Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.

Gunawardana SC, Head WS, Piston DW
Am J Physiol Endocrinol Metab. 2008 294 (6): E1097-108

PMID: 18413672 · DOI:10.1152/ajpendo.00748.2007

Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine. Thus both DMA and arginine have the potential to correct the secretory defect in diabetes by enabling or enhancing TDP. In the current study we have demonstrated the ability of these agents to improve blood glucose homeostasis in three mouse models of type 2 diabetes. The pattern of TDP under different conditions indicates that inhibition of NOS is not the only mechanism through which DMA exerts its positive effects. Thus we also have explored another possible mechanism through which DMA enables/enhances TDP, via the activation of mitochondrial alpha-ketoglutarate dehydrogenase.

MeSH Terms (23)

Amiloride Amino Acids, Cyclic Animals Arginine Blood Glucose Diabetes Mellitus, Type 2 Disease Models, Animal Drug Synergism Homeostasis Hydrogen-Ion Concentration Insulin Insulin-Secreting Cells Insulin Secretion Keto Acids Ketoglutarate Dehydrogenase Complex Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria NG-Nitroarginine Methyl Ester Nitric Oxide Synthase Type I Sodium-Calcium Exchanger

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