Exercise Improves Insulin Sensitivity Research Articles

Contractile activity per se induces transcriptional activation of SLC2A4 gene in soleus muscle: involvement of MEF2D, HIF-1a, and TRα transcriptional factors

Skeletal muscle is a target tissue for approaches that can improve insulin sensitivity in insulin-resistant states. In muscles, glucose uptake is performed by the GLUT-4 protein, which is encoded by the SLC2A4 gene. SLC2A4 gene expression increases in response to conditions that improve insulin sensitivity, including chronic exercise. However, since chronic exercise improves insulin sensitivity, the increased SLC2A4 gene expression could not be clearly attributed to the muscle contractile activity per se and/or to the improved insulin sensitivity. The present study was designed to investigate the role of contractile activity per se in the regulation of SLC2A4 gene expression as well as in the participation of the transcriptional factors myocyte enhancer factor 2D (MEF2D), hypoxia inducible factor 1a (HIF-1a), and thyroid hormone receptor-alpha (TRalpha). The performed in vitro protocol excluded the interference of metabolic, hormonal, and neural effects. The results showed that, in response to 10 min of electrically induced contraction of soleus muscle, an early 40% increase in GLUT-4 mRNA (30 min) occurred, with a subsequent 65% increase (120 min) in GLUT-4 protein content. EMSA and supershift assays revealed that the stimulus rapidly increased the binding activity of MEF2D, HIF-1a, and TRalpha into the SLC2A4 gene promoter. Furthermore, chromatin immunoprecipitation assay confirmed, in native nucleosome, that contraction induced an approximate fourfold (P < 0.01) increase in MEF2D and HIF-1a-binding activity. In conclusion, muscle contraction per se enhances SLC2A4 gene expression and that involves MEF2D, HIF-1a, and TRalpha transcription factor activation. This finding reinforces the importance of physical activity to improve glycemic homeostasis independently of other additional insulin sensitizer approaches.

Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: the role of vascular vasorelaxation to insulin

Aging is an independent risk factor for hypertension, and hypertension and insulin resistance commonly coexist in the elderly. This study was designed to examine the effects of aging-related insulin resistance on blood pressure (BP) and its underlying mechanisms, with specific focus on the role of exercise in reversing hypertensive response. Adult (6-month-old) and aging (24-month-old) male Sprague-Dawley rats were subjected to a 10 weeks free-of-loading swim training (60 min/day, 5 days/week). Arterial vasorelaxation, cardiac contraction, eNOS activation, and iNOS and gp91(phox) expression were determined. Under aging-related insulin resistance conditions, insulin infusion significantly elevated BP (P < 0.05). Aging caused significant endothelial dysfunction (P < 0.05 - 0.01), which was responsible for decreased arterial vasorelaxation to insulin. Aging attenuated myocardial contractile response to insulin, decreased eNOS expression and its phosphorylation by insulin, and increased iNOS and gp91(phox) expression in aging arteries (P < 0.01). Exercise improved insulin sensitivity, potentiated insulin's positive inotropic effects, facilitated arterial vasorelaxation to insulin, increased arterial eNOS activation in adult and aging rats, and thus attenuated insulin resistance-related hypertensive response to insulin. Moreover, exercise markedly reversed increased iNOS and gp91(phox) expression in aging arteries. Inhibition of eNOS with Cavtratin or L-NAME significantly blocked exercise-facilitated arterial vasorelaxation to insulin and exercise-lowered BP response to insulin. In conclusion, these results demonstrate that endothelial dysfunction in response to insulin, but not insulin's positive inotropic effects, plays an important role in the development of aging-related hypertension. The reversal of hypertensive response to insulin by exercise is most likely associated with improved insulin sensitivity in an eNOS-dependent manner and reduced oxidative and nitrative stresses.

Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice

Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 +/- 0.3 g, while HFD mice gained 6.8 +/- 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 +/- 0.3 g and 3.3 +/- 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-alpha, MCP-1, PAI-1 and IKKbeta was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD.

Low-Frequency Electro-Acupuncture and Physical Exercise Improve Metabolic Disturbances and Modulate Gene Expression in Adipose Tissue in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. Pharmacotherapy is often unsatisfactory. This study evaluates the effects of low-frequency electro-acupuncture (EA) and physical exercise on metabolic disturbances and adipose tissue mRNA expression of selected genes in a rat PCOS model characterized by insulin resistance and adiposity. Dihydrotestosterone (inducing PCOS) or vehicle (control) was administrated continuously, beginning before puberty. At age 10 wk, PCOS rats were randomly divided into three groups; PCOS, PCOS EA, and PCOS exercise. PCOS EA rats received 2-Hz EA (evoking muscle twitches) three times/wk during 4-5 wk. PCOS exercise rats had free access to a running wheel for 4-5 wk. EA and exercise improved insulin sensitivity, measured by clamp, in PCOS rats. Exercise also reduced adiposity, visceral adipocyte size, and plasma leptin. EA increased plasma IGF-I. Real-time RT-PCR revealed increased expression of leptin and IL-6 and decreased expression of uncoupling protein 2 in visceral adipose tissue of PCOS rats compared with controls. EA restored the expression of leptin and uncoupling protein 2, whereas exercise normalized adipose tissue leptin and IL-6 expression in PCOS rats. Thus, EA and exercise ameliorate insulin resistance in rats with PCOS. This effect may involve regulation of adipose tissue metabolism and production because EA and exercise each partly restore divergent adipose tissue gene expression associated with insulin resistance, obesity, and inflammation. In contrast to exercise, EA improves insulin sensitivity and modulates adipose tissue gene expression without influencing adipose tissue mass and cellularity.

Exercise training‐induced improvements in insulin action

Individuals with insulin resistance are characterized by impaired insulin action on whole-body glucose uptake, in part due to impaired insulin-stimulated glucose uptake into skeletal muscle. A single bout of exercise increases skeletal muscle glucose uptake via an insulin-independent mechanism that bypasses the typical insulin signalling defects associated with these conditions. However, this 'insulin sensitizing' effect is short-lived and disappears after approximately 48 h. In contrast, repeated physical activity (i.e. exercise training) results in a persistent increase in insulin action in skeletal muscle from obese and insulin-resistant individuals. The molecular mechanism(s) for the enhanced glucose uptake with exercise training have been attributed to the increased expression and/or activity of key signalling proteins involved in the regulation of glucose uptake and metabolism in skeletal muscle. Evidence now suggests that the improvements in insulin sensitivity associated with exercise training are also related to changes in the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle such as the AMP-activated protein kinase (AMPK) and the protein kinase B (Akt) substrate AS160. In addition, increased lipid oxidation and/or turnover is likely to be another mechanism by which exercise improves insulin sensitivity: exercise training results in an increase in the oxidative capacity of skeletal muscle by up-regulating lipid oxidation and the expression of proteins involved in mitochondrial biogenesis. Determination of the underlying biological mechanisms that result from exercise training is essential in order to define the precise variations in physical activity that result in the most desired effects on targeted risk factors, and to aid in the development of such interventions.

Abstract 1651: Exercise Improves Aging-associated Myocardial Insulin Resistance by Enhancing Mitochondrial Function in an eNOS Dependent Mechanism

Objective . This study sought to determine whether exercise reduces aging-associated myocardial insulin resistance, with a specific focus on the role of eNOS and its relation to mitochondria. Methods . Aging male Sprague-Dawley rats (24 months) were subjected to swim training (60 min/d, 5 d/wk, 9 wk) or assigned as sedentary control. The myocardial contraction, myocardial glucose uptake, mitochondrial function, and eNOS signaling were determined. Results. Aging rats had myocardial insulin resistance as shown by decreased insulin-induced glucose uptake (0.22±0.05 μmol/min/g in aging heart vs.1.29 ± 0.13 μmol/min/g in adult heart, n=8, P &lt;0.01) and attenuated insulin’s positive inotropic role as evidenced by reduced left ventricular developed pressure (90±12 mmHg in aging heart vs. 155±14 mmHg in adult heart, P &lt;0.01). Mitochondrial function was decreased in aging hearts as manifested by the attenuated maximum O 2 consumption by FCCP (1.85±0.39 μmol/min/g in aging hearts vs. 3.72±0.40 μmol/min/g in adult hearts, P &lt;0.01). This was accompanied with the reduced insulin-induced O 2 consumption (1.37±0.31 μmol/min/g in aging heart vs. 2.35±0.31 μmol/min/g in adult heart, P &lt;0.01). In addition, eNOS expression and its phosphorylation by insulin were reduced by 1.2- and 2.3-fold in aging heart, respectively ( P &lt;0.01). Swim training upregulated eNOS expression by 72% ( P &lt;0.01), facilitated eNOS phosphorylation by insulin ( P &lt;0.01), and improved myocardial insulin sensitivity as shown by enhanced glucose uptake by insulin ( P &lt;0.01). Moreover, mitochondrial function was facilitated as manifested by the enhanced O 2 consumption by insulin ( P &lt;0.05), and maximum O 2 consumption ( P &lt;0.01) following swim training. Pretreatment with Cavtratin, an eNOS inhibitor, abolished exercise-improved mitochondrial response to insulin, blocked exercise-improved myocardial insulin sensitivity and the positive inotropic response to insulin in aging heart. Conclusion . These results demonstrate that impaired eNOS signaling and subsequent mitochondrial depression is a major mechanism contributes to aging-associated myocardial insulin resistance, and that exercise improves insulin sensitivity by restoring eNOS signaling and enhancing mitochondrial function.

Post-Exercise Insulin Sensitivity and Glucose Disposal are Unaffected by Intramuscular Triglyceride (IMTG) Levels

PURPOSE The relationships between exercise, IMTGs and insulin sensitivity are still not fully understood. The aim of this study was, therefore, to determine the effects of acute (5 hr) vs. chronic (6 days of 1 hr/day) swimming exercise on whole-body insulin sensitivity and glucose disposal in male Wistar rats following 6 wk of high-fat (60% fat) feeding. METHODS 9-week old male Wistar rats were assigned to one of four treatment groups (high-fat fed chronic exercise, high-fat fed acute exercise, high-fat fed control, chow-fed control). Post-exercise, all animals fed ad libitum for 6–7 hr, before an overnight fast. Approximately 24 hr post-exercise, half of the animals from each group were randomly assigned to a euglycemic/hyperinsulinemic clamp to assess insulin sensitivity and 2- deoxyglucose uptake. IMTG levels and glycogen levels were also assessed. RESULTS Chronic exercise improved insulin sensitivity when compared to acute exercise (p= 0.03), while glycogen levels paralleled this improvement in insulin sensitivity. IMTG levels were not altered significantly, but there was a trend towards an increase in both exercise groups when compared to the high-fat fed control group (p = 0.06). IMTG values were identical between exercise groups and did not, therefore, parallel the changes in insulin sensitivity. CONCLUSIONS These data suggest that post-exercise, mechanisms other than IMTGs are the major factor in insulin sensitivity improvement. Improvements in oxidative capacity and mitochondrial function, which occur following chronic training, are likely to be involved in these changes.

Post-Exercise Insulin Sensitivity and Glucose Disposal are Unaffected by Intramuscular Triglyceride (IMTG) Levels

PURPOSE The relationships between exercise, IMTGs and insulin sensitivity are still not fully understood. The aim of this study was, therefore, to determine the effects of acute (5 hr) vs. chronic (6 days of 1 hr/day) swimming exercise on whole-body insulin sensitivity and glucose disposal in male Wistar rats following 6 wk of high-fat (60% fat) feeding. METHODS 9-week old male Wistar rats were assigned to one of four treatment groups (high-fat fed chronic exercise, high-fat fed acute exercise, high-fat fed control, chow-fed control). Post-exercise, all animals fed ad libitum for 6–7 hr, before an overnight fast. Approximately 24 hr post-exercise, half of the animals from each group were randomly assigned to a euglycemic/hyperinsulinemic clamp to assess insulin sensitivity and 2- deoxyglucose uptake. IMTG levels and glycogen levels were also assessed. RESULTS Chronic exercise improved insulin sensitivity when compared to acute exercise (p= 0.03), while glycogen levels paralleled this improvement in insulin sensitivity. IMTG levels were not altered significantly, but there was a trend towards an increase in both exercise groups when compared to the high-fat fed control group (p = 0.06). IMTG values were identical between exercise groups and did not, therefore, parallel the changes in insulin sensitivity. CONCLUSIONS These data suggest that post-exercise, mechanisms other than IMTGs are the major factor in insulin sensitivity improvement. Improvements in oxidative capacity and mitochondrial function, which occur following chronic training, are likely to be involved in these changes.

Regulation of metabolic transcriptional co‐activators and transcription factors with acute exercise

Endurance exercise improves insulin sensitivity and increases fat oxidation, which are partly facilitated by the induction of metabolic transcription factors. Next to exercise, increased levels of FFA's also increase the gene expression of transcription factors, hence making it difficult to discern the effects from contractile signals produced during exercise, from those produced by increased circulatory FFA's. We aimed to investigate, in human skeletal muscle, whether acute exercise affects gene expression of metabolic transcriptional co-activators and transcription factors, including PGC-1alpha, PRC, PPARalpha, beta/delta, and gamma and RXR, SREBP-1c and FKHR, and to discern the effect of exercise per se from those of elevated levels of FFA. Two hours of endurance exercise was performed either in the fasted state, or following carbohydrate ingestion prior to and during exercise, thereby blunting the fasting-induced increase in FA availability and oxidation. Of the genes measured, PGC-1alpha and PRC mRNA increased immediately after, while PPARbeta/delta and FKHR mRNA increased 1-4 h after exercise, irrespective of the increases in FFA's. Our results suggest that the induction in vivo of metabolic transcription factors implicated in mitochondrial biogenesis are under the control of inherent signals, (PGC-1alpha, PRC), while those implicated in substrate selection are under the control of associated signals (PPARbeta/delta, FKHR) stimulated from the contracting skeletal muscle that are independent of circulating FFA levels.

A Reduced-Fat Diet and Aerobic Exercise in Japanese Americans With Impaired Glucose Tolerance Decreases Intra-Abdominal Fat and Improves Insulin Sensitivity but not β-Cell Function

Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, beta-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or beta-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 +/- 1.3 years; mean +/- SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. beta-Cell function (disposition index [DI]) was calculated as S(i) x AIRg, where S(i) is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 +/- 2.4 vs. 71.3 +/- 2.9 kg; P = 0.004) and IAF (75.0 +/- 7.9 vs. 112.7 +/- 10.4 cm(2); P = 0.03) and SCF (196.5 +/- 18.0 vs. 227.7 +/- 19.9 cm(2); P < 0.001) areas, greater S(i) (4.7 +/- 0.5 vs. 3.3 +/- 0.3 x 10(-5) min . pmol(-1) . l(-1); P = 0.01), and a trend toward lower AIRg (294.9 +/- 50.0 vs. 305.4 +/- 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 +/- 350.7 vs. 8,902.0 +/- 367.2 mg . dl(-1) . 2 h(-1); P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. S(i) was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve beta-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term.

Insulin sensitivity of protein and glucose metabolism in overweight female adolescents with type 1 diabetes mellitus: positive modulation by physical exercise

Impairment of insulin sensitivity of glucose metabolism, a prominent feature of type 1 diabetes (DM), is also well documented in adolescence and obesity. Overweight is frequently present during adolescence in females. Spurt in growth is significantly reduced during puberty in females with type 1 DM, while it is normal in males. In this study we assessed the effect of the coexistence of type 1 DM, adolescence, overweight, and their possible interference with growth. Moreover, we evaluated whether dietetic control associated with physical exercise improved insulin sensitivity in adolescence. The study enrolled 11 female adolescents and young adults (aged 18.5±0.6 years), affected by type 1 DM for 8.3±0.9 years, who were overweight (BMI, 27.3±0.8 kg/m2) and receiving conventional insulin therapy (0.78±0.10 U/kg day). We used the euglycemic hyperinsulinemic clamp technique coupled to [2H2]glucose and [13C]leucine infusion. The results show a striking increase in insulin resistance of glucose metabolism: the suppression of endogenous glucose production (EGP) was 59% in comparison to 90%–100% recorded by others at similar insulin levels in subjects at different periods of life. Insulin resistance in type 1 DM overweight adolescents was also present on protein metabolism: the postabsorptive plasma leucine (146.9±10.1 μM) and the endogenous leucine flux (ELF, 88.8±4.5 µmol/kg min) were higher than in healthy controls. The suppression of ELF during hyperinsulinemia was defective in diabetic adolescents (27%, p<0.001) with respect to controls (36%). Only three of the 11 overweight diabetic subjects completed the 6-month physical exercise and diet program, and showed improvement of insulin sensitivity at the final evaluation. The EGP suppression by insulin shifted from 41% to 79%; ELF suppression increased from 26% to 34%. All the parameters of glucose metabolism correlated with the weight loss (BMI reduction from 27.8±1.9 to 25.6±1.2 kg/m2). In conclusion, overweight female adolescents with type 1 DM have an impaired insulin action on glucose and protein metabolism. Physical exercise and correct dietary regimen positively influence insulin sensitivity. The present preliminary data are relevant for an improved control of glucose homeostasis and a normal growth in adolescence.

AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats.

Exercise improves insulin sensitivity. As AMP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMPK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMPK may have potential in treating insulin-resistant states and type 2 diabetes.

Are the reductions in triacylglycerol and insulin levels after exercise related?

Moderate exercise improves insulin sensitivity and reduces triacylglycerol (triglyceride; TG) concentrations. We hypothesized that changes in insulin sensitivity are an important determinant of exercise-induced changes in postprandial TG concentrations. Altogether, 38 men and 43 women, all of whom were normotriglyceridaemic and normoglycaemic, each underwent two oral fat tolerance tests with different pre-conditions: control (no exercise) and prior exercise (90 min of exercise at 60% of maximal O(2) uptake the day before). Venous blood samples were obtained in the fasting state and for 6 h after a high-fat mixed meal. In the control trial there were significant correlations between log fasting TG concentration and log fasting insulin concentration (r=0.42, P<0.0005) and between log postprandial TG response (area under the curve) and log postprandial insulin response (r=0.48, P<0.0005). Prior exercise reduced the fasting TG concentration by 18.2 +/- 2.2% (mean +/- S.E.M.) (P<0.0005), the postprandial TG response by 21.5 +/-1.9% (P<0.0005), the fasting insulin concentration by 3.8 +/- 3.1% (P<0.01) and the postprandial insulin response by 11.9 +/- 2.5% (P<0.0005). However, there was no relationship between the exercise-induced changes in log fasting TG and log fasting insulin (r=0.08, P=0.50), nor between the exercise-induced changes in log postprandial TG response and log postprandial insulin response (r=0.04, P=0.70). These data suggest that the reductions in fasting and postprandial TG levels elicited by a session of moderate-intensity exercise are not mediated by an increase in insulin sensitivity.

Non Alcoholic Fatty Liver Disease- Is It Always Benign?

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease observed in the clinical practice of hepatology affecting approximately 20% of the general population. It is increasingly apparent that non alcoholic steatohepatits (NASH) and NAFLD are not Western disease. There is evolution of Western-style life among the Asian population and NASH has increasingly been diagnosed in several regions in Asia. NASH is considered as a type of a larger spectrum of NAFLD that is a consequence of insulin resistance and other underlying factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. Although liver biopsy is currently the gold standard for diagnosis, there is a need for less invasive methods. Imaging by ultrasound, computerized tomography and magnetic resonance are all able to demonstrate fat. Ultrasound, although probably not the most reliable imaging method, has many advantages and, when positive, gives a high degree of certainty of the diagnosis depending on the prevalence of fatty liver in the population being studied. Unlike liver biopsy, none of these techniques is able to differentiate simple steatosis from non- alcoholic steatohepatitis. The ultimate goal of treating the patient with NASH is to prolong life by avoiding the end-organ diseases associated with insulin resistance and the metabolic syndrome. Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions as well as discontinuation of potentially hepatotoxic drugs. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs. &#x0D; &#x0D; In this article, we will review (1) various processes that are involved in the pathogenesis of NASH (2) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging and potentially useful medications. &#x0D; &#x0D; (J Bangladesh Coll Phys Surg 2007; 25 : 144-152)