The MHO group had a similar BMI compared to NAFLD patients, with this group being just slightly less obese by DXA (P < 0.05). Despite the similar BMI, liver fat content in patients with NAFLD was much higher versus MHO subjects (24.7% ± 0.9% versus 1.7% ± 0.4%, respectively; P < 0.0001) and a higher prevalence of metabolic syndrome (MetS) (92% vs. 23%; P < 0.001), higher aspartate EMD 1214063 datasheet aminotransferase (AST) and alanine aminotransferase (ALT), and a much worse lipid profile (i.e., triglycerides [TGs] and high-density lipoprotein cholesterol [HDL-C];

all P < 0.05 to P < 0.001). Plasma adiponectin was >50% higher in lean, compared to obese, patients without NAFLD, suggesting an early defect in adipose tissue regulation, whereas obese NAFLD patients had a further decrease, compared to MHO subjects (Table

1). This was consistent with severe adipose tissue IR and worse Adipo-IRi in patients with NAFLD versus MHO patients (P < 0.001). We also examined the effect of adipose tissue IR across other target tissues. Patients with NAFLD had severe hepatic IR, compared to MHO patients, either measured as the HIRi or the suppression of EGP (hepatic) by low-dose insulin infusion (both P = 0.05) (Table 1). Patients with NAFLD also had severe muscle IR, compared to MHO patients, with ∼50% reduction in Rd (5.8 ± 0.3 versus 12.1 ± 0.8 mg·kgLBM−1·min−1; P < 0.0001). To further investigate the relationship between adipose tissue IR with metabolic and histological parameters, we divided Baf-A1 concentration NAFLD patients based on quartiles of Adipo-IRi (Q1 = more sensitive; Q4 = more insulin-resistant adipose tissue). The four groups of patients with NAFLD were well matched for age, gender, body

fat, visceral fat, Small molecule library and A1c (Table 2). Adipose tissue IR was associated with a threshold effect in relation to liver fat content between patients without, compared to those with, NAFLD, increasing rapidly in the presence of dysfunctional fat (Q1) and remaining rather constant between quartiles 1 to 3. However, there was a progressive stepwise increase in the homeostasis model assessment (HOMA), an indirect measure of hepatic IR. This was consistent with worsening IR at the level of the liver when directly assessed by means of the HIRi from Q1 to Q4 (see below). Similarly, plasma adiponectin decreased markedly by 39% and abruptly at the least severe quartile (Q1) versus MHO patients (P < 0.001), but did not deteriorate further from Q2 to Q4. There was no significant difference in fasting (3.2 ± 0.4 versus 3.8 ± 0.5 μU/L, respectively; P = 0.82) or postprandial (28.7 ± 6.2 versus 27.8 ± 3.6 μU/L, respectively; P = 0.98) plasma insulin concentration between lean and MHO patients (Fig. 1A). In contrast, fasting plasma insulin increased by 1.5-, 2.5-, 3.4-, and 6.2-fold from Q1 to Q4 (from 6.4 ± 0.5 to 24.7 ± 1.4 μU/L; Q4 versus MHO; P < 0.0001). Similarly, compared to MHO patients, the postprandial insulin increased by 2-fold in patients with mildly abnormal fat (Q1 versus MHO; P = 0.