The Discovery Of The Incretin Hormones Gastric Inhibitory Polypeptide And Glucagonlike Peptide

Early in the first half of the 20th century it was already hypothesized that gastrointestinal hormones are important for glucose homeostasis and stimulation of insulin secretion after a meal (1,2). In the late 1960s it was finally shown that orally administered glucose leads to a greater insulin response than intravenously administered glucose dosed to lead to identical serum glucose excursions (3). This difference in insulin secretion is termed the "incretin effect." The gastrointestinal hormones promoting the pronounced insulin response after an oral glucose load are called "incretins." The incretin effect is responsible for approximately 30% to 60% of the postprandial C-peptide response depending on the amount of glucose consumed. In patients with type 2 diabetes the incretin effect is markedly reduced (4,5).

Gastric inhibitory polypeptide (GIP) was discovered as an incretin in 1970 and accounts for approximately 60% of the total incretin effect (6). It is synthesized by the K cells in the upper small intestine (6,7) and released in response to a carbohydrate- or fat-rich meal. Mice lacking the GIP receptor show an impairment in glucose tolerance and interestingly also a resistance to nutrient-induced weight gain by hypercaloric feeding (8,9).

Glucagon-like peptide-1 (GLP-1) was discovered in 1985 after the cloning of the glucagon gene and is generated by tissue-specific post-translational processing of proglucagon in neuroendocrine L cells of the lower small intestine and the hypothalamus (10), while glucagon is the major product of the proglucagon processing in alpha cells of the pancreatic islet (11). GLP-1 is a physiological incretin (6,11,12). It is a 29 amino acids containing peptide and has a high sequence similarity with GIP, glucagon and other peptides of the glucagon family of hormones (13).

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