Differential changes in islet amyloid polypeptide (Amylin) and insulin mRNA expression after high-fat diet-induced insulin resistance in C57BL/6J mice

Islet amyloid, derived from islet amyloid polypeptide (IAPP or amylin), fre quently occurs in type 2 diabetes. Availability of this peptide for amyloid formation may be enhanced by increased islet expression of IAPP. In the in sulin resistant state, euglycemia is maintained by hypersecretion of insuli n. Whether IAPP expression, which is regulated by glucose, or its ratio to that of insulin is altered by the metabolic perturbations associated with i nsulin resistance is not known. Therefore, we studied islet expression of I APP and insulin mRNA in insulin resistance-prone C57BL/6J mice. Thus, after a long-term (48 weeks) challenge with a high-fat diet (58% fat on a calori c base compared with 11% in the control diet) hyperglycemia, hyperinsulinem ia, hyperlipidemia, and hyperleptinemia evolved in the mice. An intraperito neal (IP) glucose tolerance test showed a marked impairment of glucose disp osal. Also, plasma IAPP levels were elevated in high-fat fed mice (11.3 +/- 1.2 v 2.1 +/- 0.6 pmol/L, P < .001). Quantitative in situ hybridization sh owed increased <beta>-cell mass in high-fat fed mice, as evidenced by appro ximately 50% increase in area labeled for islet IAPP and insulin mRNA. IAPP mRNA expression per islet cell remained unchanged in both groups. In contr ast, insulin mRNA expression per cell was significantly decreased in the hi gh-fat fed mice (P < .001). We therefore conclude that glucose intolerance after long-term high-fat feeding in C57BL/6J mice is accompanied by reduced cellular expression of insulin, but not of IAPP. The increased ratio of IA PP versus insulin expression might underlie the amyloidogenicity of high-fa t diet in species carrying an amyloidogenic form of IAPP. Copyright (C) 200 0 by W.B. Saunders Company.