Pharmacological Inhibition of Pyruvate Dehydrogenase Kinase 4 Enhances Insulin Sensitivity in Mouse Models of Diabetes and Obesity

Abstract

Background: Insulin resistance is a central feature of type 2 diabetes mellitus (T2DM), which remains a major global health burden with limited therapies that directly address upstream molecular defects. Pyruvate dehydrogenase kinase 4 (PDK4), a regulator of glucose and lipid metabolism, has emerged as a promising therapeutic target. Here, we evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance. Methods: We evaluated the metabolic effects of GM-10395, an orally available PDK4 inhibitor, in preclinical models of insulin resistance. In alpha mouse liver 12 (AML12) hepatocytes, we assessed protein kinase B (AKT) phosphorylation, mitochondrial reactive oxygen species (ROS), and oxygen consumption rate (OCR). In vivo, long-term oral administration of GM-10395 (8 weeks in KKAy mice [n=6 per group] and 5 weeks in diet-induced obesity [DIO] mice [n=6 per group]) was evaluated for effects on glucose tolerance, glycosylated hemoglobin, lipid profiles, and liver histology. Results: GM-10395 restored AKT phosphorylation, reduced ROS generation, and normalized OCR in palmitate-treated AML12 cells. In both KKAy and DIO mice, GM-10395 significantly improved glucose tolerance and reduced hepatic steatosis. Serum lipid analysis revealed reductions in low-density lipoprotein cholesterol and triglycerides, with histology confirming decreased lipid deposition. Enhanced insulin signaling, evidenced by increased phosphorylated AKT/total AKT ratios in liver, muscle, and adipose tissues, was consistently observed. Conclusion: GM-10395 improves systemic glucose and lipid homeostasis by restoring insulin sensitivity via PDK4 inhibition. These results support GM-10395 as a promising oral therapeutic candidate for insulin resistance in T2DM.