Table I.

Examples of roles of heterotrimeric G-proteins and regulators of G-protein signaling [RGS] in islet β-cells in health and diabetes

Observations
Stimulatory glucose or a membrane depolarizing concentration of KCl transiently increased the carboxylmethylation [CML] of the Gγ-subunits of heterotrimeric G-proteins in HIT-T15 cells, rat islets and human islets. Mastoparan, a known activator of G-proteins also stimulated the CML of Gγ subunits. Pertussis toxin [Ptx] markedly attenuated the stimulatory effects of glucose, KCl or mastoparan.52
Fluoride, a known activator of trimeric G-proteins, induced apoptosis in RINm5F cells and normal rat islets. Potential involvement of G-proteins was confirmed by culture of β-cells with Ptx prior to exposure to fluoride.53
The β-subunit of trimeric G-proteins underwent phosphorylaton at a histidine residue in the membrane and secretory granule fraction in pancreatic β-cells. Incubation of phosphorylated β-subunit with Gα.GDP accelerated the dephosphorylation of the β-subunit, accompanied by the formation of GαGTP. This is the first evidence for a non-receptor-mediated activation of trimeric G-proteins by glucose in the pancreatic islet.54
Overexpression of G11α and PLCβ1 or PLCβ3 did not affect glucose- or carbachol-stimulated insulin secretion in INS-1 and βG40/110 cells. These findings suggested no correlation between inositol triphosphate accumulation and insulin secretion.55
Insulin secretion elicited by glucose, KCl and mitochondrial fuels was significantly blunted in islets from the GK rat. Mastoparan, a global activator of trimeric G-proteins circumvented such a secretory defect. These findings suggested a defect late in stimulus-secretion coupling is responsible for insulin secretory defects in this animal model.56
Glucotoxic conditions reduced the ADP ribosylation of Gαs and Gαolf subunits in the membrane fraction in HIT-T15 cells and [fed or fasted] rodent islets. It was concluded that defects in cAMP-dependent insulin secretion under the duress of glucotoxicity may, in part, be due to reduced ADP ribosylation of specific Gα subunits.57
Expression levels of Gαs and Gαolf, adenylyl cyclases 1 and 3 are significantly higher in GK rat islets compared to their control counterparts.58
Gαz-null mice exhibited increased glucose clearance following intraperitoneal and oral glucose challenge as compared with WT controls. Islets isolated from these mice also exhibited increased GSIS compared to those of WT mice. It was concluded that Gαz is negative regulator of insulin secretion.59
siRNA-Regulator of G-protein Signaling4 [RGS4] expression in MIN6 cells resulted in significantly higher M3 muscarinic receptor-mediated GSIS and calcium release. These findings were replicated in islets derived from RGS4-deficient mice. Based on these and additional supporting evidence, it was concluded that RGS4 plays a negative modulatory role in in vitro and in vivo models of insulin secretion.60
Whole pancreas or β-cell-specific Gαs deficiency leads to early-onset insulin-deficient diabetes with a severe defect in β-cell proliferation. These findings provide compelling evidence in support of critical roles of Gαs signaling in β-cell growth and function.61
Gαo2 deficient mice, but not Gαo1 or Gαi deficient mice exhibited higher glucose clearance more efficiently than WT mice via increased GSIS.62
Gαz-deficient mice are resistant to developing glucose intolerance following a high fat diet. These mice also exhibited increased β-cell proliferation and β-cell mass.63
Regulator of G-protein Signaling16 [RGS16] is abundantly expressed in pancreatic β-cells. Overexpression of RGS16 augmented GSIS in mouse and human islets suggesting a critical regulatory role for this protein in physiological insulin secretion. siRNA-RGS16 inhibited GSIS. Based on additional experimental evidence it was concluded that RGS16 plays a positive modulatory role of β-cell function including insulin secretion and proliferation by suppressing inhibitory signals elicited by somatostatin derived from the δ-cell of the islet.64