Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets

Derek K. Hagman, Martin G. Latour, Swarup K. Chakrabarti, Ghislaine Fontes, Julie Amyot, Caroline Tremblay, Meriem Semache, James A. Lausier, Violet Roskens, Raghavendra G. Mirmira, Thomas L. Jetton, Vincent Poitout

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

OBJECTIVE-Prolonged exposure of isolated islets of Langer-hans 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 B-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.

Original languageEnglish (US)
Pages (from-to)424-431
Number of pages8
JournalDiabetes
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Hagman, D. K., Latour, M. G., Chakrabarti, S. K., Fontes, G., Amyot, J., Tremblay, C., Semache, M., Lausier, J. A., Roskens, V., Mirmira, R. G., Jetton, T. L., & Poitout, V. (2008). Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. Diabetes, 57(2), 424-431. https://doi.org/10.2337/db07-1285