The GTPase-Activating Protein RGS2 reduces pancreatic β-cell insulin release

Background Insulin-secreting β-cells are important regulators of blood glucose homeostasis. In individuals susceptible to develop type 2 diabetes (T2D), chronically elevated levels of glucose and fatty acids can cause β-cell stress, exhaustion, and death. We previously described β-cell expression of the transcription factor NPAS4 in response to glucose exposure or cellular stressors. NPAS4 promotes β-cell survival by dampening insulin production and secretion. Our goal was to identify target genes mediating these effects. The GTPase-accelerating protein RGS2 of the Regulator of G-protein Signalling (RGS) family was a promising candidate, since other RGS proteins regulate β-cell function and survival. Consequently, we hypothesized that RGS2 inhibits β-cell insulin secretion. Methods: We employed both gain-of-function (adenoviral overexpression in MIN6 cells or mouse islets) and loss-of-function (MIN6-derived Rgs2 knockout cell lines) models. Glucose-stimulated β-cell function was assessed via insulin ELISA, calcium imaging, and measurement of oxygen consumption rate (OCR). Results: Rgs2 overexpression diminished glucose-stimulated insulin secretion (GSIS) in islets and MIN6 cells by 30 % and 55-70 %, respectively, while KCl-driven insulin release and insulin content were unchanged. Additionally, Rgs2-overexpressing MIN6 cells showed 17 % lower glucose-stimulated calcium influx. Changes in these parameters coincided with a 30 % reduction in OCR during high glucose exposure of Rgs2-overexpressing islets. In contrast, Rgs2 knockout cells exhibited slightly elevated GSIS. Finally, RGS2 expression was decreased in islets from T2 D donors (results presented as: SEM; Student’s t-test; p < 0.05). Conclusion: Our findings suggest that RGS2 reduces oxidative phosphorylation, thus limiting calcium influx and insulin secretion. The exact mechanism remains to be discovered.

Publication History

Article published online:
06 May 2021