Modulation of Insulin Resistance in NAFLD

Abstract

Non‐alcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to Non‐Alcoholic Steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation and yet there is a lack of effective licensed treatments. There is a close relationship between insulin resistance and NAFLD, with the prevalence of NAFLD being five‐fold higher in patients with diabetes compared to patients without. Insulin resistance is implicated both in the pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus modulation of insulin resistance represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking insulin resistance and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid oxidation, changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Further, it goes on to discuss the main pharmacological strategies used to treat insulin resistance in patients with NAFLD, and their efficacy based on recently published experimental and clinical data. These include (biguanides, glucagon‐like peptide 1 receptor (GLP‐1) agonists, Dipeptidyl peptidase 4 (DPP‐4) inhibitors, Peroxisome Proliferator‐Activated Receptor (PPAR‐ γ/ α/δ) agonists, Sodium Glucose Cotransporter (SGLT2) inhibitors and Farnesoid X receptor (FXR) agonists), with further novel treatments on the horizon. Ideally treatment would improve insulin resistance, reduce cardiovascular risk and produce demonstrable improvements in NASH histology ‐ this is likely to be achieved with a combinatorial approach.

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