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1846 First clues about cause of diabetes and existence of glycogen demonstrated 1855 Term ketone coined to describe colourless liquid with fruity smell 1869 Pancreatic islets found to stain differently from surrounding tissue 1889 Surgical removal of pancreas noted to cause diabetes in dogs 1890 Extracts from pancreatic islets shown to help reduce excretion of glucose into urine 1893 Pancreatic islets theorised to secrete an endocrine substance 1894 Pancreatic islets suggested to play role in blood sugar levels 1902 Discovery of first gastrointestinal hormone - secretin 1903 Preparation of pancreatic extracts found to help treat diabetes mellitus in dogs and humans 1905 Term 'hormone' coined 1905 Discovery of second gastrointestinal hormone - gastrin 1906 First diabetic patient successfully treated with pancreatic extracts 1906 Duodenum theorised to produce hormone to help activate pancreatic secretions 1907 Two sets of cells found in pancreatic islets 1911 Hoffmann-La Roche begin production of Acomatol, pancreatic extract, to treat diabetes Sep 1914 Use of acomatol abandoned due to war 1915 Pancreatic extracts shown to lower blood sugar in animal experiments 1916 Aqueous pancreatic extract shown to lower blood and urine sugar levels in pancreatitis dog May 1921 Injections of insulin shown to be therapeutically effective in diabetic dogs Jan 1922 First human patient successfully treated with insulin injections Apr 1922 Patent taken out on aqueous pancreatic extract 1923 Glucagon isolated in duodenal and pancreatic mucosa 1925 Gastric secretions demonstrated in dogs to be inhibited by fatty food 1928 Discovery of pancreozymin, subsequently renamed cholecystokinin - small intestine hormone 1929 Secretin extracts shown to lower blood glucose in animals Jun 1930 Enterogastrone coined as a term to describe hormone released from upper small intestine to inhibit gastric acid 1932 Incretin proposed as therapy for treating human diabetes 1936 Diabetes classified into two groups - type 1 and type 2 1939 Incretin idea dismissed due to difficulties reproducing La Barre's experiments 1953 First description of contrasting functions of insulin, and first suggestion that glucose plays role in diabetes 1958 Glucagon observed to cause profound hypoglycemia in patients with insulinoma 1959 First radioimmunoassay for diagnosing patients hypoglycemia 1959 First radioimmunoassay developed for measuring glucagon May 1959 Simple diagnostic test developed for determining low blood glucose Jan 1962 Glucagon suggested to stimulate insulin secretion in B cells of the pancreas 23 Feb 1963 First evidence provided for the clinical application of radioimmunoassay technique 1964 First beta-blocker drug approved 1964 Higher levels of plasma insulin found when glucose taken orally than when given by injection Sep 1964 Secretin injections show to accelerate disappearance of glucose by activating insulin 1966 Intravenous injections of glucagon demonstrated to elevate plasma insulin levels in healthy individuals 1967 Incretin-like substance suspected to originate from the gut Aug 1967 Insulin demonstrated to be synthesised from precursor protein 1970 Existence of gastric inhibitory polypeptide (GIP) established 1971 First amino acid sequence worked out for porcine GIP 1977 First H2 blocker drug approved 1980 Precursor gene found for glucagon 1981 Guinea pig experiments reveal peptide in saliva of gila monster causes sharp rise in amylase Feb 1981 Glicentin gastrointestinal peptide sequence published 1982 Oxyntomodulin gastrointestinal peptide isolated 1983 First human proglucagon gene cloned 1983 Biologically active region of GLP-1 predicted 1984 Pathway of insulin mapped from pancreatic islet cells 5 Sep 1986 GLP (7-37) demonstrated to exist in the gut 26 Jan 1987 GLP-1 (7-36) amide demonstrated to stimulate insulin release in a perfused pig pancreas Feb 1987 GLP-1 (7-37) demonstrated to stimulate insulin release in the perfused rat pancreas May 1987 GLP-1 (7-37) demonstrated to stimulate insulin in rat pancreatic cells 5 Dec 1987 First testing of GLP-1 physiological action in humans 1989 Trial showed GLP-1 (7-37) to have therapeutic potential for treating type-2 diabetes 5 Aug 1989 Truncated GLP-1 confirmed to be important in metabolism control and glucose turnover 15 Jan 1990 Second biologically active form of GLP-1 discovered 1 Jun 1990 US Patent 5,120,712 filed for the use of GLP-1 (7-37) as a potential treatment for diabetes mellitus Feb 1992 First paper published demonstrating GLP-1 to be promising treatment for type 2 diabetes Apr 1992 New peptide - exendin-4 - discovered to stimulate insulin secretion like GLP-1 and to last longer in the body 2 Jun 1992 US Patent 5,120,712 granted to Massachusetts General Hospital for use of GLP-1 (7-37) for diabetes mellitus 2 Jun 1992 US Patent 5,118,666 granted to Massachusetts General Hospital for use of GLP-1 (7-37) for diabetes mellitus Sep 1992 GLP-1 receptor cloned for first time May 1993 Patent filed for extending-4 for the treatment of diabetes and hyperglaecaemia Jun 1993 GLP-1 shown to not last long in the body due to the enzyme dipeptidyl peptidase-IV 23 Nov 1993 US Patent 5,614,492 filed for the use of GLP-1 (7-36) as a potential treatment for type II diabetes mellitus

( B ) GCG (the gene encoding GLP-1) mRNA levels in ileum

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Doggrell, S

A tight junction-associated Merlin-angiomotin complex mediates Merlins regulation of mitogenic signaling and tumor suppressive functions