Molecular adaptations in islets from neonatal rats reared artificially on a high carbohydrate milk formula.

Four day-old rat pups artificially raised on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia which persists into adulthood despite weaning onto lab chow on day 24. The present study investigates the molecular adaptations in islets isolated from neonatal rats in response to this dietary treatment during their suckling period. There is a significant increase in the level of preproinsulin mRNA and insulin biosynthesis in 12 day-old HC islets compared to islets from age-matched mother-fed (MF) control rats. Pancreatic duodenal homeobox factor-1 (PDX-1) modulates pancreatic ontogeny as well as preproinsulin gene expression in islets from neonatal rats. The mRNA level, DNA binding activity and protein content of PDX-1 are significantly increased in HC islets. The stress-activated protein kinase-2 and phosphatidylinositol 3-kinase have been reported to modulate PDX-1 activity in islets. The mRNA levels of these kinases are increased in HC islets. The mRNA level of upstream stimulatory factor (a modulator of PDX-1 gene expression) is also significantly increased in HC islets. These results indicate that the upregulation of several molecular events, including increases in the gene expression of preproinsulin, transcription factors and kinases may contribute to the chronic hyperinsulinemic state in the HC rats.