Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.
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.
Gunawardana
Subhadra C
SC
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Head
W Steven
WS
Piston
David W
DW
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D006706:Homeostasis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007651:Keto Acids / Q000494:pharmacology; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000598:Amino Acids, Cyclic; D001786:Blood Glucose; D007328:Insulin; D007651:Keto Acids; D019831:Sodium-Calcium Exchanger; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; C039465:5-dimethylamiloride; D000584:Amiloride; C013082:alpha-ketoisocaproic acid; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D007655:Ketoglutarate Dehydrogenase Complex; D019331:NG-Nitroarginine Methyl Ester