Effect of PAI-1 inhibitor on pancreatic islet function and hepatic insulin resistance in db/db mice

Type 2 diabetes mellitus (T2DM) is a global health challenge, necessitating innovative antidiabetic treatments. Levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in patients with T2DM and may be an important but underappreciated risk factor for diabetes. However, its relationship with T2DM remains unclear. To this end, we developed a potent and highly specific PAI-1 inhibitor named PAItrap3. We aimed to elucidate the metabolic effects of PAItrap3 using a preclinical db/db mouse model. PAItrap3 was administered to mice intravenously, followed by an assessment of biochemical markers, histopathological examination of the liver and pancreas, and evaluation of the expression of hepatic proteins integral to insulin signaling. PAItrap3 demonstrated potent efficacy in alleviating hyperglycemia and enhancing glycemic control. This therapeutic action was supported by its ability to enhance β-cell function, consequently mitigating β-cell apoptosis and preserving their integrity. Furthermore, PAItrap3 alleviated hepatic insulin resistance through the regulation of lipid and glucose metabolism, thereby maintaining the delicate homeostasis of systemic lipid and glucose metabolism. These findings suggest that PAItrap3 is a promising therapeutic candidate for T2DM. The multifaceted benefits of PAItrap3 highlight its potential to vastly improve the effectiveness and specificity of T2DM treatment paradigms.