Developmental Regulation of Amylin and Insulin-Gene Expression in Lean (Fa/Fa) and obese (fa/fa) Zucker rats

Obese individuals are hyperinsulinemic and insulin resistant. Because amylin is cosecreted with insulin and may contribute to the insulin resistance of obesity, this study tested the hypothesis that insulin and amylin genes are coordinately regulated by obesity and carbohydrate feeding. Insulin and amylin gene expression were measured during the suckling/weaning transition in lean (Fa/Fa) and obese (fa/fa) Zucker rats, a period associated with marked changes in tissue insulin sensitivity. There was a decline in insulin mRNA (−90 ± 15%, P < 0.01) and amylin mRNA (−72 ± 21%, P < 0.01) content in pancreases of lean rats maintained on a high-fat diet from days 15 to 30, probably reflecting the relative increase in exocrine/endocrine development during this neonatal period and the effects of fat feeding. Weaning on high-carbohydrate versus high-fat diets resulted in enhanced expression of both insulin (P < 0.05) and amylin (P < 0.05) mRNAs. In contrast to the decline in pancreatic insulin and amylin mRNA content observed in lean rats, there was an increase in insulin mRNA (421.3 ± 57.5%, P < 0.05) and no change in amylin mRNA in obese rats maintained on a high-fat diet from days 15 to 30. There was no enhancement of insulin or amylin gene expression in obese rats with high carbohydrate relative to high-fat feeding, perhaps reflecting maximum rates of transcription in these obese insulin-resistant rats. Direct comparisons of insulin and amylin mRNA content between lean and obese rats revealed no differences at days 15–22 but enhanced expression of both mRNA types in obese rats by day 30, whether weaned on high-fat (P < 0.01) or high-carbohydrate (P < 0.05) diets. There was a significant correlation between pancreatic content of insulin and amylin mRNA (r = 0.749, P = <0.001) for all of the rats and nutritional conditions studied. These studies show enhanced expression of insulin and amylin genes with carbohydrate feeding and obesity and suggest coordinate expression of the genes that encode these two copackaged and secreted peptides.