Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors
Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens
Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens
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Article Metabolism

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Abstract

The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R–/– but not in Gipr–/– mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.

Authors

Frédéric Preitner, Mark Ibberson, Isobel Franklin, Christophe Binnert, Mario Pende, Asllan Gjinovci, Tanya Hansotia, Daniel J. Drucker, Claes Wollheim, Rémy Burcelin, Bernard Thorens

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Glucose-induced insulin secretion in RipGlut1Glut2–/– female mice. (a) I...
Glucose-induced insulin secretion in RipGlut1Glut2–/– female mice. (a) IPGTTs (1 mg/g) in RipGlut1Glut2–/– compared to C57BL/6J WT mice (n = 7). §P < 0.005. (b) Glucose-induced insulin secretion in perfused pancreata of RipGlut1Glut2–/– (n = 4) compared to WT mice (n = 6). Pancreata were perfused as described in Figure 4 (b, inset). Quantification of the AUCs corresponding to first- and second-phase insulin secretion from pancreata of WT (white bars) and RipGlut1Glut2–/– (gray bars) mice. Data are presented as means ± SEM from four to six separate experiments. *P < 0.001, **P < 0.04, for mutant vs. WT mice. (c) Glycemic profiles of control mice infused through the portal vein, between 60 and 150 minutes (open bar at the top), with saline (diamonds) or exendin-(9–39) (0.5 pmol/kg/min, squares) and receiving an intraperitoneal (i.p.) glucose injection (1 mg/g) at 90 minutes (arrow, i.p. glucose). The glycemic profiles were similar in the two groups. (d) Plasma insulin levels for the experiment presented in c. Basal (0 and 60 minutes) insulin levels were similar in both groups of mice. First peak of insulin secretion (92 minutes) was, however, strikingly reduced in exendin-(9–39)–infused mice. Plasma insulin levels at 105 minutes (i.e., 15 minutes after glucose injection) were similar in both groups of mice. These data demonstrate that inhibition of the hepatoportal vein glucose sensor significantly blunts first-phase insulin secretion after intraperitoneal glucose injection. Data are mean ± SEM with n = 7 and n = 5 for saline- and exendin-(9–39)–infused mice, respectively.