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Department of Physiology and Chronic Disease Research Center, Keimyung University School of Medicine, 194 Dongsan-Dong, Jung-Gu, Daegu, 700-712, South Korea
¹ Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, 138-736, South Korea
² Department of Food Science and Nutrition, University of Ulsan College of Medicine, Seoul, 138-736, South Korea

(Requests for offprints should be addressed to D-K Song; Email: dksong{at}kmu.ac.kr)

^* (Y-H Suh and S-Y Kim contributed equally to this work)

The short heterodimer partner (SHP) (NR0B2) is an orphan nuclear receptor whose function in pancreatic ß-cells is unclear. Mitochondrial uncoupling protein (UCP2) in ß-cells is upregulated in obesity-related diabetes, causing impaired glucose-stimulated insulin secretion (GSIS). We investigated whether SHP plays a role in UCP2-induced GSIS impairment. We overexpressed SHP in normal islet cells and in islet cells overexpressing UCP2 by an adenovirus-mediated infection technique. We found that SHP overexpression enhanced GSIS in normal islets, and restored GSIS in UCP2-overexpressing islets. SHP overexpression increased the glucose sensitivity of ATP-sensitive K⁺ (K_ATP) channels and enhanced theATP/ADP ratio. A peroxisome proliferator-activated receptor gamma (PPAR) antagonist, GW9662, did not block the SHP effect on GSIS. SHP overexpression also corrected the impaired sensitivity of UCP2-overexpressing ß-cells to methylpyruvate, another energy fuel that bypasses glycolysis and directly enters the Krebs cycle. K_ATP channel inhibition mediated by dihydroxyacetone, which gives reducing equivalents directly to complex II of the electron transport system, was similar in Ad-Null-, Ad-UCP2- and Ad-UCP2+Ad-SHP-infected cells. The mitochondrial metabolic inhibitor sodium azide totally blocked the effect of SHP overexpression on GSIS. These results suggest that SHP positively regulates GSIS in ß-cells and restores glucose sensitivity in UCP2-overexpressing ß-cells by enhancing mitochondrial glucose metabolism, independent of PPAR activation.

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