Understanding the Role of Statins in Induction of Insulin Resistance and Aggravating the Diabetes Characteristics

Abstract

Statins inhibit cholesterol synthesis in the liver by lowering intracellular cholesterol and LDL concentration in circulation. It is often prescribed to individuals with high risk of cardiovascular diseases, high LDL cholesterol(70 and 189 mg/dl). It is reported that statins have propensity to induce insulin resistance and hyperglycemia. Also, there may be significantly increased risk of new onset diabetes in pre-diabetic individuals. We administered statins orally to prediabetic rats (previously fed on high sugar diet, HSD) to see whether the drugs alter gut microbiota and induce diabetes. As compared to control rats, body weight of HSD fed rats and statin treated rats was increased while compared to HSD fed rats statin treated rats did not show significant difference in body weight. White adipose tissue mass justified weight gain in HSD fed group while treatment group showed lower adipose tissue mass. Lower liver weight and elevated SGOT levels in atorvastatin treated group signify liver damage. Simvastatin treatment group also showed increase in SGOT & SGPT levels. Raised pro-inflammmatory (TNF-α, IL-6) to anti-inflammatory (IL-10) cytokine ratio also indicates inflammation in liver of diabetic (HSD) and treated groups. Histopathology of these groups confirms liver damage. Reduced level of LXR expression in the liver of HSD, and treatment groups indicated reduction in insulin sensitivity and glucose uptake. As cholesterol overload drops due to statin treatment there is no need to synthesize Liver X receptors. Higher TLR4 as compared to TLR2 as well as increased bacteriodetes to fermicutes ratio shows increase in Gram-negative bacteria population in the gut. This altered ratio depicts LPS mediated inflammation in the liver. Reduced serum insulin, glucagon and elevated fasting glucose concentration (hyperglycemia) in statin treatment group suggest beta-cell dysfunction which can be confirmed by presence of non-intact langerhans cell in pancreas. Collectively, statin treatment aggravates diabetes in prediabetic rats by inducing pancreatic dysfunction and insulin resistance.