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Functional Genomics of the ß-Cell: Short-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase Regulates Insulin Secretion Independent of K⁺ Currents

Departments of Genetics (O.T.H., R.K.G., P.W., K.H.K.) and Biochemistry and Biophysics (N.M.D., F.M.M.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology and Medicine (H.E.H., T.C.B., C.B.N.), Duke University Medical Center, Durham, North Carolina 27704; and Computational Biology and Informatics Laboratory (E.M., C.J.S.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Klaus H. Kaestner, Ph.D., Department of Genetics, University of Pennsylvania, 415 Curie Boulevard, 560 Clinical Research Building, Philadelphia, Pennsylvania 19104. E-mail: kaestner{at}mail.med.upenn.edu.

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 ß-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 ß-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 K_ATP channel with diazoxide, suggesting that SCHAD regulates insulin secretion through a K_ATP channel-independent mechanism. Our results suggest a molecular explanation for the hyperinsulinemia hypoglycemic seen in patients with SCHAD deficiency.

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