Insulin resistance and "lipotoxic liver diseases".

An expanded dysfunctional adipose tissue that fails to accommodate, utilise and store as much fat as it should has emerged as the prime mover of the patho physiological sequence that leads to accumulation of fat at ectopic sites – including the liver, in metabolic syndrome and cluster of disorders that include Non alcoholic fatty Liver Disease(NAFLD). Non alcoholic steato hepatitis ( NASH) represent the aggressive subset of NAFLD that can progress to cirrhosis . Insulin is the key driver of metabolic homeostasis, particularly glucose flux across cell membrane – a phenomenon that have connotations for survival and evolution of the organism. An impaired sensitivity to insulin action at the adipocyte level is a characteristic biological event in metabolic syndrome. ,7 The associations of Insulin resistance(IR) with metabolic syndrome is nearly universal – so that the two often have interchangeable pathophysiological inferences, a classical example being type 2 diabetes and the other example is NAFLD/NASH. IR through metabolic syndrome is the template that provide a point of convergence for linked clinical conditions diabetes, obesity, dyslipidemia, hypertension and NAFLD/NASH. IR needs to be conceptualised not as a fixed cellular event – exerting an all or none effect like many biological processes, rather as a dynamic and regulated physiological response to a host of environmental factors and triggers including inflammation. IR possibly challenges energy homeostasis, nutrient availability and handling and connects metabolism with immune phenomenon. 12 There are different methods for measurement of IR, of which HOMA-IR is the simplest and the most widely used one in clinical and epidemiological studies. Ever since its’ initial descriptions, NAFLD has been strongly correlated with obesity; body mass index (BMI) has been the most widely used marker of adiposity in clinical studies. Large epidemiological studies on prevalence of fatty liver have also demonstrated this association , while other studies on the impact of BMI on health outcomes have upheld the connection between BMI , socio economic affluence and overall mortality in a population. BMI has been an independent predictor of fat infiltration in the liver with increasing BMI being associated with increased prevalence of NASH in subjects with NAFLD. Ethnic and racial differences in body composition suggest that Asians( Indians , more specifically): a) Have a lower BMI in general as compared to Caucasians yet , b) Have an increased percentage of body fat as well as a higher proportion of fat in the visceral fat(VF) compartments, c) Are predisposed to metabolic abnormalities and adverse health outcomes at a comparatively lower BMI. The signifcance of these observations is the shift of spotlight on waist circumference as a more meaningful and relevant measure of body composition. It soon became evident that a subset of non overweight (BMI<25 ) individuals do have NAFLD along with metabolic syndrome related metabolic dysfunction including diabetes. ,25,26 This entity, “lean” NAFLD, has subsequently been shown to be a distinct phenotype , described primarily amongst Asians – particularly Indians although it has been reported from occidental populations subsequently. Since fatty liver, NASH and even cirrhosis have been shown to occur with subtle anthropometric markers of obesity and a spectrum of metabolic