Abstract
Insufficient plasma insulin levels caused by deficits in both pancreatic β-cell function and mass contribute to the pathogenesis of type 2 diabetes. This loss of insulin-producing capacity is termed β-cell decompensation. Our work is focused on defining the role(s) of guanine nucleotide-binding protein (G protein) signaling pathways in regulating β-cell decompensation. We have previously demonstrated that the α-subunit of the heterotrimeric G(z) protein, Gα(z), impairs insulin secretion by suppressing production of cAMP. Pancreatic islets from Gα(z)-null mice also exhibit constitutively increased cAMP production and augmented glucose-stimulated insulin secretion, suggesting that Gα(z) is a tonic inhibitor of adenylate cyclase, the enzyme responsible for the conversion of ATP to cAMP. In the present study, we show that mice genetically deficient for Gα(z) are protected from developing glucose intolerance when fed a high fat (45 kcal%) diet. In these mice, a robust increase in β-cell proliferation is correlated with significantly increased β-cell mass. Further, an endogenous Gα(z) signaling pathway, through circulating prostaglandin E activating the EP3 isoform of the E prostanoid receptor, appears to be up-regulated in insulin-resistant, glucose-intolerant mice. These results, along with those of our previous work, link signaling through Gα(z) to both major aspects of β-cell decompensation: insufficient β-cell function and mass.
Highlights
G␣z can block insulin secretion, but no one had looked at its role in glucose intolerance
We have previously shown that the heterotrimeric Gi protein ␣-subunit, G␣z, modulates an endogenous signaling pathway that is inhibitory to glucose-stimulated insulin secretion (GSIS) in a rat -cell-derived cell line [7]
The results of this pilot study indicated that both the wild-type and G␣z-null mice became obese when fed on high fat diet (HFD) compared with the wild-type control diet groups, with the G␣znull HFD-fed mice exhibiting a greater initial weight gain that plateaued at the same level as the wild-type HFD mice
Summary
G␣z can block insulin secretion, but no one had looked at its role in glucose intolerance. We show that mice genetically deficient for G␣z are protected from developing glucose intolerance when fed a high fat (45 kcal%) diet In these mice, a robust increase in -cell proliferation is correlated with significantly increased -cell mass. An endogenous G␣z signaling pathway, through circulating prostaglandin E activating the EP3 isoform of the E prostanoid receptor, appears to be up-regulated in insulin-resistant, glucose-intolerant mice. These results, along with those of our previous work, link signaling through G␣z to both major aspects of -cell decompensation: insufficient -cell function and mass
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