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Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets.
Diabetes. 2003 Apr; 52(4):965-73.D

Abstract

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.

Authors+Show Affiliations

Division of Metabolic Diseases, MitoKor, San Diego, California 92121, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12663468

Citation

Lee, Bumsup, et al. "Inhibition of Mitochondrial Na+-Ca2+ Exchanger Increases Mitochondrial Metabolism and Potentiates Glucose-stimulated Insulin Secretion in Rat Pancreatic Islets." Diabetes, vol. 52, no. 4, 2003, pp. 965-73.
Lee B, Miles PD, Vargas L, et al. Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets. Diabetes. 2003;52(4):965-73.
Lee, B., Miles, P. D., Vargas, L., Luan, P., Glasco, S., Kushnareva, Y., Kornbrust, E. S., Grako, K. A., Wollheim, C. B., Maechler, P., Olefsky, J. M., & Anderson, C. M. (2003). Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets. Diabetes, 52(4), 965-73.
Lee B, et al. Inhibition of Mitochondrial Na+-Ca2+ Exchanger Increases Mitochondrial Metabolism and Potentiates Glucose-stimulated Insulin Secretion in Rat Pancreatic Islets. Diabetes. 2003;52(4):965-73. PubMed PMID: 12663468.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets. AU - Lee,Bumsup, AU - Miles,Philip D, AU - Vargas,Leonardo, AU - Luan,Peng, AU - Glasco,Susan, AU - Kushnareva,Yulia, AU - Kornbrust,Elisabeth S, AU - Grako,Kathryn A, AU - Wollheim,Claes B, AU - Maechler,Pierre, AU - Olefsky,Jerrold M, AU - Anderson,Christen M, PY - 2003/3/29/pubmed PY - 2003/5/20/medline PY - 2003/3/29/entrez SP - 965 EP - 73 JF - Diabetes JO - Diabetes VL - 52 IS - 4 N2 - 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. SN - 0012-1797 UR - https://www.unboundmedicine.com/medline/citation/12663468/Inhibition_of_mitochondrial_Na+_Ca2+_exchanger_increases_mitochondrial_metabolism_and_potentiates_glucose_stimulated_insulin_secretion_in_rat_pancreatic_islets_ L2 - https://diabetes.diabetesjournals.org/lookup/pmidlookup?view=long&pmid=12663468 DB - PRIME DP - Unbound Medicine ER -