Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome, which includes hypertension, central obesity, dyslipidemia and insulin resistance. NAFLD includes a wide spectrum of liver alterations, ranging from simple hepatic steatosis to variable degrees of fibrosis, cirrhosis and even hepatocellular carcinoma. Although the etiology and progression of the disorder remain poorly understood, insulin resistance is considered to play a pivotal role in the pathogenesis. Insulin sensitizers such as biguanides, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years. Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase (ALT/AST) levels in the majority of subjects; however, it has no significant effect on liver histology. TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are the main points. These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer. The present review provides an overview of insulin sensitizers in the treatment of NAFLD.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin

“…Insulin-sensitizing therapies are increasingly available, 33,34 and high-risk patients previously benefitted from lifestyle interventions or metformin. 9 Although population-based prevalence data are not available, our results, in line with previous estimates, 5,31 suggest that a large number of obese humans are insulin resistant and may profit from such interventions.…”

Effect of incretin therapies compared to pioglitazone and gliclazide in non-alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study

“…20 Although a meta-analysis including 862 patients, 38% of them diabetics, showed that thazolidinediones improve steatosis, hepatocellular ballooning, and inflammatory events, delaying the progression of fibrosis, 21 pioglitazone has been related to multiple adverse effects including bladder cancer, osteoporosis, weight gain, lower limb edema, and congestive heart failure. 22 Because of these adverse effects, other alternative drugs may be of interest. In our pilot study, exenatide combined with metformin achieved the highest percentages of qualitative ultrasonographic improvement in NAFLD, but the difference was not statistically significant, possibly because of the small sample size.…”

Non-alcoholic fatty liver disease: The diagnosis and management

“…Two classes of drugs have been shown to correct insulin resistance: biguanides (e.g., metformin) and thiazolidinediones. Metformin, a biguanide that reduces hyperinsulinemia and improves hepatic insulin sensitivity, reduces hepatomegaly and hepatic steatosis in ob/ob mice [109] , but results in human studies have been less impressive [110,111] as in human studies, although ALT improved and liver size decreased, metformin was not consistently found to improve liver histology [110,112] .…”