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Diabetes 52:965-973, 2003
© 2003 by the American Diabetes Association, Inc.

Inhibition of Mitochondrial Na+-Ca2+ Exchanger Increases Mitochondrial Metabolism and Potentiates Glucose-Stimulated Insulin Secretion in Rat Pancreatic Islets

Bumsup Lee1, Philip D. Miles2, Leonardo Vargas1, Peng Luan1, Susan Glasco1, Yulia Kushnareva1, Elisabeth S. Kornbrust1, Kathryn A. Grako1, Claes B. Wollheim3, Pierre Maechler3, Jerrold M. Olefsky2, and Christen M. Anderson1

1 Division of Metabolic Diseases, MitoKor, San Diego, California
2 Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
3 Department of Medicine, University Medical Center, Geneva, Switzerland

The mitochondrial Na+-Ca2+ exchanger (mNCE) mediates efflux of Ca2+ from mitochondria in exchange for influx of Na+. We show that inhibition of the mNCE enhances mitochondrial oxidative metabolism and increases glucose-stimulated insulin secretion in rat islets and INS-1 cells. The benzothiazepine CGP37157 inhibited mNCE activity in INS-1 cells (50% inhibition at IC50 = 1.5 µmol/l) and increased the glucose-induced rise in mitochondrial Ca2+ ([Ca2+]m) 2.1 times. Cellular ATP content was increased by 13% in INS-1 cells and by 49% in rat islets by CGP37157 (1 µmol/l). Krebs cycle flux was also stimulated by CGP37157 when glucose was present. Insulin secretion was increased in a glucose-dependent manner by CGP37157 in both INS-1 cells and islets. In islets, CGP37157 increased insulin secretion dose dependently (half-maximal efficacy at EC50 = 0.06 µmol/l) at 8 mmol/l glucose and shifted the glucose dose response curve to the left. In perifused islets, mNCE inhibition had no effect on insulin secretion at 2.8 mmol/l glucose but increased insulin secretion by 46% at 11 mmol/l glucose. The effects of CGP37157 could not be attributed to interactions with the plasma membrane sodium calcium exchanger, L-type calcium channels, ATP-sensitive K+ channels, or [Ca2+]m uniporter. In hyperglycemic clamp studies of Wistar rats, CGP37157 increased plasma insulin and C-peptide levels only during the hyperglycemic phase of the study. These results illustrate the potential utility of agents that affect mitochondrial metabolism as novel insulin secretagogues.


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