Transcription Factors in Type 2 Diabetes: Molecular Mechanisms of Insulin Resistance and β-Cell Dysfunction

Type 2 diabetes mellitus (T2DM) is a common global disease affecting more than 588 million people. This number is projected to reach 852 million by 2050, imposing a significant socioeconomic burden. Type 2 diabetes results from insulin resistance (IR) in peripheral tissues and dysfunction of pancreatic beta cells. These two mechanisms and their proper functioning in the body are influenced by genetic and environmental factors. Transcription factors (TFs) play pivotal roles in these processes by regulating the expression of genes governing glucose and lipid metabolism. This study reviews the current knowledge on key transcription factors involved in the pathophysiology of type 2 diabetes. In the liver, FOXO1 enhances gluconeogenesis through upregulation of PEPCK and G6Pase expression under IR conditions, whereas SREBP1c and ChREBP enhance de novo lipogenesis and exacerbate hepatic steatosis and systemic IR. In adipose tissue, PPARγ coordinates adipocyte differentiation and insulin sensitivity, but phosphorylation at Ser273 impairs adiponectin expression. NF-κB stimulates chronic inflammation and links metabolic stress to insulin resistance. In skeletal muscle, MEF2 isoforms coordinate mitochondrial biogenesis and oxidative metabolism with PGC-1α, which are impaired in T2DM. Disruption of these transcription factors results in metabolic dysfunction. This highlights their potential as therapeutic targets. Therapeutic options such as FOXO1 inhibitors or PPARγ agonists are promising, although challenges such as off-target effects remain. Understanding the mechanisms by which transcription factors contribute to the pathophysiology of T2DM provides insights into novel strategies to reduce the progression and complications of T2DM.