Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes

Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression?

“…Their results provide one explanation for differential insulinotropic potential of incretins in human T2D and point to a potentially unifying model for T2D progression itself. Gq signaling, may have therapeutic value ( Figure 1B) (14). For the results of Oduori et al to provide the explanation for incretin bias in T2D, T2D must involve chronic depolarization.…”

“…Oduori et al (14) follow up on their earlier studies, which showed that GLP-1 induced insulin secretion (GLP-1IIS) from perfused pancreas was partially retained, while GIPIIS was severely diminished in these K ATP -KO mice (15). They now show that β cell-specific Kir6.2-KO mice (βKcnj11 -/mice) also exhibit severe glucose intolerance and impaired GIIS and that insulin secretion can be stimulated by GLP-1, but not by GIP, confirming that the K ATP -KO phenotype reflects β cell-specific phenomena.…”

“…They now show that β cell-specific Kir6.2-KO mice (βKcnj11 -/mice) also exhibit severe glucose intolerance and impaired GIIS and that insulin secretion can be stimulated by GLP-1, but not by GIP, confirming that the K ATP -KO phenotype reflects β cell-specific phenomena. By careful and extensive biochemical and pharmacological studies, Oduori et al (14) show that GLP-1 sensitivity (and GIP insensitivity) in these hyperexcited β cells results from a relative shift from Gs to Gq signaling. Notably, membrane potential can modulate GPCRs, and sodium ions can allosterically affect class A GPCRs to modulate activation and signaling.…”

“…Notably, membrane potential can modulate GPCRs, and sodium ions can allosterically affect class A GPCRs to modulate activation and signaling. Oduori et al (14) suggest that persistent β cell depolarization might induce a signaling bias, from Gs to Gq signaling, by chronically elevating internal sodium concentration. However, calcium control of G protein function may offer an alternative explanation.…”

β-cell SENP1 facilitates responsiveness to incretins and limits oral glucose intolerance in high fat fed mice

“…These pathways could be required for robust insulin secretory responses to receptormediated secretagogues such as the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) 2 which amplify glucose-stimulated responses via G-protein coupled receptors through cAMP-dependent and cAMP-independent mechanisms 3,4 . The action of the incretins to facilitate insulin secretion is impaired in type 2 diabetes (T2D), although the underlying mechanism for such a failure appears complex 5 and could involve altered incretin receptor signalling 6 . Our recent study showed that incretin-induced insulin secretion from human islets correlates with the ability of glucose to augment depolarization-induced insulin exocytosis in single b-cells 7 .…”