Diabetes mellitus has a remarkable history starting from antiquity which can be divided into different historical periods (ancient observational, diagnostic, experimental and insulin periods). This story includes incredible discoveries to assign sign and symptoms of diabetes as a single disease, to find out its causative factors, to diagnose and manage it. Research is still inconclusive regarding its molecular basis.

Observational period

Egyptians were first to write documents about diseases proved by discovery of Ebers papyrus in graves of Thabes in 1862 by Georg Ebers which was written in near about 1550 BC. It contained descriptions of a polyuric state resembling diabetes mellitus. [1-3] Hippocrates famously known as Buqrat (460 BC), mentioned a disease with excessive urinary flow and wasting of body. [2, 4] Demetrius of Apameia also noted diabetes in 1st or 2nd century BC. [5]

Aretaeus (81-138) of Cappadocia in second century, coined the term 'diabetes', derived from Greek words 'dia' (through) and 'bainein' (to go), meaning a siphon, "because fluid does not remain in body but uses man's body as a ladder whereby to leave it as if patient was a siphon" which describes polyuria. He described disease, ".....melting down of flesh into urine, thirst unquenchable, kidneys never stop making water". [3, 6, 7, 8]

Jalinoos also known as Galen (131-201) defined diabetes as "Diarrhoea Urinosa (diarrhoea of urine)" and "dipsakos (thirsty disease)". He described it as a disease specific to kidneys because of weakness in their retentive ability and secondly had seen only two cases therefore termed it a rare disease. [6, 8, 9] He believed that diabetics' urine was "unchanged drink" which may have accounted for a different aroma. [10]

Chinese (Chang Chung-Ching in AD 229) and Japanese (Li Hsuan) literature explained a disease with sweet urine which attracted dogs and insects. Such patients were more prone to develop boils and tuberculosis. [2, 9, 10] During 5th and 6th century, sweet taste of urine in polyuric patients was also described in Sanskrit (Indian) literature by Susruta, Charaka and Vaghbata and disease was named "Madhumeha". They described that urine of these patients tasted like honey (madhu), sticky to touch and ants are strongly attracted to it. They differentiated two forms of disease, one affecting thin people who do not survive long and other affecting older and obese. This description was parallel to subdivision of diabetes into type 1 and 2 diabetes. Indian literature gets credit for term 'honey urine' (from which moniker mellitus was derived) referring to clear colourless nature of diabetic urine. This name has nothing to do with awareness of sugar in urine. They also described relation of diabetes to heredity, obesity, sedentary life and diet. [2, 3, 4, 11]

Ali Ibne Sina (960-1037) described accurately clinical features of disease and its complications e.g. gangrene and collapse of sexual function. Musa Bin Maimoon near about 1135 wrongly proposed that diabetes was caused by sweet water of river Nile. [2, 12]

Diagnostic period

From 16th to 18th century, diabetic medicine falls into diagnostic period and was recognized as a separate disease entity. Disease was observed more closely for its etiology and importance was given to find out the organ whose damage was causing diabetes. [9] Still there were few physicians during ancient period, whose name had to be mentioned here as they tried hard to diagnose diabetes. Theophilos Protospatharios (630 AD) was first to mention applying heat to urine as a diagnostic test. Avicenna (980-1037) recommended tasting urine of diabetics. He noted a sticky residue as sweet as honey remained after urine was left to stand in ambient air. However source of sweet taste of urine remained unknown. He described other complications of disease e.g. mental troubles, impotence, gangrene and furunculosis. [8, 10]

Then there came a dark era when no further research occurred regarding diabetes till Von Hohenheim also known as Paracelsus (1493-1541) reported in 16th century that urine of diabetic patients after evaporation contained an abnormal substance remaining as a white powder. He concluded that this substance was salt and that disease was due to deposition of salt in kidneys. [2, 8, 10] Thomas Willis (1621-1675) referred diabetes in 1674 as "Pissing evil" and observed that "urine was wonderfully sweet after evaporation, as if it were imbued with honey". He added Latin word ' mellitus' to diabetes, literally meaning honey sweet to describe nature of urine. He proposed that sweetness first appeared in blood and later in urine, therefore diabetes was primarily a disease of blood and not kidneys.[2,7,10,13] He later noticed that some urine samples were sweet whereas others were insipid (tasteless). Hence he was the first one to differentiate between diabetes mellitus and diabetes insipidus. [8, 13] Cullen in 1769 and John Rollo in 1809 also observed and confirmed these two types. [4, 9, 14]

Thomas Sydenham (1624-1689) speculated that diabetes was a systemic disease arising in blood where chyle was incompletely digested and its non- absorbed residue had to be excreted. Johann Conrada Brunner (1653-1727) came very close to discovering pancreatic diabetes when he observed in 1682 that, after incomplete removal of pancreas from a dog, "animal made water very frequently and drinking largely of water". Matthew Dobson in 1776 performed an experiment which leads to belief that diabetes was not just a disease of kidneys, but rather a systemic disorder. He noticed white residue when he heated urine to dryness about which he wrote "it was granulated and broke easily; smelled sweet like sugar neither could it be distinguished from sugar, except that sweetness left a slight sense of coolness on palate". He also observed sweetish taste of sugar in their blood. He concluded that this substance of saccharine nature had previously existed in serum rather than being formed in kidneys. He wrote "this idea of disease explains its emaciating effects from so large a proportion of alimentary matter being drawn off by kidneys, before it is perfectly assimilated and applied to purpose of nutrition. [2, 8, 14] Therefore Willis's observations and Dobson's experiments established diagnosis of diabetes in presence of sugar in urine and blood and suggested that diabetes was primarily a disease of blood and not kidneys. Diabetes was no longer considered a rare ailment. [10]

After Dobson's observations, research got intensified to find out exact cause. In 1788, Thomas Cowley described that diabetes may follow damage to pancreas, such as through calculus formation. In 1797, Matthew Baillie stated that "Diabetes depends upon a deranged action of secretory structure of kidneys, by which blood is disposed to new combinations" effect of which is production of "a saccharine matter". He proposed that "chyle may be so imperfectly formed, as to make blood be more readily changed into a saccharine matter, by action of kidneys". [2, 15]

John Rollo described cataract and odor of acetone in breath of diabetes patients. He observed that carbohydrates increased sugar levels and animal product consumption resulted in less sugar. He promoted the idea that treatment for diabetes should be a diet low in carbohydrates and high in fat and protein. This was such a great observation that modification of diet became the recommended treatment for diabetes until the discovery of insulin. [2, 9, 10, 11]

In 1815, Michel Eugene Chevreul (1786-1889) stated that sweet substance found in urine of diabetes patients was to be identical to grape sugar. So glucose was identified in the urine first time. [2]

Soon first clinical tests for glycosuria were developed. In 1841, Karl Trommer developed a qualitative test for sugar. In 1850, Hermann von Fehling developed a quantitative test. Frederick Pavy (1829-1911) established a quantitative relationship between degree of hyperglycemia and glycosuria. He also improved upon Fehling's test for quantitative sugar urinalysis by substituting ammonia for caustic potash and thereby facilitating production of first urinalysis tablets. [10]

Among these diagnostic discoveries, a very important statement was made by Harley in 1866' that there were at least two distinct forms of diabetes requiring different treatments.[3,16] During mid 19th century, William Prout (1785-1859) described "exposure to cold", "attacks of rheumatism and gout" and "mental anxiety and distress" as causes of diabetes. He was first to recognize coma as a complication of diabetes. Further in 1869, Noyes observed retinitis in glycosuric patients. [2]

Experimental Period

Glucoregulatory role of pancreas became clear and biochemical mechanisms were recognized during this era starting from mid 19th century. Claude Bernard (1813-1878) is considered to be founder of experimental medicine by applying physical and chemical methods in artificial induction of diseases. He discovered that liver releases a substance which affects blood sugar level. In 1857, he successfully isolated a starch like substance that he called "Glycogen", which was precursor of glucose, "internal secretion" of liver. Thus vital role of liver in diabetes was established.[2,4,7,17] In 1869, Langerhans (1847-1888) described small clusters of ductless cells in teased preparations of pancreas but did not know their function.[18] In 1874, Kussmaul described "air hunger" of ketoacidosis. In 1875, Dickinson defined diabetes as "a disease of nervous system characterized by secretion of saccharine containing urine". [2] In 1877, Etienne Lancereaux made a distinction between fat (diabetic gras) and thin (diabetic meagre) forms of diabetes in 1880. [3, 16]

Modern therapy of diabetes was advocated by Apollinaire Bauchardat (1806-1886) by limiting carbohydrates in diet, advocating fast days and using exercise to help control glycosuria.[2,19] In 1889, Oskar Minkowski and Josef Von Mering demonstrated that removal of pancreas from a dog resulted in diabetes and established the role of pancreatic disorders in causing diabetes.[2,20] It was only in 1893 that Edouard Laguesse (1861-1927) suggested that clumps of cells noticed by Langerhans, which he named "islets of langerhans"; might constitute endocrine tissue of pancreas. In 1901, Eugene Undsay Opie established that diabetes was caused by a lesion of langerhans. [2, 21] In 1908, Georg L Zuelzer and Nicolas Paulesco had prepared potent pancreatic extract. In 1909, Jean De Meyer gave name "insulin" derived from Latin word insula (insula=island), to glucose lowering hormone, whose existence at that time was still hypothetical, which he postulated was produced by islet tissue. [2, 22] Two diagnostic tests were developed meanwhile. In 1907, Stanley Benedict developed a test for glycosuria using a copper reagent with a carbonate base. In 1913, Ivar Bang pioneered a method to test blood glucose levels whereby blood proteins were fixed to filter paper and filtrate was used to measure glucose using copper sulfate and KCl. [10, 23] In 1920, Moses Barron gave conclusion that islets secrete a hormone directly into lymph or blood streams (internal secretion), which has a controlling power over carbohydrate metabolism. [2]

Insulin era

After finding the link between pancreas and diabetes, researchers focused on treating diabetes with pancreatic extracts and were trying to find out active principal of insulin during this period. In early 1900s, Zulzer (German researcher) experimented with pancreatic compounds, made an injection "acomatrol" and used into a dying diabetic patient. The patient improved but later died when acomatrol supply was exhausted. Later in 1911, he experimented with his drug called "Pancreas Preparation Suitable for the Treatment of Diabetes". But Zulzer's laboratory was turned over to the military during First World War.[9] The findings of Barron inspired Frederick Grant Banting, his assistants Charles Herbert Best and James Bertram Collip in Macleod's laboratory. They demonstrated reversal of metabolic changes of diabetes by injection of a potent extract of pancreatic islands. In December 1921, they got success in isolation of insulin; a milestone event. Banting and Macleod got Noble prize for that in 1923. Sadly Best and Collip was ignored for award but Banting publicly acknowledged Best's role and shared monetary prize with him. Macleod agreed to do same with Collip. On 11th Jan 1922, 14 year old diabetic boy named Leonard Thombson was treated with insulin first time. [2, 4] In 1923, Eli Lilly begins commercial production of insulin (Isletin Insulin). In 1925, Home testing for sugar in urine through Benedict's solution was introduced. In 1926, John Jacob Abel purified insulin, isolated its crystalline structure and hence chemically identified. In 1927, an oral medication "horment" or "glukohorment" was developed as a replacement for insulin, but dropped out due to its side effects. In 1928, Wintersteiner and his colleagues described insulin as a protein composed of amino acids. In 1930s, Insulin was further refined to Protamine zinc insulin, a long-acting insulin. Insulin therapy soon became backbone of management that enabled individuals affected by this disease to live an almost-normal life. It soon became apparent that insulin did not cure diabetes. As people began to live longer, they experienced complications that had not previously been seen.[2,4,9,10] In 1936 Himsworth proposed two types of diabetes as insulin sensitive and insulin insensitive, former being due to insulin deficiency. This observation laid the foundation for the concept of impaired insulin action, which is now known to be a crucial factor in pathogenesis of type 2 diabetes. Research was focused also on to find out other drugs and to revisit ancient method of treatment. Herbs and plants have been used for treating diabetes in Egypt, India, and China from thousands of years ago. Diet low in carbohydrates was in use for diabetes. In 1923, Collip found that onion has a hypoglycemic effect in fasting and depancreatized animals. The first oral hypoglycemic agent sulfonylurea was discovered in 1942 by M.J. Janbon. Franke and Fuchs in Berlin applied it clinically. [2, 9]

It was Fredrick Sanger who first determined that insulin molecule was composed of two different chains of 51 amino acids held together by two bridges of sulfur atoms in 1945 and discovered exact amino acid sequence of insulin in 1955. In 1958, he was recognized with a Noble Prize in chemistry. [1, 9] In 1940's, neutral protamine Hagedorn insulin was introduced and connection was established between diabetes and long-term complications of kidney and eye diseases. In 1941, Ames Company introduced first "stick" or "strip"urine tests (Clinitest) based on copper sulfate reduction and later on more accurate Clinistix based on enzymatic reaction of glucose oxidase. In late 1940's, Helen developed "dip-andread" urine test (Clinistix) allowing instant monitoring of blood glucose levels. In 1951, Lawrence and Bornstein measured amount of insulin in blood and noted that older and obese diabetics have insulin, but those who were young have none. In 1955, oral drugs that help lower blood glucose levels were introduced. [2, 10]

At this time, focus of research was changed from diagnose to monitor disease by introducing methods to measure insulin precisely, monitor blood glucose and manufacture synthetic insulin to treat diabetes. During 1959-1960 Yallow and Berson developed radioimmunological assay to measure insulin with much greater precision for which he received Nobel Prize in 1977. In 1964, first strips for testing blood glucose were used. In1970, first blood glucose meter (Ames) and insulin pumps were introduced. During the same year, laser therapy was used to slow down or prevent blindness due to diabetes. In1973, U-100 insulin was introduced. In 1976, the glycosylated haemoglobin (A1C) test was introduced as a monitor of glycaemic control. It was established that chronically elevated blood sugars will lead to a higher production of haemoglobin A1c than normal (less than 5%). It is at present not recommended for diabetes screening or diagnosis. There are many controversies about this test as many conditions like haemoglobinopathies, uraemia, ethnic variations and recent blood transfusion can affect HbA1c estimation. Still a lot of work has to be done to standardize the test.[10,24] The manufacturing of insulin changed dramatically with the advent of DNA technology that allows synthesis of a genetically engineered "human" type of insulin and in 1978, first recombinant DNA insulin was produced.[2,9,10]

In 1979, Type 1 or Insulin Dependent Diabetes Mellitus (IDDM) and type 2 or Non Insulin Dependent Diabetes Mellitus (NIDDM) diabetes were formally recognized by American Diabetes Association (ADA). [2] National Diabetes Data Group and World Health Organization (WHO) developed diagnostic criteria for diagnosis of diabetes using an oral glucose tolerance test which were updated in 1997 by ADA, and then revised in 2003. These guidelines require meeting one of the three criteria in order to diagnose diabetes: a) fasting blood glucose concentration ? 7.0 mmol/L with symptoms of hyperglycemia, which include polydipsia, polyuria, and weight loss; b) random blood glucose ? 11.1 mmol/L; c) a two hour value in an OGTT of 11.1 mmol/L or higher. The diagnosis must then be confirmed on a different day with any of the three criteria. [10]

In 1983, first biosynthetic human insulin and "Reflolux", later known as "Accu- Chek" (allows blood glucose self-monitoring) was introduced. Glucosidase inhibitors became more widely used in the 1980s. Thiazolidinediones were introduced in the 1990s. Recent additions include non sulfonylureas repaglidine and nateglinide. In 1996, the FDA (Food and Drug Administration, USA) approved first recombinant DNA human insulin analogue, lispro (Humalog). In 2001, FDA approved Cygnus' first-generation model of the GlucoWatch Biographer for use by adults - the first frequent, automatic and noninvasive glucose monitor. In 2003, the names IDDM and NIDDM were formally dropped. [2, 9]

Latest developments

Today Researchers are working on an insulin patch. [2] A sensor-computer-pump system (implantable pump) that mimics insulin response of normal pancreas is being developed to function as an "artificial pancreas". Genetic engineering is being used to manipulate cells so they secrete more insulin e.g. insulin sensitizers. Pancreatic or islet cell transplantation is also underway. [25] Oral-Lyn is an oral spray formulation of human insulin. Its clinical use has been started in Ecuador in 2005. Inhaled insulin (Exubera) is one of the greatest breakthroughs in 2006 for people who must take short-acting insulin. [26] Taiwan scientists Sung et al. reported the success in early tests of an oral insulin solution in diabetic rats. The use of Rituximab in turning off the immune attack on beta cells is under research. Another under way study is testing whether Mycophenolate Mofetil (MMF) or MMF plus Daclizumab (DZB) can slow or arrest the autoimmunity of type 1 diabetes. [9]

Conclusion

Diabetes mellitus has a long history during which it was considered to be a disease of the kidneys well into the middle of the 19th century. Although term "diabetes" was first coined by Aretaeus, actually Willis's observations and Dobson's experiments established diagnosis of diabetes in presence of sugar in urine and blood and suggested that diabetes was primarily a disease of blood and not kidneys in18th century. Chevreul (1786-1889) identified first time glucose in urine. Banting and Macleod isolated insulin in 1921-22 and soon it with proper diet became the backbone of treatment. Oral hypoglycemic drugs were introduced in later part of 20th century. Today Researchers are working on insulin patch, implantable pump, insulin-sensitizers, pancreatic or islet cell transplantation. Effective use of oral insulin is the target of the 21st century. Soon the injecting insulin will become a thing of the past.

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PEER REVIEW

Not commissioned. Externally peer reviewed.

CONFLICTS OF INTEREST

No conflict of interests

Author affiliation:

Manjeet Singh1 Naresh Kumar1 Sushma Sood1 Beena Makkar1 Varun Arora2

1Department of Physiology, 2Community Medicine Pt B.D. Sharma PGIMS, Rohtak, Haryana.

Corresponding Author:

Manjeet Singh

11J/48, Medical Enclave

PGIMS, Rohtak, Haryana, India.

msbatrtk@yahoo.com