Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets
| Autor: | Philip D.G. Miles, Christen M. Anderson, Claes B. Wollheim, Leonardo Vargas, Kathryn A. Grako, Yulia Kushnareva, Susan Glasco, Pierre Maechler, Bumsup Lee, Elisabeth S. Kornbrust, Peng Luan, Jerrold M. Olefsky |
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| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty Thiazepines Endocrinology Diabetes and Metabolism medicine.medical_treatment Gene Expression Mitochondrion Biology Transfection Clonazepam Sodium-Calcium Exchanger Cell Line Rats Sprague-Dawley chemistry.chemical_compound Islets of Langerhans Adenosine Triphosphate Aequorin Internal medicine Insulin Secretion Internal Medicine medicine Animals Insulin Uniporter Voltage-dependent calcium channel Sodium-calcium exchanger Pancreatic islets Cell Membrane Metabolism NAD Mitochondria Rats Endocrinology medicine.anatomical_structure Glucose L-Glucose chemistry Calcium Reactive Oxygen Species |
| Zdroj: | Diabetes. 52(4) |
| ISSN: | 0012-1797 |
| Popis: | The mitochondrial Na(+)-Ca(2+) exchanger (mNCE) mediates efflux of Ca(2+) 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 IC(50) = 1.5 micro mol/l) and increased the glucose-induced rise in mitochondrial Ca(2+) ([Ca(2+)](m)) 2.1 times. Cellular ATP content was increased by 13% in INS-1 cells and by 49% in rat islets by CGP37157 (1 micro mol/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 EC(50) = 0.06 micro mol/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 [Ca(2+)](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. |
| Databáze: | OpenAIRE |
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