imeglimin and Insulin-Resistance

The aim of the present study was to evaluate the effect of 18-week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients.. The study was an 18-week, double-blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h-glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity.. Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin Secretion

To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes.. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated.. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion.. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucose Clamp Technique; Hepatobiliary Elimination; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Triazines

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.

Topics: Animals; Blood Glucose; Diet, High-Fat; Fasting; Glucose; Glucose Clamp Technique; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Mice; Mice, Inbred C57BL; Postprandial Period; Rats; Rats, Sprague-Dawley; Triazines

Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.

Topics: Animals; Diet, High-Fat; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Triazines