Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

Abstract

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD⁺ ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD⁺ metabolites may contribute to the increase in GSIS (via enhanced Ca⁺⁺ mobilization). Imeglimin has also been shown to preserve β-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists.

Keywords: Imeglimin, mechanism, mitochondria, therapeutic, type 2 diabetes.

FIGURE 1

Chemical structure of Imeglimin hydrochloride salt

FIGURE 2

In vivo effect of Imeglimin (150 mg/kg) to enhance glucose‐stimulated insulin secretion (GSIS) in a rodent model of type 2 diabetes. A, Plasma insulin levels and B, insulin area under the curve (AUC) obtained during an oral glucose tolerance test in HFF rats are shown. Although there is a trend towards higher plasma insulin levels at the end of this experiment (90 minutes time point), glucose levels returned to baseline at this time point and no hypoglycaemia was observed. Additional details are described in Perry et al. ⁴³ Copyright © 2016 The American Physiological Society

FIGURE 3

Imeglimin improves insulin sensitivity in vivo. Male Wistar rats (age 40‐42 weeks, weighing 200‐225 g) were treated with streptozotocin (STZ) (50 mg/kg in citrate buffer via intraperitoneal injection) to produce mild diabetes (mean basal fasting glucose 5‐6 mM); after 1 week, animals were randomized into two groups based on their fasting glucose levels. Beginning 10 days post‐STZ, animals were treated with Imeglimin (150 mg/kg BID; red bars) or vehicle (0.5% methylcellulose; black bars ) for 15 days. An euglycaemic hyperinsulinaemic clamp was then conducted, beginning 45 minutes after the last administration of Imeglimin or vehicle in overnight fasted rats (15 hours). Plasma insulin was increased to a constant level via primed, continuous infusion of exogenous insulin (0.5 UI/kg/h); plasma glucose was maintained at a constant euglycaemic level by varying the infusion of exogenous glucose. Two key variables were assessed during the clamp: A, The steady state glucose infusion rate (GIR) was measured as an index of whole body insulin sensitivity. B, [3‐³H]‐glucose was infused to assess endogenous glucose production (glucose production rate [GPR]). Both basal and hyperinsulinaemic conditions were studied. *P < .05; **P < .01 vs. vehicle control (Student t‐test); n = 10 rats per group

FIGURE 4

Summary of Imeglimin's dual mode of action. Imeglimin has direct effects on islet β‐cells to enhance glucose‐stimulated insulin secretion (GSIS) (and to potentially prevent loss of β‐cell mass); enhanced insulin action occurs in both liver and skeletal muscle. Underlying cellular effects include modulation of mitochondrial function and an additional effect in islet β‐cells to enhance generation of NAD⁺ that contributes to Ca⁺⁺ mobilization in the insulin secretion amplification pathway. *reactive oxygen species; #permeability transition pore; Nicotinamide Phosphoribosyl‐transferase; Nicotinamide Adenine Dinucleotide (NAD⁺)