Hepatic steatosis rather than visceral adiposity is more closely associated with insulin resistance in the early stage of obesity.

The aim of the present study was to investigate the specific relationship between hepatic steatosis and insulin resistance in the early stage of obesity. Among general health examinees who received an ultrasound scanning, 131 subjects without fatty liver (non-FL group) and 142 subjects with fatty liver (FL group) were selected so that both groups were matched for age, sex, body mass index, and % body fat. The FL group was then subdivided into 2 groups according to the severity of steatosis by ultrasound. Insulin resistance was assessed by homeostasis model assessment for insulin resistance, serum high-molecular-weight (HMW) adiponectin, and insulin-like growth factor binding protein 1 concentrations. Unexpectedly, the non-FL group showed higher waist circumference than the FL group. Nevertheless, homeostasis model assessment for insulin resistance as well as conventional insulin resistance indexes such as serum insulin, free fatty acid, and triglyceride levels demonstrated a stepwise increase, and HMW adiponectin and insulin-like growth factor binding protein 1 demonstrated a stepwise decrease with increasing degree of hepatic steatosis. Overall, insulin resistance markers correlated with obesity indexes, but only HMW adiponectin no longer showed any meaningful correlation in the presence of fatty liver. The prevalence of BP, fasting serum glucose, and high-density lipoprotein cholesterol above or below cutoff points and subjects having 2 or more metabolic syndrome components were higher in the moderate to severe FL group compared to the non-FL group. In conclusion, these results in nondiabetic and relatively normal-body mass index subjects suggest that hepatic steatosis is independently associated with insulin resistance regardless of extrahepatic adiposity and might be the earliest event in pathogenesis of the metabolic syndrome.

Adenosine triphosphate-sensitive potassium (K(ATP)) channel activity is coupled with insulin resistance in obesity and type 2 diabetes mellitus.

ATP sensitive potassium (K(ATP)) channels reside in the plasma membrane of many excitable cells such as pancreatic beta-cells, heart, skeletal muscle and brain, where they link cellular metabolic energy to membrane electrical activity. They are composed of two subunits, K+ ion selective pore (Kir) and sulfonylurea receptor (SUR). In addition to the central role of pancreatic beta-cell K(ATP) channels in glucose-mediated insulin secretion, several lines of evidence support the hypothesis that K(ATP) channels modulate glucose transport in the insulin target tissues. Inhibition of K(ATP) channels by glibenclamide or gliclazide or an increase in intracellular ATP during hyperglycemia (glucose effect) or exercise facilitates glucose utilization, while activation of the channels by potassium channel openers, hypothermia (cardiac surgery), or ischemic damage (myocardial and brain infarction) reduces glucose uptake induced by insulin or hyperglycemia. Because insulin action has been known to depend on the energy level of the target cells, K(ATP) channel may function as an effector in this respect. It is now evident that long chain acyl-CoA esters, metabolically active forms of fatty acids, are the most potent and physiologically important activator of K(ATP) channels. Thus, I suppose that the sustained activation of K(ATP) channels by long chain fatty acyl-CoA seems to be a missing link between lipotoxicity and insulin resistance in obesity and type 2 diabetes mellitus.

[Glucagon-like peptide-1(GLP-1)].

Glucagon-like peptide-1(GLP-1), an intestinal hormone secreted by L cells in response to luminal nutrients(carbohydrate and fat), enhances glucose-induced insulin secretion. Impairment of glucose-induced insulin secretion in patients with type 2 diabetes can be restored to near-normal by GLP-1 administration. In addition, GLP-1 possesses multiple biological effects which are favorable for the treatment of type 2 diabetes: inhibition of glucagon secretion, slowing of gastric emptying, reduction of appetite and food intake, upregulation of genes essential for insulin secretion(glucokinase, GLUT-2 etc), and beta cell proliferation and differentiation. Some long-acting GLP-1 derivatives which are resistant to the degradation by enzyme dipeptidyl peptidase-IV are currently under the clinical trial and are reportedly promising for the treatment of type 2 diabetes, because of impressive effects on glycemic control, availability by oral administration and very few adverse effects.

Increase in gamma-glutamyltransferase level and development of established cardiovascular risk factors and diabetes in Japanese adults.

BACKGROUND: We investigated the predictive value of changes in serum gamma-glutamyltransferase (GGT) for the development of cardiovascular disease (CVD) risk factors in Japanese. METHODS: A total of 1514 adult participants in a general health examination program were followed for 3 years until January, 2006. The subjects were divided into two groups according to whether their serum GGT level had decreased (< or =0 U/L) or increased (> or =1 U/L) from the baseline level of GGT during the study period. The logistic regression model was used to analyze the relationship between increases in GGT levels and the incidence of diabetes (DM), impaired fasting glucose (IFG), dyslipidemia, and hypertension (HT). RESULTS: The mean value of GGT level was significantly higher at baseline than the 3-year follow-up point (47 +/- 41 versus 41 +/- 51, P < 0.0001), and the average 3-year GGT change was -5.7 +/- 32.3 U/L. The subjects with an increased GGT over the 3 years had an increased risk of developing DM, IFG, high triglyceride (TG) levels, and HT, in comparison with that of the subjects with a decreased GGT level, with an odds ratios (OR) of 6.13 (95% confidence interval [CI], 2.83-13.25), 2.70 (1.68-4.34), 2.65 (1.76-3.99), and 1.54 (1.12-2.13), respectively, after adjusting for age, sex, and alcohol habits. Further adjustments for baseline GGT, alanine aminotransferase (ALT), body mass index (BMI), and 3-year changes in BMI did not alter these associations. CONCLUSIONS: The increased change in GGT over 3 years was a significant and an independent risk factor for the development of high TG, HT, IFG, and DM in Japanese.