Anti‐Diabetic Effects of Ayanin, a Flavonoid Compound, in <scp>STZ</scp> / <scp>HFD</scp> ‐Induced Diabetic Mice by Upregulating <scp>GLUT4</scp> and Suppressing Macrophage‐Driven Inflammation in Adipose Tissues

Insulin resistance, marked by reduced GLUT4 expression in metabolic tissues such as adipose tissue and skeletal muscle, is a key contributor to the pathogenesis of Type 2 diabetes. Therapeutic agents that enhance GLUT4 expression in these tissues have demonstrated potential in the treatment of diabetes. Ayanin (AYN) is a flavonoid found in red wine grapes. This study evaluated the anti-diabetic properties of AYN and investigated its mechanisms. In an in vivo study, the oral administration of AYN to diabetic mice resulted in ameliorated hyperglycemia and glucose tolerance and alleviated lipid dysfunction. The investigation into the underlying mechanisms revealed that AYN activated p-AMPKα, which subsequently enhanced GLUT4 and CPT-1α expression in both adipose and muscle tissues, as well as increased CPT-1α expression in livers. In vitro experiments demonstrated that AYN activated AMPKα, increased GLUT4 expression, and facilitated glucose uptake in 3T3-L1 adipocytes. Additionally, the metabolic dysfunctions related to lipids and glucose in adipocytes triggered inflammatory activation of macrophages within adipose tissue, leading to the exacerbation of insulin resistance and the downregulation of GLUT4 expression. AYN reduced macrophage infiltration and pro-inflammatory mRNA expression in adipose tissues, contributing to the amelioration of diabetes. In vitro results for macrophages indicated that AYN decreased LPS-induced pro-inflammatory cytokine secretion. These findings suggest that AYN has potential for improving glucose tolerance and hyperglycemia, reducing insulin secretion, alleviating macrophage inflammation, and mitigating lipid dysfunction.