Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K+ currents.
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.
Hardy
Olga T
OT
Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, 560 Clinical Research Building, Philadelphia, Pennsylvania 19104, USA.
Hohmeier
Hans E
HE
Becker
Thomas C
TC
Manduchi
Elisabetta
E
Doliba
Nicolai M
NM
Gupta
Rana K
RK
White
Peter
P
Stoeckert
Christian J
CJ
Matschinsky
Franz M
FM
Newgard
Christopher B
CB
Kaestner
Klaus H
KH
D000818:Animals; D044926:Butyryl-CoA Dehydrogenase / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D015221:Potassium Channels / Q000502:physiology*; D034622:RNA Interference; D051381:Rats
D007328:Insulin; D015221:Potassium Channels; D044926:Butyryl-CoA Dehydrogenase