Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes
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
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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Research Article Endocrinology Metabolism

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 2

GLP-1– but not GIP-based treatment restores glucose tolerance and insulin secretion in βKcnj11–/– mice.

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GLP-1– but not GIP-based treatment restores glucose tolerance and insuli...
(A) Effects of sitagliptin (Sita) on oGTT. Sita (2 mg/kg) was orally administered to mice 45 minutes before glucose challenge (1.5 g/kg) (n = 5–8 mice per group). Veh, vehicle (water). (B) Plasma active incretins before and 15 minutes after glucose challenge shown in A (n = 5–10 for each point). (C) Plasma insulin before and 15 minutes after glucose challenge shown in A (n = 5–10 for each point). (D) Effects of exendin-9 (Ex9) on blood glucose and plasma insulin during oGTT following sitagliptin treatment. Sitagliptin (orally) and exendin-9 (50 μg/kg, i.p.) were administered 45 minutes and 15 minutes, respectively, before glucose challenge (n = 6–10 per group for blood glucose; n = 7–8 for each point for plasma insulin). Vehicle, water. (E) Effects of liraglutide (Lira) on blood glucose and plasma insulin. Liraglutide (50 μg/kg, i.p.) was administered to mice 120 minutes before glucose challenge (n = 7–12 per group for blood glucose; n = 6–8 for each point for insulin). Vehicle, saline. (F) Effects of incretins on insulin secretion from perfused pancreases. Total amount of GLP-1IIS or GIPIIS over a period of 15–30 minutes is expressed as AUC, in insert (n = 4 for both groups). (G) Dose-dependent effects of incretins on insulin secretion from pancreatic islets. Amplifying effects of each incretin at the indicated concentrations (0, 0.05, 0.1, 0.5, and 1 nM) (n = 6–8 for each point). Statistical analyses were performed by 2-way ANOVA followed by Dunnett’s post hoc test (A–D, G) or by 2-tailed Student’s unpaired t test (F). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01.