Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents

Abstract

Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin.

Keywords: glucose-stimulated insulin secretion; imeglimin; β-cell.

Fig. 1.

One week of imeglimin treatment does not alter body weight, basal energetics, body composition, or food intake in chow-fed mice. A–C: body weight, %body fat, and %body muscle. D and E: food intake during light and dark hours. F: food intake time course. G: water drinking. H: 24-h activity. I: activity time course. J: 24-h energy expenditure. K: energy expenditure time course. L and M: average V̇o₂ and V̇o₂ time course. N and O: average V̇co₂ and V̇co₂ time course. P and Q: average respiratory exchange ratio (RER) and RER time course. Data are means ± SE of n = 8/group. *P < 0.05. NS, not significant.

Fig. 2.

Three weeks of imeglimin treatment does not alter body weight, basal energetics, body composition, or food intake in chow-fed mice. A–C: body weight, %body fat, and %body muscle. D and E: food intake during light and dark hours. F: food intake time course. G: water drinking. H: 24-h activity. I: activity time course. J: 24-h energy expenditure. K: energy expenditure time course. L and M: average V̇o₂ and V̇o₂ time course. N and O: average V̇co₂ and V̇co₂ time course. P and Q: average RER and RER time course. Data are means ± SE of n = 8/group. *P < 0.05.

Fig. 3.

One week of imeglimin treatment does not alter basal energetics, body composition, or food intake in high-fat-fed mice. A–C: body weight, %body fat, and %body muscle. D and E: food intake during light and dark hours. F: food intake time course. G: water drinking. H: 24-h activity. I: activity time course. J: 24-h energy expenditure. K: energy expenditure time course. L and M: average V̇o₂ and V̇o₂ time course. N and O: average V̇co₂ and V̇co₂ time course. P and Q: average RER and RER time course. Data are means ± SE of n = 8/group, with comparisons by t-test. *P < 0.05.

Fig. 4.

Five weeks of imeglimin treatment does not alter basal energetics, body composition, or food intake in high-fat-fed mice. A–C: body weight, %body fat, and %body muscle. D and E: food intake during light and dark hours. F: food intake time course. G: water drinking. H: 24-h activity. I: activity time course. J: 24-h energy expenditure. K: energy expenditure time course. L and M: average V̇o₂ and V̇o₂ time course. N and O: average V̇co₂ and V̇co₂ time course. P and Q: average RER and RER time course. Data are means ± SE of n = 8/group. *P < 0.05.

Fig. 5.

Imeglimin increases glucose-stimulated insulin secretion in vivo and in vitro in chow-fed rats. A and B: plasma glucose and glucose area under the curve (AUC) during a glucose tolerance test. C and D: plasma insulin and insulin AUC during a glucose tolerance test. Data are means ± SE of n = 6/group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by t-test.

Fig. 6.

Imeglimin increases glucose-stimulated insulin secretion in vivo in high-fat-fed rats. A and B: plasma glucose and glucose AUC during a glucose tolerance test. C and D: plasma insulin and insulin AUC during a glucose tolerance test. Data are means ± SE of n = 6/group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by t-test.

Fig. 7.

Imeglimin does not alter insulin sensitivity in chow-fed rats. A and B: AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) phosphorylation. C: plasma insulin at the end of the clamp. D: plasma glucose. E: glucose infusion rate to maintain euglycemia. F: hepatic glucose production. ****P < 0.0001 relative to basal. G: skeletal muscle glucose uptake during the clamp. Data are means ± SE of n = 6/group, with comparisons by t-test.

Fig. 8.

Imeglimin does not alter insulin sensitivity in high-fat-fed rats. A: plasma insulin at the end of the clamp. B: plasma glucose. C: glucose infusion rate to maintain euglycemia. D: hepatic glucose production. *P < 0.05 and **P < 0.01 relative to basal. E: skeletal muscle glucose uptake during the clamp. Data are means ± SE of n = 6/group, with comparisons by t-test.

Fig. 9.

Imeglimin amplifies insulin secretion in rat islets. A and B: insulin release and AUC in perifusions from intact islets at 100 μmol/l imeglimin (n = 4 replicates/group). C: insulin secretion from static rat islet aggregates following 2 h of stimulation at indicated concentrations of glucose and/or stimulus (n = 4 replicates/group). D: acute static insulin secretion following 2-h incubations at increasing concentrations of glucose as indicated for control and imeglimin (1 mM; n = 3 replicates/group). E: acute static insulin secretion following 2-h incubations at increasing concentrations of imeglimin at indicated glucose concentrations (n = 4 replicates/group). F, G, I, and J: insulin secretion from islet perifusions at the indicated times (F and I) or AUC (G and J) in the presence of 1 mM imeglimin and the indicated substrate and concentration [monomethyl ester of succinic acid (SAME)]. Glutamine was present at 4 mM in all perifusions and n = 3 replicates/group. H: acute static insulin secretion following 2-h incubations with 1 mM imeglimin at increasing concentrations of leucine at 2.5 mM glucose (n = 4 replicates/group). Data are means ± SE of n = 6/group, with comparisons by t-test or 1-way ANOVA.