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

Abstract

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.

Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes

“…While classical studies pioneered by Henquin and colleagues have elucidated that extracellular glucose induces acute/transient (e.g., 0-10 minutes) intracellular alkalinization, likely through HCO 3 --mediated transport mechanisms, previous work has mainly focused on the acute role of insulin secretagogues on islet pH i (64,65). Our current work builds on early studies that demonstrated β cell alkalinization in islets of multiple mouse models of T2DM and the corresponding enhancement of insulin secretion after administration of pH i -lowering agents (26,27). Interestingly, it was recently noted that chronic hyperglycemia in vitro induces β cell alkalinization (66).…”

“…Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes to repress GSIS (25). Moreover, decreasing islet cell pH i with dimethyl amiloride was demonstrated to augment time-dependent potentiation of insulin secretion and improve glucose metabolism in T2DM rodent models (24,26,27).…”

Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

“…Derivatives of amiloride have been reported to increase insulin secretion from β-cells in vitro and in vivo (30,31). In contrast, no association between propafenone and insulin secretion has been previously reported.…”

A unique modulator of endoplasmic reticulum stress‐signalling pathways: the novel pharmacological properties of amiloride in glial cells

“…Interestingly, amiloride and its derivatives have been reported to be effective in treating type 2 diabetes (Gunawardana et al. , 2008), Huntington's disease (Wong et al.…”