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

¹ Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Quebec, Canada
² Department of Medicine and the Diabetes Center, University of Virginia, Charlottesville, Virginia
³ Division of Endocrinology, Diabetes and Metabolism, University of Vermont College of Medicine, Burlington, Vermont
⁴ Departments of Medicine, Nutrition, and Biochemistry, Université de Montréal, Montréal, Quebec, Canada

Address correspondence and reprint requests to Vincent Poitout, DVM, PhD, Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Technopole Angus, 2901 Rachel Est, Montréal, QC, H1W 4A4, Canada. E-mail: vincent.poitout{at}umontreal.ca

Key Words: ChIP, chromatin immunoprecipitation • GSIS, glucose-stimulated insulin secretion • NEFA, nonesterified fatty acid • Pdx-1, pancreas-duodenum homeobox-1

OBJECTIVE—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 pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore 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 plus 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 versus 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 that may contribute to β-cell failure in type 2 diabetes.

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