Ursodeoxycholic Acid as add-on Therapy in Type 2 Diabetes Mellitus

Diabetes mellitus (DM) is a complex metabolic disorder characterized by hyperglycemia and abnormalities in carbohydrate, fat, and protein metabolism. It is one of the most prevalent metabolic disorders globally. More than 75% of diabetic patients live in low- and middle-income countries. About 90% of diabetic patients have type 2 diabetes. Insulin resistance (IR) and β-cell dysfunction are the two main pathophysiological events contributing to type 2 diabetes. Insulin resistance is a pathological condition in which insulin-dependent tissues fail to properly respond to normal circulatory levels of insulin. Inflammatory mediators play a key role in insulin resistance. For example, tumor necrosis factor alpha (TNF-α) impairs insulin signaling via serine phosphorylation of insulin receptor substrate (IRS-1). Additionally, it reduces glucose transporter-4 (GLUT-4) expression, limiting glucose entry into adipocytes and skeletal muscle cells. Similarly, IL-6 induces IRS degradation. Oxidative stress interferes with insulin signal transduction leading to IR. It activates several serine-threonine kinase pathways, which, in turn, phosphorylates IRS proteins leading to subsequent degradation. β-cell dysfunction is associated with β-cell death. In an excessive nutritional state, as in obesity, hyperglycemia and hyperlipidemia are often present, favoring IR and chronic inflammation. Under these circumstances, β-cells are subject to toxic pressures including inflammation, endoplasmic reticulum stress, oxidative stress, as well as amyloid stress, that ultimately lead to loss of islet integrity. Ursodeoxycholic acid (UDCA) is an endogenous hydrophilic bile acid normally present in human bile and traditionally used for the treatment of liver diseases. UDCA has direct antioxidant properties. It decreased glucose levels, alleviated hyperinsulinemia, and improved islet function in rats with liver fibrosis. Therefore, this study is designed to evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in patients with type 2 diabetes mellitus.