The AMPK-SIRT1 Axis: Redefining type 2 diabetes mellitus management

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder strongly associated with obesity and excessive fat accumulation in the liver and pancreas leading to insulin resistance and hyperglycemia. While lifestyle modifications are the first-line approach to managing T2DM, many patients require oral hypoglycemic medications to regulate and maintain blood glucose levels. Although the precise mechanisms of action for these drugs remain unclear, emerging evidence suggests that they may exert their effects through the AMP-activated protein kinase (AMPK) and/or Sirtuin 1 (SIRT1) pathways. Activation of the AMPK pathway promotes fatty acid oxidation, suppresses cholesterol biosynthesis, and enhances glucose uptake. Similarly, SIRT1, an NAD⁺-dependent deacetylase, regulates many proteins involved in glucose homeostasis and insulin signaling. This review explores the therapeutic potential of AMPK and SIRT1 in T2DM. It provides an in-depth analysis of AMPK's role in T2DM pathogenesis and highlights the benefits of AMPK modulation by polyphenols. Additionally, it delves into the mechanisms of oral hypoglycemic drugs, emphasizing the significance of AMPK activation. Furthermore, the review discusses the impact of calorie restriction and SIRT1 activation in T2DM, considering both non-pharmacological interventions and synthetic SIRT1 activation as viable therapeutic options.