these agents has hit a roadblock due to their suspected link to bladder malignancy. The US Food and Drug Administration has asked for more data before the approval process can be restarted.
 
A Cure for Diabetes—Still a Mirage?
Type 1 (insulin-dependent) diabetes is a classical endocrinopathy in which the main and often only pathophysiology is absence of insulin due to destruction of pancreatic beta cells. This disorder therefore lends itself to a cure if only an alternative source of beta cells could be provided to the patient's body. Several approaches have been tried toward this end. The first attempts involved transplantation of the whole pancreas. Unfortunately, the limited availability of donor pancreata, complications involved in major surgery and the problems involved with immunosuppression have precluded this from gaining wider acceptance. Transplantation of pancreatic islet cells was first attempted by Paul Lacy in 1967 and the first clinical trial was done in 1990. The introduction of the Edmonton Protocol by James Shapiro in 2000 improved patient responses to islet transplantation,24 but the long-term efficacy of this procedure remains uncertain, with less than 10% of patients remaining free of insulin injections 10 years after the procedure.25
Recent efforts have been directed at utilizing stem cells as a source of insulin-producing beta cells in patients with diabetes. This approach is currently experimental and is limited by ethical concerns about the use of embryonic stem cells.12
 
THE TIGER CHANGES ITS STRIPES: TRANSFORMATION IN THE NATURAL HISTORY OF DIABETES AND EFFECT ON COMPLICATIONS
The discovery of insulin and its widespread clinical use in the early 1920s was accompanied by a wave of optimism bordering on euphoria among clinicians dealing with diabetes. In 1930, Frederick Allen confidently stated that diabetes had been conquered and that every diabetic could expect to live out his normal lifespan. However, it soon became clear that the increased life expectancy afforded by insulin was something of a mixed blessing. On the one hand, deaths from the acute complications of diabetes, particularly diabetic ketoacidosis (DKA), dwindled drastically, on the other hand, the very longevity of these patients meant that many of them could now expect to develop one or other of the vascular complications of diabetes, which were considered rarities in the pre-insulin era. Insulin therefore had the effect of converting diabetes from a fulminant, frequently fatal illness to a chronic lifelong disorder attended by the involvement of various organ systems of the body.
Diabetic ketoacidosis (DKA) has been known to physicians from olden days. In 1874, the German physician Adolf Kussmaul described the typical labored respiration of patients with this condition.26 The peculiar fruity odor of the breath in DKA was described by Watson and Foster independently in the 1870s.27,28 In the pre-insulin era, most patients with type 1 diabetes died due to DKA. However, the starvation regime of Allen (vide supra) was able to bring down the mortality rate from 60% to 40%. The advent of insulin therapy revolutionized the outlook for DKA. Today, in most recognized centers in the world, the mortality rate for DKA is less than 1%.29
The other major hyperglycemic emergency, known as hyperosmolar non-ketotic (HONK) state was described by Dreschfield in 1886.30 This entity has recently been renamed hyperosmolar hyperglycemic state (HHS).
Much was known about chronic diabetes complications even in the preinsulin era. Distinctive lesions were described in the retinae of patients with diabetes by Jaeger in 1855.31 In 1888, Nettleship described the ophthalmoscopic appearance of new vessel formation in the retina.32 In the pre-insulin era, retinopathy occurred only in older diabetic patients and was considered to be due to atherosclerosis. This was disproved by Waite and Beetham, who drew clear distinction between the lesions of diabetic microangiopathy and those of atherosclerosis in the retina.33
Until the late 1960s there were no effective treatments for diabetic retinopathy. Various pharmacological agents like rutin, Vitamin K and Vitamin C were tried with disappointing results. In 1953, Jacob Poulsen suggested that hypophysectomy could improve retinopathy by reducing insulin resistance and improving the “metabolic hormonal imbalance”. Although never very popular, this procedure continued to be performed in the 1970s for want of a better alternative; the results were equivocal.
Laser photocoagulation therapy was the brainchild of the German ophthalmologist, Gerd Meyer-Schwickerath, who postulated that he might be able to stop new vessels from bleeding by coagulating them with heat.34 After various trials during the 1940s, he settled on a xenon arc lamp as the source of light. Although the results were impressive, the procedure was painful and needed up to 1.5 seconds to make the burn. The advent of the ruby laser solved these problems. By the mid 1970s, the American Diabetic Retinopathy Study (DRS) had established laser photocoagulation as the treatment of choice for sight-threatening retinopathy. Meanwhile, in 1972, the German surgeon Robert Machemer pioneered vitrectomy surgery, which offered a ray of hope to individuals who had lost vision due to intraocular bleeding from proliferative retinopathy.
Proteinuria has been described from the days of Rollo and Darwin, who described the presence of coagulable material in the urine of diabetic patients. The first reports on diabetic kidney disease were published in 1936 by Paul Kimmelsteil and Clifford Wilson.35 They described this disease as characterized by proteinuria, edema and a characteristic microscopic appearance of the kidney, the so called Kimmelsteil Wilson lesion (nodular intercapillary glomerulosclerosis). These pathological changes were further delineated by Bell in 1953. The development of the microalbuminuria assay in the 1970s has helped in the early detection and prevention of diabetic kidney disease. Work by Mogensen et al. has identified the risk factors for diabetic nephropathy and elucidated the clinical stages of the disease.
The first description of neuropathy in diabetes is attributed to John Rollo in the 18th century.3 In 1883, Bouchard described erectile dysfunction in poorly controlled diabetes.36 The first comprehensive description of the cardinal features of diabetic polyneuropathy was given by Pavy in 1885.37 Trophic ulcers and autonomic neuropathy were described by Auche in 1890.3813
In 1868, Brigham noted that cerebral artery occlusion and sudden death were more common in patients with diabetes than those without.39 In 1895, Bose reported that angina was more common in diabetes patients compared to the general population.40 By the middle of the 20th century, the relationship between coronary artery disease and diabetes had been proven beyond doubt and many physicians started considering diabetes as a coronary risk equivalent.
Gangrene of the feet was known to be more common in diabetes patients from olden days; however, it was only in the 1920s that this was proven beyond doubt following the work of Bell and colleagues.4143
Before the discovery of insulin, it was quite unusual for a diabetic woman to conceive. A successful completion of pregnancy was even more uncommon. As late as the 1950s, the outcome of pregnancy in women with diabetes continued to be poor. However, work done by Priscilla White at the Joslin Clinic and Jorgen Pedersen in Copenhagen helped in identifying good diabetes control as the key to a successful outcome. By the 1980s, the fetal mortality rate in diabetic pregnancies had fallen to less than 6% in most of the Western world.
 
ADVANCES IN OUR UNDERSTANDING OF THE ETIOPATHOGENESIS OF DIABETES
The widespread clinical use of insulin also helped in elucidating the pathophysiology of diabetes. It was soon found that not all patients responded in the same way to insulin. In the 1930s, Wilhelm Falta and Harold Himsworth proposed that some patients were more sensitive to the glucose-lowering effects of insulin than others.44,45 Patients in the former group were usually thin and ketosis-prone (corresponding to the 19th century category of diabete maigre) while those in the latter group were usually obese and ketosis-resistant even without insulin therapy (diabete gras). These two categories were variously termed as juvenile-onset and adult-onset diabetes, insulin-dependent and non-insulin-dependent diabetes, and finally, in the 1990s, as type 1 and type 2 diabetes. The work of DeFronzo et al. in the 1970s46 led to the development of the insulin clamp technique, which has helped in relating the role of insulin resistance to the development of type 2 diabetes. Many groups, including DeFronzo's, have also looked at the role of beta cell dysfunction in the pathogenesis of type 2 diabetes.
In type 1 diabetes, lymphocytic infiltration of the islets—the so called insulitis was first described by Eugene Opie in 1901.47 However, its clinical significance was recognized only in the 1960s following the work of Willy Gepts.48 The autoimmune basis of beta cell destruction in type 1 diabetes was postulated by Doniach and Bottazzo,49 while the genetic basis was established by Cudworth and Woodrow.50
The pathogenesis of diabetic vascular complications has been a subject of intense study for over a century. Developments in molecular biology in the second half of the 20th century enabled the elucidation of the biochemical pathways involved in the development of these complications such as the polyol pathway, the advanced glycosylation end product (AGE) mechanism, the protein kinase-C pathway and the hexokinase pathway. The work of Michael Brownlee in the early years of the 21st century has helped to define a unified mechanism by which activation of these pathways can lead to diabetes complications.51
 
TIGHT CONTROL OR NO TIGHT CONTROL—CHANGING PARADIGMS IN DIABETES MANAGEMENT
In the preinsulin era, the treatment options for insulin-dependent diabetes (type 1 and advanced type 2 diabetes) were limited. The main aim of treatment was to prolong the life of the patient by avoiding episodes of acute metabolic decompensation such as DKA. The concept of tight control of diabetes was unknown and since patients rarely lived for more than few years after diagnosis, chronic complications were virtually unheard of.
The introduction of insulin therapy meant that diabetes patients were now able to escape the death sentence which the diagnosis would have earlier entailed. However, this development threw up other challenges to physicians as to what the aims of treatment should be, now that the risk of death from acute complications had receded. Should one try to get the glucose levels to normal, or should one just be satisfied with keeping the patient alive, avoiding episodes of DKA? Elliott P Joslin of Boston, considered as the Father of Modern Diabetology, was of the former persuasion. In 1935, he wrote that “the aim of diabetes treatment is to keep the blood glucose levels as close to normal as possible”.52 As obvious as this may sound to modern ears, there were many like Marvin Siperstein who disagreed with Joslin, as they felt that diabetic complications may even precede diabetes. While the attainment of normoglycemia was indeed a desirable aim, the problem was that any attempts of tight control would 14invariably be accompanied by an increase in the incidence of hypoglycemia. Also, there was not enough evidence at the time to show that tight control would have any benefits over and above those which could be attained by conventional control. The debate raged on for nearly 70 years. The advocates of tight control were not helped by the results of the University Group Diabetes Program (UGDP) study, which showed increased mortality in patients randomized to receive intensive treatment with sulfonylureas compared to those given conventional treatment.53 The issue was not resolved until the 1990s, when the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) unequivocally established the benefits of tight glycemic control in preventing the development of chronic vascular complications in type 1 and type 2 diabetes patients respectively.5456
The conduct of these landmark studies was helped to a great extent by developments in clinical chemistry. The most important among these was the development of a robust indicator for long-term glycemic control. In 1969, Rahbar described the relationship between the blood levels of an “unusual hemoglobin” called glycosylated hemoglobin (HbA1c) and diabetes.57,58 In 1972, Bunn et al. showed that the cause of the rise in HbA1c in diabetic subjects is the increased non-enzymatic glycation of the hemoglobin molecule, which was essentially irreversible.59 Koenig et al. were the first to demonstrate the relationship between HbA1c and fasting blood glucose; they also suggested that HbA1c levels might also correlate with the mean glucose levels.55 By the 1980s, HbA1c was being widely used in clinical practice to assess long-term glycemic control. However, the wide variety of assays available and lack of standardization remained as formidable roadblocks to its wider use. To solve this problem, the National Glycohemoglobin Standardization Program (NGSP) was set up in 1996 to standardize HbA1c assays throughout the US. As a result of this program, more than 99% of the HbA1c assays in the US, UK and Canada today are standardized, i.e. they are back traceable to the DCCT assay. However, in countries such as India, the problems of standardization remain unsolved to a great extent.
More recently, a joint working group set up by the American Diabetes Association, European Association for the Study of Diabetes, the International Diabetes Federation and the International Federation of Clinical Chemistry (IFCC) and Laboratory Medicine has recommended that the HbA1c value should be reported in IFCC units (mmol/mol) in addition to percentage values, with a view to switch completely to the former in the future.60
 
DIABETES GOES GLOBAL
At the beginning of the 20th century, type 2 diabetes was a disease of the better-off populations of the more advanced nations of the world. However, by the second half of the century, it had become clear that no nation or ethnic group was exempt from the disease. Countries like India, China and the Arab nations of the Middle East, which experienced rapid economic growth after centuries of deprivation, found themselves at the epicenter of a global epidemic, which they were ill-equipped to handle.
In order to tackle the burgeoning epidemic, diabetes organizations were set up in many countries, bringing together physicians, paramedical staff, educators and patients under one roof. These organizations not only helped to improve the standards of care of individuals with diabetes in the respective countries, but also often acted as powerful advocacy groups forcing through policy changes for the benefit of patients with diabetes. In 1934, the British physician R D Lawrence (himself afflicted with type 1 diabetes) and the renowned author H G Wells founded the Diabetic Association (now known as Diabetes UK). In the United States, 28 physicians got together and formed the American Diabetes Association in 1940. The European Association for the Study of Diabetes was formed in 1965. In 1950, several diabetes associations from different parts of the globe formed the International Diabetes Federation (IDF), which now has 200 member associations spread over seven regions. In India, the Research Society for the Study of Diabetes in India (RSSDI) was established in 1972 and now has more than 6,000 members, and is the largest in Asia.
 
CONCLUSION
The story of diabetes has been a long and eventful one. The path is strewn with glittering achievements and exciting discoveries, but at the same time the journey is nowhere near complete. The prospect of a cure for diabetes remains as elusive today as it was a century ago. Many aspects of the etiopathogenesis of diabetes and its complications await further elucidation. Nevertheless, we have every reason to be grateful to the pioneers in the field of diabetology whose efforts have enabled our patients to lead lives virtually indistinguishable from those of their peers without diabetes.15
FURTHER READINGS
  1. Bliss M. The Discovery of Insulin. University of Chicago Press;  Chicago:  1982.
  1. Rosenfeld L. Insulin: discovery and controversy. Clin Chem. 2002;48:2270–88.
  1. Holleman F, Gale EA. Nice insulins, pity about the evidence. Diabetologia. 2007;50:1783–90.
  1. Tattersall RB. Diabetes—the Biography. Oxford University Press;  Oxford:  2009.
REFERENCES
  1. Parivallal T. Diabetes in ancient India. In: Mohan V, Rao G (Eds). Type 2 Diabetes in South Asians: Epidemiology, Risk Factors and Prevention. Jaypee Brothers Medical Publishers (P) Ltd Under the Aegis of SASAT.  New Delhi:  2006. pp. 97–103.
  1. Schadewaldt H. The history of diabetes mellitus. In: Englehardt DV (Ed). Diabetes: Its Medical and Cultural History. Springer Verlag;  Berlin:  1987. pp. 43.
  1. Dobson M. Experiments and observations on the urine in diabetes. In: Medical observations and Inquires by a Society of Physicians in London, Vol. 5. Thomas Cadell;  London:  1776. pp. 298–316.
  1. Rollo J. The history, nature and treatment of diabetes mellitus. In: Gillet T, Dilley C (Eds). Cases of the Diabetes Mellitus, Vol. 1. London; 1798.
  1. Von Mering J. Minkowski O. Diabetes mellitus nach pancreas extirpation. Zentralbl Klin Med. 1889;10:93–394.
  1. Langerhans P. Beitrage zun mikroscopishen Anatomie der Bauch speicheldruse. Med Diss (Berlin); 1869.
  1. Languesse E. Structure et development du pancreas d'apres les travaux recents. J Anat (Paris). 1894;30:591.
  1. De Meyer J. Action de la secretion interne du pancreas sur differents organs et en particular sur la secretion Renale. Arch Fisiol. 1909;7:96–9.
  1. Joslin EP. Present-day treatment and prognosis in diabetes. Am J Med Sci. 1915;150:495–6.
  1. Paulesco NC. Action de l'extrait pancreatique injecte dans le sang, Chez un animal diabetique. C R Soc Biol. 1921;85: 555–9.
  1. Bliss M. The Discovery of Insulin. University of Chicago Press;  Chicago:  1982. pp. 45–58.
  1. Banting FG, Best CH, Collip JB, et al. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922;12:141–6.
  1. Somogyi M. Exacerbation of diabetes by excess insulin action. Am J Med. 1959;26:169–91.
  1. Hagedorn HC. Jensen NB, Krarup NB, et al. Protamine insulinate. JAMA 1936;251:389–92.
  1. Jorpes JE. Recrystallized insulin for diabetic patients with insulin allergy. Arch Intern Med. 1943;83:363–71.
  1. Frank E, Nothman M, Wagner A. Uber die experimentelle und Klinische Wirkung des dodekamethy lindiguanids (Syntholin B) Klin Wschr 1928;7:1996–2000.
  1. Janbon M, Chaptal J, Vedel A, et al. Accidents hypoglycemiques graves par un sulfamidothiazol (le UK 57 on 2254 RP). Montpellier Med. 1942;21-22:441–4.
  1. Loubatieres A. Quoted by Pyke DA. Preamble: the history of diabetes. In: Alberti KGMM, Zimmet P, Defronzo RA (Eds). International Textbook of Diabetes Mellitus, 2nd edition. John Wiley;  Chichester:  1997.
  1. Loubatieres A. The mechanism of action of hypoglycemic sulphonamides; A concept based on investigations in animals and in man. Diabetes. 1957;6:408–17.
  1. Franke H, Fuchs J. Ein neues antidiabetisches princip: Ergebnisse Klinische Untersuchungen. Dtsch Med Wochenschr. 1955;80:1449–52.
  1. Tyberguein JM, Williams RH. Metabolic effects of phenethyldiguanide, a new hypoglycemic compound. Proc Soc Exp Biol Med. 1957;96:29–32.
  1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.
  1. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645.
  1. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–8.
  1. Robertson RP. Islet transplantation a decade later and strategies for filling a half-full glass. Diabetes. 2010;59:1285–91.
  1. Kussmaul A. Deutch Arch Klin Med. 1874;14:1-46. Cited in Major RH. Classic Description of Diseases. Springfield, IL: Charles C Thomas; 1932. p. 200.
  1. Watson T. Lectures on the Principles and Practice of Physic, Vol. 2, 5th edition. Longmans;  London:  1871. p. 725.
  1. Foster B. Diabetic Coma: Acetonaemia. Br Med J. 1878;1: 78–81.
  1. Kitabchi AE, Umpierrez GE, Miles JM, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335–43.
  1. Dreshfeld J. The Bradshaw lecture on diabetic coma. Br Med J 1886; 2:358–363.
  1. Jaeger E. Beitrage Zu Pathologie des Auges, siete 33. Eien: KK Hofund and Staatsdruckerei, 1855.
  1. Nettleship EN. Chronic retinitis in diabetes. Trans Ophthal Soc UK 1888;8:159–162.
  1. Waite JH, Beetham WP. The visual mechanism in diabetes mellitus. N Engl J Med. 1935;212:367-79, 429–43.
  1. Root HF. The use of insulin and the abuse of glucose in treatment of diabetic coma. JAMA. 1945;127:557–63.
  1. Kimmelstiel P, Wilson C. Intercapillary lesions in the glomeruli of the kidney. Am J Pathol. 1936;12:83–98.
  1. Bouchardat A. De la glycosurie ou diabetic sucre. Geremer-Balliere. Paris, Vol. II
  1. Pavy FW. Introductory address to the discussion on the clinical aspect of glycosuria. Lancet. 1885;2:1033–35.
  1. Auche B. Des ulterations des nerfs peripherique chez les diabetiques. Arch Med Exp. 1890; 2:635–76.16
  1. Brigham CB. An essay upon diabetes mellitus. Press of Abner A Kingman,  Boston,  1868.
  1. Bose KC. Diabetes mellitus and its prevention. Ind Med Gaz. 1895;30:135–44.
  1. Bell ET. Postmortem study of vascular disease in diabetics. Arch Pathol Lab Med. 1952; 53:444–55.
  1. Bell ET. Incidence of gangrene of the extremities in non-diabetic and diabetic persons. Arch Pathol Lab Med. 1950; 49:469–73.
  1. Bell ET. Atherosclerotic gangrene of the lower extremities in diabetic and non-diabetic persons. Am J Clin Path. 1957; 28:27–36.
  1. Falta W. Die Zuckerkrankheir. Urban and Schwarzenberg;  Berlin:  1936.
  1. Himsworth HP. Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types. Diabet Med. 2011;28:1440–4.
  1. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237:E214–23.
  1. Opie EL. On the relation of chronic interstitial pancreatitis to the islands of Langerhans and to diabetes mellitus. J Exp Med. 1901;5:397–428.
  1. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965;14:619–33.
  1. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2:1279–83.
  1. Cudworth AG, Woodrow JC. Evidence for HL-A-linked genes in “juvenile” diabetes mellitus. Br Med J. 1975;3:133–5.
  1. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.
  1. Aragona M, Giannarelli R, Del Prato S. Intensive insulin treatment and postprandial control in Type 1 diabetes. Acta Biomed. 2005;76:26–30.
  1. University Group of Diabetes Study Program (UGDP). A study of effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes. 1970;19:747–830.
  1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.
  1. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.
  1. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317: 703–13.
  1. Rahbar S. An abnormal hemoglobin in red cells of diabetics. Clin Chim Acta. 1968;22:296–8.
  1. Rahbar S Blumenfeld O, Ranney HM. Studies of a unusual hemoglobin in patients with diabetes mellitus. Biochem Biophys Res Commun. 1969;36:838–43.
  1. Bunn HF, Haney DN, Kamin S, et al. The biosynsthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo. J Clin Invest. 1976;57:1652–9.
  1. ADA/EASD/IDF: Report of the ADA/EASD/IDF working group of the HbA1c assay. Diabetologia. 2004;47: R53-R54.