Insulin resistance plays an important role in the pathogenesis of NAFLD. Pharmacological treatment of patients with NAFLD is still evolving. Insulin sensitizing drugs like metformin may be effective in these patients. Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases (ALT) after 6 months of lifestyle interventions and UDCA were treated with metformin 500mg tid for 6 months. Insulin resistance was determined by HOMA- IR. Liver function tests were done monthly and patients were defined having no response, partial response or complete biochemical response depending on the change in ALT. Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions (disease controls).
Thirteen (52%) patients had class III (n = 5) or class IV (n = 8) disease amounting to histological NASH. Of these 13 patients none had severe inflammation and none had stage 4 fibrosis (cirrhosis). All 25 patients with NAFLD had insulin resistance in comparison to healthy controls. In comparison to disease controls (127.5 +/- 41.8 vs. 118 +/- 21.6 p = NS), all patients treated with metformin had partial biochemical response (mean ALT 122.2 +/- 26.8 vs 74.3 +/- 4.2 p < 0.01) and 14 (56%) of them achieved complete normalization of ALT.
Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions and UDCA.
"However, data about improvement in liver enzymes and hepatic histology during treatment with metformin in patients with NAFLD/NASH are controversial. Several open-label clinical studies [75–84] supported the beneficial effects on serum aminotransferases levels , and on IR markers [75, 76, 80–84] of NAFLD/NASH patients treated for at least 6 months with metformin (dose ranging 1.4–2.0 g/day) alone or in association with vitamin E  or lifestyle intervention [75, 78, 84]. "
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance is a clinical condition shared by many diseases besides type 2 diabetes (T2DM) such as obesity, polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). Experimental evidence, produced over the years, suggests that metformin has many benefits in the treatment of these diseases. Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients, offering a selective pathophysiological approach by its effect on insulin resistance. Moreover, a number of studies have established the favorable effect of metformin on body weight, not only when evaluating BMI, but also if body mass composition is considered, through the reduction of fat mass. In addition, it reduces insulin resistance, hyperinsulinemia, lipid parameters, arterial hypertension and endothelial dysfunction. In particular, a new formulation of metformin extended-release (ER) is now available with different formulation in different countries. Metformin ER delivers the active drug through hydrated polymers which expand safe uptake of fluid, prolonging gastric transit and delaying drug absorption in the upper gastrointestinal tract. In addition, Metformin ER causes a small, but statistically significant decrease in BMI, when added to a lifestyle intervention program in obese adolescents. Because of the suggested benefits for the treatment of insulin resistance in many clinical conditions, besides type 2 diabetes, the prospective exists that more indications for metformin treatment are becoming a reality.
"The primary effect is thought to be the suppression of hepatic glucose production and hepatic lipogenesis . Metformin activates AMPK in hepatocytes, resulting in the phosphorylation and inactivation of ACA, a rate-limiting enzyme in lipogenesis , and theoretically might be useful and safe in the treatment of NAFLD . Surprisingly, the beneficial clinical effects seem to be limited, despite the effects of metformin on insulin resistance, most likely because long-term treatment is an absolute requirement for the prevention of progressive disease. "
[Show abstract][Hide abstract] ABSTRACT: Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.
Mediators of Inflammation 02/2013; 2013(6):135698. DOI:10.1155/2013/135698 · 3.24 Impact Factor
"hesini et al . , 2001 ) . Metformin is well tolerated in the NAFLD population , with no problem of weight gain and the only side effect being gastrointestinal intolerance . It improved aminotransferases as well as histology in patients with NASH ( Marchesini et al . , 2001 ; Nair et al . , 2004 ; Uygun et al . , 2004 ; Bugianesi et al . , 2005 and Duseja et al . , 2007 ) . Another group of drugs that is under extensive study is peroxisome proliferation - activated receptor - agonist , commonly called " glitazones " in the context of NAFLD . Thiazolidinediones ( TZDs ) are high - affinity ligands of proliferation - activated receptor - , which improve insulin resistance by redistributing the storag"
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