title: Amylin-insulin relationships in insulin resistance with and without diabetic hyperglycemia.
abstract: To determine if increased secretion of amylin can be implicated in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) in vitro and in vivo, we studied its relationships to insulin in insulin-resistant rats with and without NIDDM. In obesity-associated and dexamethasone-induced insulin resistance without diabetes, basal and stimulated secretion of amylin and insulin by isolated pancreata were proportionately elevated, leaving the amylin-to-insulin ratio (A/I) unchanged. By contrast, whenever diabetes occurred in dexamethasone-treated rats or in spontaneously diabetic obese insulin-resistant ZDF-drt male rats, a doubling of A/I was invariably observed due to an increase in amylin without a proportional increase in insulin secretion. Correction of dexamethasone-induced hyperglycemia with the glucocorticord receptor antagonist RU-486 was accompanied by a decline in A/I. Longitudinal in vivo studies demonstrated in both spontaneous and dexamethasone-induced models of NIDDM an increase in plasma A/I at the onset of hyperglycemia. In dexamethasone-induced diabetes, the increased A/I was associated with a high proamylin mRNA relative to proinsulin mRNA. We conclude that amylin and insulin expression and secretion rise in concert in compensated insulin-resistant states, but when hyperglycemia is present the increase in amylin exceeds that of insulin. Although a role of an increased A/I in the pathogenesis of NIDDM has not been established directly, these studies indicate that such a role could be possible.
authors.affiliation: Gifford Laboratories, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas 75235.
authors.forename: T R
authors.initials: TR
authors.lastname: Pieber
authors.forename: D T
authors.initials: DT
authors.lastname: Stein
authors.forename: A
authors.initials: A
authors.lastname: Ogawa
authors.forename: T
authors.initials: T
authors.lastname: Alam
authors.forename: M
authors.initials: M
authors.lastname: Ohneda
authors.forename: K
authors.initials: K
authors.lastname: McCorkle
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: J D
authors.initials: JD
authors.lastname: McGarry
authors.forename: R H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D000682:Amyloid / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D006943:Hyperglycemia / Q000209:etiology* / Q000503:physiopathology*; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D058228:Islet Amyloid Polypeptide; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013004:Somatostatin / Q000378:metabolism
chemical_list: D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D013004:Somatostatin; D003907:Dexamethasone