Stimulatory effect of imeglimin on incretin secretion

• Published in: Journal of diabetes investigation 2023-06, Vol.14 (6), p.746-755
• Main Authors: Yingyue, Quan, Sugawara, Kenji, Takahashi, Harumi, Yokoi, Norihide, Ohbayashi, Kento, Iwasaki, Yusaku, Seino, Susumu, Ogawa, Wataru
• Format: Article
• Language: English
• Subjects: Animals; Antidiabetics; Blood Glucose; Diabetes; Diabetes mellitus; Drug dosages; Gastric Inhibitory Polypeptide; GIP protein; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose - pharmacology; Glucose tolerance; Glucose‐stimulated insulin secretion; Hypoglycemic Agents - pharmacology; Imeglimin; Incretins - pharmacology; Insulin; Insulin secretion; Metformin; Mice; Mice, Inbred C57BL; Original; Plasma; Plasma levels; Secretion; Sitagliptin Phosphate - pharmacology; Statistical analysis; Variance analysis
• ISSN: 2040-1116; 2040-1124
• DOI: 10.1111/jdi.14001

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.