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 1

Specific deletion of the Kcnj11 gene in β cells (βKcnj11–/–) severely impairs glucose tolerance and GIIS in mice.

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Specific deletion of the Kcnj11 gene in β cells (βKcnj11–/–) severely im...
(A) Electrophysiology of β cells of Kcnj11fl/fl and βKcnj11–/– mice. Left: representative recordings of whole-cell KATP currents in primary β cells isolated from Kcnj11fl/fl and βKcnj11–/– mice. Middle: conductance normalized to cell capacitance (n = 14 for Kcnj11fl/fl; n = 16 for Kcnj11fl/fl mice). Right: resting membrane potential of primary β cells from control and βKcnj11–/– mice measured by perforated patch (n = 7). (B) oGTT and corresponding plasma insulin levels. Left: blood glucose (n = 12). Right: plasma insulin (n = 17–20 for each point). (C) Plasma levels of total incretins in Kcnj11fl/fl and βKcnj11–/– mice. Glucose (1.5 g/kg) was administered to conscious mice fasted for 6 hours (n = 9–14 for each point). (D) Insulin secretion from perfused mouse pancreases. Mice were fasted overnight before perfusion experiments commenced (n = 4). (E) Dose-dependent effects of glucose on insulin secretion from the islets of Kcnj11fl/fl and βKcnj11–/– mice. Islets were preincubated for 30 minutes in KRBΒ containing 2.8 mM glucose and then stimulated with concentrations of glucose as indicated (0.5, 2.8, 5.6, 8.8, 11.1, and 16.7 mM) for 30 minutes (n = 6-8 for each point). A representative result of 3 independent experiments is shown. Statistical analyses were performed by 2-tailed Student’s unpaired t test (A) or 2-way ANOVA by followed by Dunnett’s post hoc test (B–E). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01.