Stimulatory effect of imeglimin on incretin secretion

Abstract

Aims/introduction: Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin.

Materials and methods: Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets.

Results: Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice.

Conclusions: Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

Keywords: Glucagon-like peptide-1; Glucose-stimulated insulin secretion; Imeglimin.

Figure 1

Effects of a single oral dose of imeglimin on blood glucose, plasma insulin, and plasma incretin levels during an OGTT. (a, e) Effect of imeglimin (Ime) on blood glucose levels in C57BL/6 (a) and KK‐Ay (e) mice (n = 8 or 9 per group). The time course (left) and AUC (right) for blood glucose are shown. Imeglimin (200 mg/kg) or vehicle (Veh, deionized water) was administered orally to the fasted mice 1 h before the glucose (1.5 g/kg) challenge. (b, f) Plasma insulin levels at the indicated times after initiation of the OGTT in C57BL/6 (b) and KK‐Ay (f) mice (n = 8 or n = 7–9 per group, respectively). The insets show the AUC for plasma insulin. (c, g) Plasma total GIP levels at the indicated times after initiation of the OGTT in C57BL/6 (c) and KK‐Ay (g) mice (n = 7–9 or n = 8 per group, respectively). (d, h) Plasma active GLP‐1 levels at the indicated times after initiation of the OGTT in C57BL/6 (d) and KK‐Ay (h) mice (n = 8 or 9 or n = 7 or 8 per group, respectively). All data are mean ± SEM. Statistical analysis was performed with the two‐tailed unpaired Student's t test (AUC in a, b, e, and f) or by two‐way anova followed by Bonferroni's multiple comparison test (all other comparisons).*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs the corresponding value for vehicle in the time courses for blood glucose or as indicated.

Figure 2

Effects of single doses of imeglimin and sitagliptin on blood glucose, plasma insulin, and plasma incretin levels during an OGTT in KK‐Ay mice. (a) Effects of imeglimin (Ime), sitagliptin (Sita), and the combination of the two drugs on the time course (left) and AUC (right) for blood glucose (n = 4 or 5 mice per group). Vehicle (Veh, 0.5% carboxymethylcellulose), imeglimin (200 mg/kg), sitagliptin (15 mg/kg), or a mixture of the two drugs was administered orally to the fasted mice 1 h before glucose (1.5 g/kg) challenge. *P < 0.05, **P < 0.01 vs the corresponding value for vehicle; ^# P < 0.05, ^## P < 0.01 vs the corresponding value for imeglimin in the time course. (b) Plasma insulin levels during the OGTT (n = 4 or 5 mice per group). ***P < 0.001, ^# P < 0.05, ^#### P < 0.0001 vs the corresponding values for imeglimin and sitagliptin, respectively, in the time course. (c) Plasma total GIP levels during the OGTT (n = 4 or 5 mice per group). (d) Plasma active GLP‐1 levels during the OGTT (n = 4 or 5 mice per group). **P < 0.01, ***P < 0.001 vs the corresponding value for imeglimin; ^## P < 0.01, ^### P < 0.001 vs the corresponding value for sitagliptin in the time course. All data are mean ± SEM. Statistical analysis was performed by one‐way anova followed by Tukey's multiple comparison test (AUC) or by two‐way anova followed by Tukey's multiple comparison test (time courses). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 for the indicated comparisons in histograms.

Figure 3

Effects of imeglimin and incretins on GSIS in mouse pancreatic islets. Pancreatic islets isolated from C57BL/6 mice were incubated for 30 min with the indicated concentrations of glucose and either imeglimin (a) or imeglimin, GIP, or GLP‐1 (b), after which insulin secreted into the medium was assayed as a percentage of total islet content. Data are mean ± SEM (n = 6 or 7 independent experiments). Statistical analysis was performed by one‐way anova followed either by Dunnett's multiple comparison test (a) or by Bonferroni's multiple comparison test (b). *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant.

Figure 4

Effects of imeglimin and exendin‐9 in KK‐Ay mice as well as of imeglimin in Glp1r KO mice. (a) Effects of imeglimin (Ime), exendin‐9 (Ex‐9), and a mixture of the two agents on the time course (left) and AUC (right) for blood glucose in KK‐Ay mice (n = 4 or 5 per group) during an OGTT. Vehicle (Veh, 0.5% carboxymethylcellulose or saline), imeglimin (200 mg/kg, oral), exendin‐9 (50 μg/body, intraperitoneal), or both imeglimin and exendin‐9 were administered to fasted mice 30 min before glucose (1.5 g/kg) loading. *P < 0.05, **P < 0.01 vs vehicle in the time course. (b) Plasma insulin levels during the OGTT for mice (n = 4 or 5 per group) as in (a). (c) Effect of imeglimin on the time course (left) and AUC (right) for blood glucose in Glp1r KO mice (n = 6 per group) during an OGTT. Imeglimin (200 mg/kg) or vehicle (0.5% carboxymethylcellulose) was administered orally to the mice 1 h before glucose (1.5 g/kg) challenge. *P < 0.05, **P < 0.01 vs vehicle in the time course. (d) Plasma insulin levels during the OGTT for mice (n = 5 or 6 per group) as in (c). Data are mean ± SEM. Statistical analysis was performed with the two‐tailed unpaired Student's t‐test (AUC in c, by one‐way anova followed by Tukey's multiple comparison test (AUC in a, b), by two‐way anova followed by Tukey's multiple comparison test (time courses in a, b), or by two‐way anova followed by Bonferroni's multiple comparison test (time course in c and d). *P < 0.05, **P < 0.01 for histograms.