Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes
Okechi S. Oduori, … , Patrik Rorsman, Susumu Seino
Okechi S. Oduori, … , Patrik Rorsman, Susumu Seino
Published November 16, 2020
Citation Information: J Clin Invest. 2020;130(12):6639-6655. https://doi.org/10.1172/JCI140046.
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Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes

Abstract

By restoring glucose-regulated insulin secretion, glucagon-like peptide-1–based (GLP-1–based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1–based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (KATP) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell–specific Kcnj11–/– mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.

Authors

Okechi S. Oduori, Naoya Murao, Kenju Shimomura, Harumi Takahashi, Quan Zhang, Haiqiang Dou, Shihomi Sakai, Kohtaro Minami, Belen Chanclon, Claudia Guida, Lakshmi Kothegala, Johan Tolö, Yuko Maejima, Norihide Yokoi, Yasuhiro Minami, Takashi Miki, Patrik Rorsman, Susumu Seino

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Figure 5

β Cell membrane potential and insulin secretion from islets in various models of β cell persistent depolarization.

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β Cell membrane potential and insulin secretion from islets in various m...
(A) Representative traces of electrophysiological recordings of primary β cells of WT mice. Recordings were made in the presence of 1 mM glucose after chronic (3 days) culture of WT mouse islets in normal glucose (5.5 mM) or high glucose (25 mM). G, glucose. (B) Membrane potential of primary β cells of WT mice measured under the same conditions as described in A (n = 5–6 for each condition). (C) Insulin secretion from WT mouse islets. Insulin secretion was measured after chronic (4 days) culture of WT mouse islets in 5.5 mM (blue) or 25 mM (red) glucose (n = 8 for each condition). (D) Representative traces of electrophysiological recordings of primary β cells of KK and KK-Ay mice. Recordings were made in the presence of glucose at the concentrations indicated. (E) Membrane potential of primary β cells of KK and KK-Ay mice. Membrane potential was measured in the presence of glucose at concentrations indicated (n = 6 for each condition). (F) Insulin secretion from the islets of KK and KK-Ay mice (n = 6–8 for each condition). Statistical analyses were performed by 2-way ANOVA (B, C, E, and F), followed by Tukey’s post hoc test (C and F). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01.