Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Abstract

Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

“…As GPCRs have been described to contribute to β cell mass through their role in mediating β cell properties such as proliferation and apoptosis1314151617181920, we examined the effect of Ffar2 deletion on β cell mass. Immunohistochemical (IHC) and morphometric analysis of normal chow (NC) fed Ffar2 −/− male mice at 26 weeks revealed significantly decreased insulin positive area (relative to total pancreatic area), smaller average β cell area per islet, and decreased β cell mass compared to age matched, WT controls (Fig.…”

A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development

“…Compromised β cell development in rats results in an insufficient number of cells to adequately control glucose metabolism (Figliuzzi et al, 2010). In mice, perinatal β cell proliferation rates can be tuned via the modulation of Gi-GPCR signaling (Berger et al, 2015). Changes to early β cell proliferation capacity in these mice correlates directly with adult β cell mass, which subsequently impacts glucose regulation (Berger et al, 2015).…”

“…In mice, perinatal β cell proliferation rates can be tuned via the modulation of Gi-GPCR signaling (Berger et al, 2015). Changes to early β cell proliferation capacity in these mice correlates directly with adult β cell mass, which subsequently impacts glucose regulation (Berger et al, 2015). Furthermore, meta analysis of human data has revealed a correlation between an early age of β cell loss and more rapid onset of T1D (Klinke, 2008), consistent with the model that failure to generate a reserve of β cells early in development increases disease risk.…”

SCFA Receptors in Pancreatic β Cells: Novel Diabetes Targets?

“…As with GSIS, Gα q/11 coupled GPCRs have been observed to augment β cell mass expansion in response to insulin resistance, whereas Gα i/o coupled GPCRs have been reported to restrict the β cell mass expansion [34, 35]. Not surprisingly, McNelis et al [19] observed reduced β cell mass in Ffar2 −/− mice on a HFD compared to WT mice, lower β cell proliferation and reduced expression of insulin and the β cell transcription factors ( Mafa , Pdx1 , NeuroD ) [19].…”