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How We Got To Know What We Know About Diabetes Moe Goodman September 21, 2016 Diabetes is an Ancient Disease ~1550 BC papyrus by physician Hesy-Ra found in 1862 contains a description of a disease resembling diabetes. Treatment: a 4 day course of a liquid extract of bones, wheat, grain, grit, green lead, and earth Ebers Papyrus ~600 BC Indian description of diabetes, Madhumeha meaning urine of honey. ~500 AD Susruta described honeyed urines produced by big eaters. The Chinese name for diabetes táng niǎo bìng means sugar urine disease. The term "diabetes" or "to pass through" was first used in 250 BCE by the Greek physician Apollonius of Memphis. Aretaeus of Cappadocia’s Description of Diabetes Aretaeus of Cappadocia Around 100 AD “Diabetes is … not very frequent ... being a melting down of the flesh and limbs into urine … for the patients never stop making water, but the flow is incessant, as if from the opening of aqueducts. It consists in the flesh and bones running together into the urine … the illness develops very slowly. The nature of the disease is chronic, and it takes a long period to form; but the patient does not live long once the disease is fully established; for the melting is rapid, the death speedy. Moreover life is disgusting and painful; thirst, unquenchable … and one cannot stop them either from drinking or making water". 1674 Willis Coins the Term “Mellitus” to Describe the Sweet Taste of the Urine of Diabetics In his “Pharmaceutice Rationalis”, Willis devoted a chapter to the “pissing evil”. Thomas Willis 1621-1675 1776 He also reported a case of “a certain noble earl” who suddenly “became much inclined to excessive pissing… in the space of twenty-four hours, he voided almost a gallon and a half of limpid, clear, and wonderful sweet water, that tasted as if it has been mixed with honey”. Dobson Finds Sweetness is Due to Sugar He also found increased sugar in blood Matthew Dobson 1732-1784 1855 Claude Bernard Discovers Glycogen and the Production of Glucose by The Liver In animals fed only protein more glucose leaves by the hepatic vein than enters through the portal vein. Claude Bernard 1813-1878 Extracts of freshly excised livers contain little glucose, but after standing contain large amounts of glucose. Boiling the extract prevents the appearance of glucose. A “fermentation process” released glucose from a precursor which he called glycogen. Livers of animals fed only meat for two weeks, but not other tissues, contain large amounts of stored glucose. He concluded that liver forms and secretes glucose into the blood. 1869 Paul Langerhans 1848-1888 Langerhans Discovers Small Islets of Tissue Embedded in the Pancreas Dietary Therapy in Treatment of Diabetes Mellitus 1858 Recommended diabetics consume large amounts of sugar to replace that lost in the urine. Pierre Adolphe Piorry 1794-1879 1871 during the 4-month siege of Paris in the Franco-Prussian war, diabetics who suffered from starvation had diminished glucose in their urine. He experimented with periodic fasting as diabetic therapy. He observed that exercise increases tolerance to carbohydrate. Apollinaire Bouchardat 1809-1886 1889 Removal of the Pancreas Produced Diabetes Mellitus in Dogs Von Mering studied the role of the pancreas in fat digestion. Joseph von Mering 1849-1908 Minkowski, a skilled surgeon, removed the pancreas The dog showed extreme thirst and excessive urination…. symptoms of diabetes. Sugar was found in the urine. Implantation of a pancreatic fragment temporarily reduced the appearance of sugar in the urine Oskar Minkowski 1858-1931 1895 Sharpey Schafer Proposes That Pancreatic Islets Secrete an Anti-Diabetic Factor Ligation of the pancreatic duct results in destruction of most of the pancreas, but not diabetes. Edward Sharpey Schafer 1850-1935 Removal of the pancreatic remnant results in diabetes. Transplantion of the remnant reversed diabetes for as long as the remnant survived. Proposed that islet tissue produce a substance that he called insuline 1901 Eugene Opie Discovers Severe Destruction of the Islets of Langerhans in Pancreata of Deceased Diabetic Patients Eugene Opie 1873-1971 . Drawing of an Islet of a patient who died of diabetes 1910 Allen Introduces “Starvation Treatment” Considered the best therapy for diabetics before the introduction of insulin. Restricted calorie intake to 1000 calories per day. Frederick Allen 1879-1964 Diet was rich in fat and protein with only 10 grams of carbohydrate per day. 1916 Joslin Publishes The Treatment of Diabetes Mellitus, Joslin was the first physician to specialize in diabetes treatment and management. Advocated diet and exercise to control symptoms including Allen’s “starvation diet”. Elliot Joslin 1869-1962 Advocated patient education enabling patients to take control of their disease. Became the foremost authority in treatment and management of diabetics. Championed tight control of glucose to minimize complications. Early Efforts to Find the Pancreatic Antidiabetic Factor 1906 Extract of calf pancreas “Acomatrol” injected into dying comatose patient showed improvement despite severe side effects and died days later after the supply of acromatrol ran out. George Zuelzer 1870-1949 1915-1919 aqueous extracts administered to diabetics at Rockefeller definitively proved that a substance from the pancreas lowered blood sugar. Israel Kleiner 1885-1966 1916 Paulescu Prepares “Pancreine”, an Active Extract of Bovine Pancreas Pancreine lowered blood glucose in diabetic dogs. Nicolae Paulescu 1869-1931 Call to military service in World War I prevented completion of experiments. Experimental results were published in June of 1921 including a statement that toxic side effects made pancreine unsuitable for humans. Pancreine was patented in April 1922 1922 The Discovery of Insulin Frederick G. Banting 1891-1941 Charles Best 1899-1978 In early 1923, just one year after the first test injection, insulin became widely available and by the fall 25,000 patients were treated in the United States and Canada. John Macleod 1876-1935 James B. Collip 1892-1965 First Patients Successfully Treated with Insulin Leonard Thompson 1908-1935 Elizabeth Hughes Gossett 1907-1981 Jim Havens 1900-1960 1923 Nobel Prize Awarded to Banting and McCleod Banting shares prize money with Best McCleod shares prize money with Collip 1923 Kimball and Murlin Isolate a Blood Glucose-Raising Substance Contaminating Insulin Preparations They name this glucose agonist Glucagon John R Murlin 1874-1960 Injection of glucagon to dogs and rabbits results in a rapid increase in blood glucose concentration 1926 Abel Crystallizes Insulin Found that the substance isolated was a protein Insulin was the first large molecule with hormonal activity. John Jacob Abel 1857-1938 Deflected interest away from glucagon contaminant 1936 Harold Himsworth 1905-1993 Himsworth Distinguishes Between the Two Types of Diabetes Mellitus 1942 Homemade Insulin 1940 Eva and Victor marry in Prague and flee to Shanghai to escape the Nazis. 1941 Eva develops diabetes and obtains insulin from local pharmacy. Eva Saxl 1921-2002 1942 Japan closes off Shanghai-Eva runs out of Insulin Victor and Eva prepare insulin from water buffalo pancreas following Banting and Best protocol as described in a physiology text book. 1942-1945 Eva and Victor’s insulin saves 400 diabetics in Shanghai ghetto. 1947 Saxyls emigrate to the United States and Eva begins career as advocate for diabetes treatment and therapy. Victor Saxyl ~1915-1968 1948 The Hyperglycemic Glycogenolytic Factor (Glucagon) is Present in Pancreatic Alpha Cells and Gut Mucosa Injection of glucagon stimulates hepatic glycogen breakdown and increased plasma glucose concentrations. Christian DeDuve 1917-2013 Glucagon is present in extracts of pancreas prepared after destruction of insulin-secreting cells, i.e. the Alpha cells. Glucagon is also present in the lining of the small intestine. Earl Sutherland 1915-1974 1949 Levine Discovers that Insulin Facilitates the Entry of Glucose into Cells Insulin Rachmiel Levine 1910-1998 galactose concentration minutes 1951-53 Frederick Sanger 1918-2013 Sanger Describes the Complete Amino Acid Sequence of Insulin 1957 Eli Lilly Scientists Describe the Amino Acid Sequence of Glucagon 1960 Berson and Yalow Develop the Radioimmunoassay for Insulin Fasting plasma insulin concentrations are higher in recently diagnosed maturity onset diabetics than normal controls. Insulin secretion increases in both groups in response to a glucose challenge. Solomom Berson 1918-1972 Plasma insulin concentrations increase faster in normal subjects than in diabetics, but increase twice as much overall in diabetics and remain elevated long after they return to baseline in normal subjects. Rosalyn Yalow 1921-2011 1965 David Kipnis 1927-2014 The Incretin Effect on Insulin Secretion 1967 Donald Steiner 1930-2014 Discovery of Proinsulin 1971 Jesse Roth 1934- Discovery of Insulin Receptors on the Cell Membrane 1975 Insulin and Glucagon Are a Bihormonal Metabolic Regulator Insulin Roger Unger 1924- Blood Glucose Glucagon 1977 Hemoglobin A1C Becomes the Gold Standard for Measuring Long-term Diabetes Control. ~Valine + glucose = Hemoglobin A1c Hemoglobin A (beta chain) (Hb A1c) 1978 Human insulin successfully produced in bacteria 1982 Recombinant human insulin approved for human treatment 1982-1998 Type I Diabetes is an Autoimmune Disease 1986 The Product of the Glucagon Gene (Proglucagon) Contains Several Bioactive Molecules Embedded within its Structure 158 1 Graeme Bell 1950- Glucagon Proglucagon 30 33 1 GRPP Pancreatic Cells GLP-1 61 69 72 GLP-2 158 78 Glucagon Principal Glucagon-like Fragment 69 1 Glicentin Intestinal K Cells 1 30 33 GLP-1 69 GRPP Oxyntomodulin 158 114 125 78 GLP-2 Actions of the Incretin Hormones Glucose-Dependent Insulinotropic Peptide (GIP) and Glucagon-like Peptide 1 (GLP1) Studies on the Actions of the Glucagon-Like Peptide (GLP1) Have Produced New Therapy GLP1 and GIP are rapidly destroyed by the enzyme dipeptidyl peptidase-4 (DPP-4 2005 Exenatide (Byetta) is a GLP-1 mimetic derived from exendin,a closely related hormone (53% homologous) found in the saliva of the Gila monster. 2006 JANUVIA (sitagliptin phosphate), the first in a new class of drugs that inhibit DPP-4 and prolongs the presence of GLP-1 in the blood. Pharmacologic Agents for Treatment of Diabetes 1942 Sulfonyl ureas stimulate insulin secretion. 1995 Metformin is a biguanide that prevents glucose production in the liver. 1996 Acarbose is an alpha-glucosidase inhibitor that slows digestion of some carbohydrates. 1997 Thiazolidinediones improve insulin sensitivity in muscle cells 1998 Repaglinide stimulates insulin secretion in the presence of glucose. 2013 Invokana blocks the activity of sodium glucose transport protein in the kidney, reducing glucose re-uptake and increasing excretion of glucose in the urine. 20?? Glucagon receptor antagonists;