UMMS Affiliation

Department of Pediatrics

Date

3-23-2007

Document Type

Article

Medical Subject Headings

Animals; Butyryl-CoA Dehydrogenase; Cells, Cultured; Gene Expression Profiling; Genomics; Insulin; *Insulin-Secreting Cells; Mice; Mice, Transgenic; Models, Biological; Potassium Channels; RNA Interference; Rats

Disciplines

Endocrinology, Diabetes, and Metabolism | Pediatrics

Abstract

Recent advances in functional genomics afford the opportunity to interrogate the expression profiles of thousands of genes simultaneously and examine the function of these genes in a high-throughput manner. In this study, we describe a rational and efficient approach to identifying novel regulators of insulin secretion by the pancreatic beta-cell. Computational analysis of expression profiles of several mouse and cellular models of impaired insulin secretion identified 373 candidate genes involved in regulation of insulin secretion. Using RNA interference, we assessed the requirements of 10 of these candidates and identified four genes (40%) as being essential for normal insulin secretion. Among the genes identified was Hadhsc, which encodes short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), an enzyme of mitochondrial beta-oxidation of fatty acids whose mutation results in congenital hyperinsulinism. RNA interference-mediated gene suppression of Hadhsc in insulinoma cells and primary rodent islets revealed enhanced basal but normal glucose-stimulated insulin secretion. This increase in basal insulin secretion was not attenuated by the opening of the KATP channel with diazoxide, suggesting that SCHAD regulates insulin secretion through a KATP channel-independent mechanism. Our results suggest a molecular explanation for the hyperinsulinemia hypoglycemic seen in patients with SCHAD deficiency.

Rights and Permissions

Citation: Mol Endocrinol. 2007 Mar;21(3):765-73. Epub 2006 Dec 21. Link to article on publisher's site

Comments

At the time of publication, Olga Hardy was not yet affiliated with the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

17185391

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