Insulin-Mediated and Non-Insulin-Mediated Metabolic Effects of Gastroenteropancreatic Peptides in Type I and Type II Diabetes
The recognition of secretion as a physiological regulator of the exocrine secretions of the pancreas in 1902 led to generalization of the concept of hormonal control of digestive sections,1 and excited interest in such mechanisms as possible mediators of the functions of the pancreas in control of glycemia.2 According to the “incretin” hypothesis, hormones released from the gastrointestinal tract in response to ingestion of nutrients serve to activate the glucoregulatory function of the pancreas.3 With the later identification of insulin as a hormonal effector of these functions, the hypothesis was adapted by suggesting that incretin stimulates insulin secretion. A variety of experiments with crude extracts of gastrointestinal tissues yielded conflicting results4, and following the recognition of direct effects of glucose on the release of insulin interest in incretin waned. However in the early 1960’s it was recognized that the glycemic stimulus to insulin secretion cannot account for differences in blood insulin levels after enteral and parenteral administration of glucose, which are also accompanied by apparent differences in glucose disposa1.5,6 These observations revived the hormonal hypothesis for stimulation of the beta cells by gastrointestinal factors, and a renewed search for candidate peptides that might fill this role was undertaken. Studies of these phenomena have yielded evidence related to the pathophysiology of disorders of intermediary metabolism in diabetes, with indications of differences between Type I and Type II diabetes in this context. However, before discussing the identification of incretins it is necessary to consider the question whether the hypothetical enteroinsular axis is necessary or sufficient to account for differences in glucose homeostasis observed with enteral and parenteral administration of the sugar, and whether mechanisms other than those simply dependent on portal perfusion of the liver and/or the recognized effects of insulin must be invoked.
KeywordsInsulin Secretion Beta Cell Glucose Disposal Continuous Subcutaneous Insulin Infusion Gastric Inhibitory Polypeptide
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- 4.Loew, E.R., Gray, J.S., Ivy, A.C., Is duodenal hormone involved in carbohydrate metabolism? Am. J. Physiol. 129: 659–663 (1940).Google Scholar
- 13.Radziuk, J., The effect of additional insulin on intravenous glucose tolerance and the forearm uptake of glucose compared to that following oral glucose, Diabetologia 25: 188 (1983).Google Scholar
- 23.Crockett, S.E., Cataland, S., Falko, J., Mazzaferri, E.L., Gastric inhibitory polypeptide: responses to variable doses of glucose in normal subjects and abnormal responses to oral glucose in patients with adult onset diabetes mellitus, Diabetes 24: 413 (1975).Google Scholar
- 26.Verdonk, C.A., Rizza, R.A., Nelson, R.L., Go, L.L.W., Gerich, J.E., Service, F.J., Interaction of endogenous gastric- inhibitory polypeptide with pancreatic alpha and beta cell function in man, Diabetes 28: 353 (1979).Google Scholar
- 28.Dupre, J., Champion, H., Rodger, N.W., Secretion of gastric inhibitory polypeptide (GIP) in insulin-dependent (IDDH) and non-insulin-dependent (NIDDM) diabetes mellitus, Ref. Program 64th Annual Meeting of Endocrine Society, p. 342 (1982).Google Scholar
- 29.Ross, S.A., Dupre, J., Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subject, Diabetes 27: 327: 333 (1978).Google Scholar
- 30.Dupre, J., Caussignac, Y., Champion, M., Kobric, M., McDonald, T.J., Rodger, N.W., Shepherd, G.A.A., VanVliet, S., Gastrointestinal Hormones: the enteroinsular axis and the secretion of glucagon, in: “Front of Hormone Res.” W. Creutzfeldt, ed., S. Karger, Basel, publisher, Vol. 7:232–245 (1980).Google Scholar
- 31.Dupre, J., Champion, M., Rodger, N.W., Abnormal response of plasma immunoreactive glucagon to meals in insulin-dependent diabetes mellitus (IDDH) during treatment by conventional depot injection therapy (CSII), Clin and Invest. Med. (2)6: 40 (1983).Google Scholar
- 33.Baer, A., Dupre, J., Prolonged intravenous infusion of gastric inhibitory polypeptide with parenteral nutrients elicits glucose intolerance and hyperinsulinemia in conscious rats, Program 63rd Annual Meeting, The Endocrine Society (1981).Google Scholar
- 37a.McDonald, T.J., Tatemoto, K., Radziuk, J., Dupre, J., Galanin produces hyperglycemia in dogs, Clin. and Invest. Med. Vol. 5, No. 3 (1984).Google Scholar
- b. McDonald, T.J., Dupre, J., Tatemoto, K., Greenburg, J., Radziuk, J., Mutt, V., Galanin inhibits insulin secretion and induces hyperglycemia in dogs, Manuscript submitted to Diabetes.Google Scholar