Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets.

Abstract

Abstract Prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of Pdx-1 and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown.

Objective: To ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo.

Research Design and Methods: Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis.

Results: Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose + Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm vs. the nucleus. In contrast, MafA mRNA and protein levels, and β-cell mass and proliferation were unchanged.

Conclusions: Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty-acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect which may contribute to β-cell failure in type 2 diabetes.