Unless pancreatic beta cell production of insulin fails (as in established diabetes), one consequence of insulin resistance is hyperinsulinemia,
which may exert multiple effects on hepatic metabolism and growth. One example is stimulation of hepatic lipogenesis via both SREBP1c, for which insulin increases nuclear expression, and ChREBP if glucose intolerance occurs, as well as suppression of fatty acid beta oxidation and VLDL production.155–157 As mentioned earlier, insulin also stimulates expression of the fatty acid uptake pathway, CD36,145,146 thereby exacerbating and potentially altering the pattern of hepatic lipid accumulation. For some time there was debate buy Trametinib about the reproducibility of relationships between NAFLD and insulin resistance (IR). Part of the confusion related to this website liver pathology (NASH versus SS), and definition of insulin resistance. The usual static estimate is by homeostatic model assessment (HOMA-IR), a computation from fasting serum glucose and insulin
values, usually referenced to an arbitrary ‘normal value’ (often 2.0) that ideally should be validated in the local normal population. HOMA-IR is inappropriate when diabetes is associated with declining serum insulin levels. Studies avoiding these pitfalls have tended to find close concordance (> 95%) between HOMA-IR and NASH,4,7,29,30,138 although normal values may be found in a few patients with less severe forms of NAFLD. Dynamic tests of insulin sensitivity, the ‘gold standard’ for which is the euglycemic insulin clamp method, would MCE be more valuable, particularly those using isotope methods for determining
peripheral glucose uptake and hepatic glucose output.179,180 One such study found that the peripheral compartment, particularly adipose, contributed most to insulin insenstivity.180 Recent data with conduct of 75G oral glucose tolerance tests (OGTT), coupled with 120 min serum insulin measurements, indicate tighter associations of NAFLD with post-prandial hyperinsulinemia and hyperglycemia than previously appreciated.132,181,182 An emerging theme in NASH pathogenesis is that metabolic abnormalities occur post-prandially. These include a series of changes in response to an oral fat load, such as post-prandial hypertriglyceridemia,96,132 as well as hypoadiponectinemia.121 Such responses could have a genetic basis; for example, subjects carrying certain polymorphisms of microsomal triglyceride transfer protein (MTP), which lipidates apolipoprotein beta to form VLDL, exhibit greater degrees of hypertriglyceridemia, higher serum FFA levels and steatosis.183 Other polymorphisms relevant to post-prandial lipemia include those within the adiponectin gene,184 and the transcription factor 7-like 2 gene.