Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression?
Colin G. Nichols, … , Nathaniel W. York, Maria S. Remedi
Colin G. Nichols, … , Nathaniel W. York, Maria S. Remedi
Published November 16, 2020
Citation Information: J Clin Invest. 2020;130(12):6235-6237. https://doi.org/10.1172/JCI143199.
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Commentary

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

Abstract

Patients with type 2 diabetes (T2D) fail to secrete insulin in response to increased glucose levels that occur with eating. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two incretins secreted from gastrointestinal cells that amplify insulin secretion when glucose is high. In this issue of the JCI, Oduori et al. explore the role of ATP-sensitive K+ (KATP) channels in maintaining glucose homeostasis. In persistently depolarized β cells from KATP channel knockout (KO) mice, the researchers revealed a shift in G protein signaling from the Gs family to the Gq family. This shift explains why GLP-1, which signals via Gq, but not GIP, which signals preferentially via Gs, can effectively potentiate secretion in islets from the KATP channel–deficient mice and in other models of KATP deficiency, including diabetic KK-Ay mice. 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.

Authors

Colin G. Nichols, Nathaniel W. York, Maria S. Remedi

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Figure 1

Model for T2D progression and treatment.

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Model for T2D progression and treatment. (A) (i) Lean individuals with n...
(A) (i) Lean individuals with normal glucose tolerance (NGT) develop increasing obesity (OB), which reduces insulin sensitivity. (ii) Pancreatic β cells respond by reducing KATP current density and increasing excitability/mean intracellular [Ca], which initially results in increased insulin secretion, maintaining normal blood glucose. However, above a certain level (iii), high excitability/intracellular [Ca] paradoxically inhibits insulin secretion itself (indicated by arrow). Impaired glucose tolerance (IGT) then progresses to overt diabetes (DIAB), coupled to an inexorable rise in blood glucose (iv), as the initially compensatory hyperinsulinemia (Hi INS) progresses to hypoinsulinemia (Lo INS). (B) As Oduori et al. (14) show, the same hyperexcitability that drives the switch to low insulin secretion also drives a shift of GPCR coupling from Gs to Gq. Consequently, GLP-1 treatment (acting via Gq) can maintain amplification of insulin secretion and, hence, slow the rise of blood glucose (indicated by arrows), whereas GIP (which does not couple to Gq) would have little to no effect.