Insulin resistance and metabolic flexibility as drivers of liver and cardiac disease in T2DM

Metabolic flexibility refers to the ability of tissues to adapt their use of energy sources according to substrate availability and energy demands. This review aims to disentangle the emerging mechanisms through which altered metabolic flexibility and insulin resistance promote NAFLD and heart disease progression. Insulin resistance and metabolic inflexibility are central drivers of hepatic and cardiac diseases in individuals with type 2 diabetes. Both play a critical role in the complex interaction between glucose and lipid metabolism. Disruption of metabolic flexibility results in hyperglycemia and abnormal lipid metabolism, leading to increased accumulation of fat in the liver, contributing to the development and progression of NAFLD. Similarly, insulin resistance affects cardiac glucose metabolism, leading to altered utilization of energy substrates and impaired cardiac function, and influence cardiac lipid metabolism, further exacerbating the progression of heart failure. Regular physical activity promotes metabolic flexibility by increasing energy expenditure and enabling efficient switching between different energy substrates. On the contrary, weight loss achieved through calorie restriction ameliorates insulin sensitivity without improving flexibility. Strategies that mimic the effects of physical exercise, such as pharmacological interventions or targeted lifestyle modifications, show promise in effectively treating both diabetes and NAFLD, finally reducing the risk of advanced liver disease.