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), frequently occurs in type 2 diabetes. Availability of this peptide for amyloid formation may be enhanced by increased islet expression of IAPP. In the insulin resistant state, euglycemia is maintained by hypersecretion of insulin. Whether IAPP expression, which is regulated by glucose, or its ratio to that of insulin is altered by the metabolic perturbations associated with insulin resistance is not known. Therefore, we studied islet expression of IAPP 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 caloric base compared with 11% in the control diet) hyperglycemia, hyperinsulinemia, hyperlipidemia, and hyperleptinemia evolved in the mice. An intraperitoneal (IP) glucose tolerance test showed a marked impairment of glucose disposal. 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 showed increased <beta>-cell mass in high-fat fed mice, as evidenced by approximately 50% increase in area labeled for islet IAPP and insulin mRNA. IAPP mRNA expression per islet cell remained unchanged in both groups. In contrast, insulin mRNA expression per cell was significantly decreased in the high-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 IAPP versus insulin expression might underlie the amyloidogenicity of high-fat diet in species carrying an amyloidogenic form of IAPP. Copyright (C) 2000 by W.B. Saunders Company.