INTRODUCTION
Any attempt at describing the history of diabetes, is by default, an attempt at describing the history of mankind. Diabetes is a disorder with which mankind has been acquainted since the dawn of recorded history and even a cursory perusal of the history of medicine throws up numerous instances when physicians of yore have given detailed descriptions of the symptoms of diabetes. These descriptions not only give us an insight into the origins of this disorder but are in effect a social commentary on the socioeconomic conditions, religious beliefs, diets, and the scientific practices of the various timelines during which diabetes has been mentioned.
For simplicity and ease of understanding, the history of diabetes can be divided into six distinct timelines:
- Antiquity—from the earliest times till the fall of Rome
- Middle ages—from the fall of Rome till the fall of Constantinople
- Renaissance—from the fall of Constantinople till the Second World War
- Modern era—from the 19th century till the discovery of insulin
- Insulin era
- Postmodern era—from the end of the Second World War till the modern era.
ANTIQUITY
The earliest known mention of diabetes appeared in 1552 BC in a 3rd Dynasty Egyptian papyrus authored by Hesy-Ra, one of the world's first documented physicians. This papyrus is well known to all students of medicine as the Ebers Papyrus,1 named after the German Egyptologist George Ebers who first purchased it in Luxor in 1862. It is presently housed in the University of Leipzig, Germany. The papyrus does not give a detailed description of diabetes or for that matter even recognize diabetes as a disease but rather mentions briefly an illness causing the passage of too much urine. Other papyri like the Brugsch Papyrus2 (1350–1250 BC) and the Hearst Papyrus3 (1600–1500 BC) that are less well known, also describe polyuria, but there is no clear differentiation between diabetes and other causes of polyuria.
Ancient India
Perhaps the first detailed and by far most accurate description of diabetes was provided circa 6th century BC in India by Sushruta.4 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. Another view is that Ganesha himself suffered from prameha in view of his predilection for sweets and sedentary lifestyle.
The Charaka Samhita, 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.4
Greco-Roman
While it is true that the father of Medicine Hippocrates does not dwell upon diabetes, in one of his works he does mention a disease associated with excess urination and withering away, for which he recommended dietary therapy. A century and a half later, around 230 BC, Apollonius of Memphis5 first called this disease with wasting and polyuria, diabetes, which was the Ionic Greek word for siphon—to signify the siphoning away of fluid from the patient's body.
Three and a half centuries later, the Latin encyclopedist Aulus Cornelius Celsus,5 a contemporary of Augustus and Tiberius, who was responsible for compiling the extensive “De Medicina“ described a painless and invariably fatal polyuria associated with thirst, hunger, and emaciation.
A century later, the Syrian dentist Archigenes, a contemporary of Trajan, recorded diabetes among his list of multiple nervous ailments and recommended narcotics as a treatment. However, noteworthy, none of these physicians of antiquity made any attempt to differentiate diabetes mellitus from insipidus or to differentiate diabetes from other disorders associated with emaciation and polyuria like renal tubular acidosis and referred to all disorders with polyuria as diabetes.
However, the first clear and complete description of diabetes was made by Aretaeus of Cappadocia,6 a famous physician of the late Hellenistic period. Born in Cappadocia, a region of eastern Asia Minor, he studied medicine in Alexandria and practiced in Rome. Aretaeus belonged to the Eclectic School of Medicine. Its members were so called because they selected, from previous medical treatises, those parts which they deemed most rational and discarded irrational concepts. His treatise on diabetes consists of three parts—in the first part, all the common signs and symptoms of the disease are presented. In the second part of Aretaeus’ text, where the patient's symptoms are intricately but eminently clearly analyzed according to the stages of disease progression, valuable new information is presented which is missing from other physicians’ medical texts. In the final part, he hypothesized a correlation of diabetes with other diseases, this leading to the conclusion, probably original in conception, that a series of events occur in the organism that manifest the onset of the disease and also provides differential diagnoses. He also provided a set of dietary modifications to offset this excess thirst that included milk, wine, and cereals in diet.
Galen
Perhaps the last great physician of antiquity to write extensively about diabetes was Aelius Galenus or Claudius Galenus (often Anglicized as Galen and better known as Galen of Pergamon, often considered the greatest of the ancient physicians. He was a Greek who lived in the Roman Empire and was a contemporary of Marcus Aurelius, Commodus and Septimius Severus. Starting from the era of Galen, most of the texts of antiquity started ascribing the etiology of diabetes to the kidney.7
MIDDLE AGES
The Middle Ages are characterized by a steep decline in arts and sciences that flourished during the antiquity and the same holds true even for diabetes. The beliefs of Galen held sway during the Middle Ages and diabetes continued to be perceived as a disease of the kidney till Paracelsus prompted a relook at the pathology of diabetes as part of his medical renaissance. While progress in the study of diabetes was often limited and dogmatic, the condition was not totally neglected and there are quite a few extant texts that still speak about diabetes, predominantly from Persian and Arabic sources. One of the first mentions of diabetes in the Middle Ages comes from the Byzantine Paul of Aegina's seven-volume Epitome,5 that followed the principles laid down by Galen and attributed diabetes to “weak kidneys”. Treatment included herbal concoctions, knotgrass, hydration, and application of topical creams and poultices to promote cooling and reduce dehydration. Based on his clinical experience, Paul was also critical of the use of diuretics in diabetes.
Later, the 9th century Arab writer Rhazea was one of the first medieval writers to translate parts of Ayurveda in Arabic, including the observations of Sushruta and Charaka about diabetes. The 10th century writer Haly Abbas also mentioned diabetes and attributed it to “excessive heat from the viscus”.
The most significant observations about diabetes in the Middle Ages were undoubtedly from the works of the legendary physician Ibn Sina or Avicenna,8 as he was known to the West. His book, “The Canon of Medicine” was remarkable for its detailed and often accurate descriptions of the complications of diabetes including gangrene, erectile dysfunction, carbuncles, tuberculosis, and blindness, as also the role of hepatic dysfunction in diabetes. He was also perhaps the first person to 5advocate the use of fenugreek in diabetes, an anecdotal and undocumented addendum to the armamentarium of folk remedies for diabetes, that continues to be wildly popular even today, in spite of no concrete evidence whatsoever as to its efficacy. The other major contribution of Avicenna was in his recognition of diabetic neuropathy and in his recognition that diabetic urine was sweet, a fact rediscovered due to his practice of outsourcing the tasting of urine to the water tasters he employed.
The first Western mention of diabetes in the Middle Ages occurs in the work of Gilbert the Englishman, in the book “Compendium Medicinae”9 where he mentioned about diabetes. However, consistent with the set of beliefs prevalent through the Middle Ages, Gilbert considered diabetes as a renal disease and the treatments he suggested for this disorder were based on the theories of humor of Galen and were fanciful at best.
THE RENAISSANCE OF DIABETES
The beginning of the renaissance of diabetic medicine can be attributed to the Swiss physician Theophrastus Bombastus von Hohenheim, better known as Paracelsus.10 He was the first person in almost 1500 years to challenge the kidney-centric theories of diabetes and was scathingly critical of water tasting physicians, whom he dismissed as piss prophets. He considered diabetes as a constitutional disease that “irritated the kidneys” and provoked excessive urination. He evaporated the urine of diabetic patients and obtained a whitish residue which he erroneously considered to be a salt, rather than sugar, which the white residue actually was. His importance in diabetes research is due to the fact that he recommended a scientific approach to the diagnosis of diabetes, rather than relying on urine testing and fantastic remedies.
The Milanese magus Gerolamo Cardano,11 who also happened to be a medical astrologer, is best known for his contribution to game theory and the first description of typhoid fever. He was the first person to measure both the input and output of fluids in diabetic patients and concluded that there was a net loss of fluid in people with diabetes.
Andrew Boorde,12 a Carthusian monk who was later discharged from his vows, became a traveling doctor in the 16th century and visited many Universities across Continental Europe. After returning back to England, he published his medical observations in a series of helpful patient information guides accessible to the general public, thus arguably becoming a predecessor of Dr Google and myriad other self-help sites for the patient, that have become the bane of the serious modern medical professional.
In the 17th century, Thomas Willis (better known for first describing the circle of Willis) described that the urine in diabetics, which he evaporated and tasted, was sweet “as if imbued with honey” and it was this observation that prompted further research into the sweet urine in diabetes and ultimately resulted in the differentiation of diabetes mellitus and insipidus. Matthew Dobson,13 a physician at the Liverpool infirmary was the first person to describe the presence of sugar in diabetic urine and hypothesized that the kidneys were perhaps excreting the excess sugar produced by fermentation in stomach. About a century earlier, the Flemish physician Jan Baptista van Helmont, had given the first description of digestion in the body, but even a century later, stomach was still considered a humoral organ. If in the above description of Dobson, fermentation was replaced by digestion, what Dobson actually proposed seemed pretty similar to the actual process of carbohydrate digestion and consequent hyperglycemia induced polyuria.
Subsequently as the concept of sugar in urine became more widespread, John Rollo,14 an army surgeon hypothesized that vegetables were responsible for the generation of sugar in urine and raised the curtains on one of the many fad diets that were to dominate the management of diabetes for the next two centuries and to a great extent still dominate the management of diabetes in the alternate medicine segment. Rollo's diet was a predominantly animal food based and majorly restricted carbohydrates from diet. With minor changes, this remained the most common type of diet prescribed to people with diabetes till the discovery of insulin. The importance of the dietary therapy was that it was one of the first rational attempts to treat diabetes by restricting carbohydrates rather than relying on laxatives, purgatives, and other such medications that were based on Galen's theory of humors.
The British apothecary and astrologer Nicholas Culpeper15 also took a keen interest in diabetes and his brand of folk medicine based on local herbs advised patients with diabetes to use locally available plants such as bistort or snake-weed in any decoction, darnel leaves boiled in wine with pigeons’ dung, and powdered tormentil root in plantain juice to treat their conditions.6
MODERN ERA
The modern era started with the application of scientific principles to the study of diabetes and culminated in the discovery of insulin.
In 1815, the French chemist Eugène Chevreul,16 the father of gerontology, was the first person to prove that the sugar in diabetic urine was glucose. Later, Karl August Trommer (1806–79) devised the first test for detecting glucose in urine in 1841. In this test, when urine heated with blue cupric sulfate, in the presence glucose, red cuprous oxide was formed. This was later supplanted by the Fehling test devised by Herrmann von Fehling and though it was quite cumbersome for regular practice, it remained one of the standard methods of detecting blood glucose and is still taught to freshmen in the biochemistry laboratory well into the 21st century, either underscoring its importance or the tendency of a section of the medical community to resist change.
Another dietary modification widely practiced in the 19th century was the starvation diet. The French physician, Apollinaire Bouchardat17 first noticed that starvation as a result food rationing due to the siege of Paris in the Franco-Prussian War of 1870 resulted in a decrease of glucose in urine. This led to his famous advice to diabetics to eat as less as possible and subsequently starvation diets became the mainstay of the management of diabetes till the discovery of insulin.
At around the same time in 1874, Adolf Kussmaul18 gave the first description of diabetic ketoacidosis (DKA). His first description concerned a multiparous obese woman of 35 years who had developed diabetes and gradually lost a lot of weight. She was first referred to Kussmaul by her family physician when she suddenly developed rapid breathing early in the morning, associated with cold extremities, rapid pulse and she eventually became comatose and subsequently died. The deep and rapid breathing was called “diese grosse athmung” (this great breathing) and eventually was labeled with Kussmaul's name. Subsequently the German physician German physician Bernard Naunyn and his pupils discovered that patients with DKA had acidosis and this acid was subsequently identified as beta-hydroxybutyric acid.
Until the 19th century, it was widely believed that diabetes was a renal disease. However, autopsies of diabetes patients failed to show any pathology in the kidneys. The initial steps in piecing together the puzzle were made by the French physiologist Claude Bernard19 in the 1840s. Initially trained as a pharmacist, he later studied medicine and eventually came to be recognized as one of the greatest physiologists in the history of medicine. He invented the term milieu intérieur, and the associated concept of homeostasis. Until Bernard's discovery, it was assumed that only plants could make sugar and that animals did not produce sugar and could only break down sugars made by plants. However, Bernard found that the blood of animals in the fasted state also contained sugar, even if they were not diabetic. He also correctly identified the liver to be the source of glucose in the blood, rather than the lung as was commonly believed and glycogen to be its immediate precursor. He was also one of the principal proponents of vivisection in Europe, a fact that resulted in him being in lifelong conflict with his wife Marie Françoise Bernard, who was a noted anti-vivisection campaigner.
The pancreas first came into the limelight due to the untiring efforts of the Lithuanian scientist Oskar Minkowski20 who discovered that removal of the pancreas in dogs caused diabetes. This focused attention on the pancreas, an organ which had hitherto been considered only as a source of digestive enzymes. Although popular opinion credits the Canadians Frederick Banting and Charles Best with the discovery of the role of pancreas in insulin secretion, it was Oskar Minkowski and his colleague von Mering who demonstrated more than 30 years earlier that the pancreas plays a major role in the cause of diabetes.
The next big step in elucidating the pathophysiology of diabetes was in 1869, when a medical student in Berlin, Paul Langerhans, identified clusters of cells in the pancreas, distinct from the enzyme producing acinar cells.21 These cells were named the “islets of Langerhans” by Gustave Laguesse, who postulated that they might be related to diabetes.
The hypothetical islet secretion was named “insulin” by the Belgian scientist Jean de Meyer in 1909.22
INSULIN ERA
The single largest achievement in the history of diabetes is beyond any doubt, and is the discovery of insulin. While Banting and Best did eventually discover insulin, five scientists came tantalisingly close to this great discovery.
In 1905, Eugene Gley, a French scientist, ligated the pancreatic duct of animal and after atrophy of the pancreas, extracted some tissue and he found that the extract decreased glycosuria in depancreatized dogs. However, he did not follow-up on this discovery. 7Similarly, in 1903, two Scottish scientists, John Rennie and Thomas Fraser, attempted to relieve glycosuria in human patients by injecting extracts from fish pancreata. 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 precluded further research in this area.
Later, in 1919, the Romanian scientist Nicolae Paulescu, in an experiment 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.23 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, the stage had been set for the orthopedic surgeon and part-time physiology lecturer at the Western University, Toronto, Frederick Grant Banting. When he was asked to lecture to some medical students on the physiology of the pancreas, preparing for his lecture, Banting studied 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 inspired Banting to set out on the discovery of insulin.
Banting applied to Macleod for financial support. Initially 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 laboratory within the facility, along with the services of an assistant. 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.
Banting and Best spent the summer of 1921 in their cramped laboratory, 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. 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, 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 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 to 120 mg/dL. This case, along with six others, was reported in the Canadian Medical Association Journal in March 1922.24
So sensational was the discovery of insulin, that 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.8
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,25 a renowned Danish scientist and Nobel laureate, happened to visit Toronto during his visit to North America to deliver a lecture at Yale University. 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). 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 Jorpes26 found that one could prevent these allergic reactions by using highly purified insulin obtained by multiple crystallization. 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 a 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 9produced 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.
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 mellitus (T1DM), although the cost remains prohibitively high.
Development of Oral Antidiabetic Agents
From the mid-19th century onward, 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 (Galega 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.27 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.28 Based on these observations, Auguste Loubatières 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.29 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.30 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, 10widely 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 mellitus (T2DM) according to most of the global algorithms.
A number of new classes of antidiabetic agents were introduced during the 1990s (Table 1). Two of these classes, namely the nonsulfonylurea secretagogues (glinides) and the alpha-glucosidase inhibitors, are relatively mild agents which have a niche role in the management of T2DM. The third drug class introduced in the 1990s, the thiazolidinediones 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 T2DM. 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 marketed 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. 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.
A Cure for Diabetes—Still a Mirage?
Type 1 (insulin-dependent) diabetes mellitus 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 transplantation31 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.
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.
Diabetes 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 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 preinsulin 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 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.32 The peculiar fruity odor of the breath in DKA was described by Watson and Foster independently in the 1870s.33,34 In the preinsulin era, most patients with T1DM 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%.
The other major hyperglycemic emergency, known as hyperosmolar nonketotic (HONK) state was described by Dreschfield in 1886. This entity has recently been renamed hyperosmolar hyperglycemic state (HHS).
Much was known about chronic diabetes complications even in the preinsulin era. Distinctive lesions 11were described in the retinae of patients with diabetes by Jaeger in 1855.35 In 1888, Nettleship described the ophthalmoscopic appearance of new vessel formation in the retina.36 In the preinsulin era, retinopathy occurred only in older diabetic patients and was considered to be due to atherosclerosis. This was disproved by Waite and Beetham,37 who drew clear distinction between the lesions of diabetic microangiopathy and those of atherosclerosis in the retina.37
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. 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 Kimmelstiel and Clifford Wilson.38 They described this disease as characterized by proteinuria, edema, and a characteristic microscopic appearance of the kidney, the so-called Kimmelstiel–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. In 1883, Bouchard described erectile dysfunction in poorly controlled diabetes.39 The first comprehensive description of the cardinal features of diabetic polyneuropathy was given by Pavy in 1885. Trophic ulcers and autonomic neuropathy were described by Auche in 1890.
In 1868, Brigham40 noted that cerebral artery occlusion and sudden death were more common in patients with diabetes than those without. In 1895, Bose reported that angina was more common in diabetes patients compared to the general population.41 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.
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 Jørgen 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.
THE ERA OF TRIALS AND THE UK PROSPECTIVE DIABETES STUDY SAGA
In the preinsulin era, the treatment options for insulin-dependent diabetes (T1DM and advanced T2DM) 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 12normal, 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”. While the attainment of normoglycemia was indeed a desirable aim, the problem was that any attempts of tight control would invariably 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.42 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.43
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. In 1972, Bunn et al. showed that the cause of the rise in HbA1c in diabetic subjects is the increased nonenzymatic glycation of the hemoglobin molecule, which was essentially irreversible. 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.44 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.
No story of the history of diabetes is complete without a mention of the UKPDS study that permanently and irrevocably changed the paradigms in the management of diabetes.
The UKPDS45 was set up in the late 1970s, by Dr Robert Turner and colleagues in Oxford. Over 5,102 subjects at 23 centers across the UK were included in the study. It was the largest and longest study then undertaken in diabetes; median follow-up was 10 years. As well as attempting to resolve unanswered clinical issues, the study generated a huge epidemiological database, comprising over 20 million data items. The primary aim was to determine the effect of intensive glycemic control on the incidence of complications; the secondary aim was to assess whether there were differences between treatments protocol amendments were made to add topics not originally included. These strengthened the study by broadening its scope, but at the cost of complicating the treatment allocation, conduct and analysis of the study. Numerous substudies were embedded, the most notable being the Hypertension in Diabetes Study. Over 84 papers have been published from the UKPDS database. UKPDS showed conclusively that the complications of T2DM, previously often regarded as inevitable, could be reduced by improving blood glucose and/or blood pressure control. When the intervention trial finished in September 1997, all surviving UKPDS patients were entered into a 10-year, post-trial monitoring program. This was completed in December, 2007. Follow-up data from the trial demonstrate that early intensive glucose control not only continued to reduce microvascular complications, but also reduced risk for MI and all-cause mortality.46 The benefits of earlier metformin therapy were also sustained as well. The importance of the UKPDS trial lies in the fact that it heralded the era of large clinical trials in diabetes like the VADT, VAHIT, etc. that consequently lead to a better understanding of diabetes.
POSTMODERN ERA
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.
The two strategies to improve the availability of glucagon-like peptide-1 (GLP-1) to the cells are: (1) to administer a GLP-1 analog which is resistant to dipeptidyl peptidase-4 (DPP-4) and (2) to inhibit the enzyme DPP-4 13so 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 from the saliva of the Gila Monster,47 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 cotransporter-2 (SGLT-2) inhibitors. These agents reduce hyperglycemia by promoting glucose loss through the urine and thereby control diabetes as well as produce weight loss. EMPA-REG, the cardiac safety trial of empagliflozin, an SGLT-2 inhibitor was the first study to demonstrate the superiority of an OAD over placebo and was quickly followed by similar findings for liraglutide (LEADER) and canagliflozin (CANVAS).
The increasing availability and decreasing cost of human genetic analysis makes it likely that precise genome analyses will become routine in clinical medicine and used for diagnosis and therapeutic recommendations in multiple subspecialties beyond the diabetes clinic.
Refinement of algorithms incorporating predictive genetic variation and biomarkers for drug responsiveness and the risk of complications, prospectively validated by clinical trial outcomes data in multiple populations with different ethnic backgrounds, should enhance our ability to transform diabetes care.
It seems certain that the increasing availability and improved accuracy and utility of genomic and clinical biomarkers will further enable precision treatment of diabetes. Simultaneously, information technology will continuously improve our capacity to do global, large-scale, and cost-effective clinical trials. Given the tremendous progress made over the past decade, it is reasonable to predict greater adoption of precision medicine approaches in the T2DM clinic in the years to come.
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.
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