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

Abstract

Background: Extensive resources are put into the noesis of lipid metabolism and its storage in the biological system. Efforts have been made to discover and develop drugs that may manipulate the lipid profile. Although making changes in the lifestyle is a prime choice for lowering down lipid levels in the body, for those who are unable to achieve or assert a sustained risk reduction on lifestyle or those who are at high risk require pharmacotherapy. Lipid lowering drugs in general, help to control the raised lipid levels in patients with hyperlipidemia. While one group of drugs, called statin, lowers cholesterol, the group called fibrates, are known to take care of free fatty acids and triglycerides. In addition to this, other drugs, such as ezetimibe, colesevelam, torcetrapibe, avasimibe, implitapibe and niacin are also bring used considered to manage hyperlipidemia. Consumption of sugar-rich diet presents pleotropic effect on alteration of gut-microbiota and related inflammation, contributing to insulin resistivity and thus onset and progression of T2DM. Recent reports have also suggested the involvement of statins in causing insulin resistivity. Statins and high sugar diet together has been found to elevate insulin resistivity and alter microflora in the gut, aggravating T2DM characteristics. Aim: The objective of the experiment was to understand the effect of administration of stains in reducing endogenous cholesterol and induction of insulin resistivity, its possible side-effect, high sugar rich diet fed rats. The response of microbiota population on receiving high sugar diet and statin therapy was also considered. Method: Two different statins, Simvastatin and Atorvastatin, were administered to two different experimental groups following the induction of a pre-diabetic state (daily; according to their body weight). The oral glucose tolerance test, total cholesterol and total TG was checked after the induction of diabetes and on at the end of statin therapy. ALT, AST, insulin level and free fatty acid was estimated. Expression of various genes were analysed at the m-RNA level. Page | 10 Results: Levels of fasting glucose, liver injury marker (AST and ALT), serum cholesterol, TG and free fatty acids significantly increased in the high-sugar fed rats. However, administration of statins following diabetes induction subsequently lowered total cholesterol in circulation but also resulted in elevated TG, FFA and glucose level. Elevated expression of proinflammatory adipokines was observed. Glucose mediated lipogenesis was found to be down-regulated due to decreased expression of ChREBP and prominent expression of PPAR-α in the treatment groups. DNA analysis of colonic content revealed the altered microflora composition, with varying expression of TLR2 and TLR4 in various tissues (compared to control group). Elevated expression of NFκB indicated stimulation of pro-inflammatory pathways through TLR2 and TLR4 mediated activation. The alteration in microbial population leading to low-grade inflammation and the prevalent biochemical charachteristics indicated signs of insulin-resistivity mediated T2DM. Conclusion: Metabolic syndrome and inflammation have complimented each other since a long time. Consumption of high calorie diet effectively alters the gut-microflora population causing endotoxemia and the resultant endotoxemia may then contribute to low-grade inflammation, diminished insulin sensitivity, adipocytes hyperplasia as well as β-cell impairment. It was found that statins administered to lower hypercholesterolemia, a characteristic of T2DM, reduced cholesterol level but contributed to low-grade inflammation. We conclude that extending the duration of the drug administration may show prominent signs of chronic inflammation leading to exaggerated response of T2DM. Key Words: Statins, Cholesterol, High Sugar Diet, Gut-microbiota, Pro-inflammation, Atorvastatin, Simvastatin, T2DM, Insulin Resistance.