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Aims T-emerge 2 was a randomized, open-label, 24-week trial comparing subcutaneous taspoglutide 10 mg weekly (Taspo10), taspoglutide 20 mg weekly (Taspo20; titrated after 4 weeks of Taspo10), with exenatide 10 mcg BID (Exe; after 4 weeks of Exe 5 mcg) in patients inadequately controlled on metformin, a thiazolidinedione, or both. T-emerge 2 showed that once-weekly Taspo provided better glycaemic control than Exe. This report focuses on a subset of T-emerge 2 participants undergoing a standardized liquid meal comparing Taspo to Exe, which has been previously shown to lower postprandial glucose. Methods Meal tolerance tests ( MTT) were performed at baseline and at week 24 in a subset of Taspo10, Taspo20 and Exe patients (n = 42, 39 and 67, respectively). Blood samples for glucose, insulin, glucagon and C-peptide were obtained before and after (30, 60, 90, 120 and 180 min) ingestion of a standardized liquid meal. Results The 2-h postprandial, mean 0-3 h and iAUC0-3 h glucose during the MTT was reduced to a similar extent in all groups and the time profile of the postprandial glucose showed a similar pattern. Taspo10 and Taspo20, but not Exe, significantly increased insulin from baseline (both mean and iAUC0-3 h). Although changes from baseline in C-peptide were not significant within any treatment group, the mean change from baseline (both mean 0-3 h and iAUC0-3 h) was significantly increased in Taspo10 vs. Exe. Mean glucagon showed significant decreases in all groups. Conclusion Taspoglutide and Exe improved postprandial glucose tolerance to a similar extent but possibly with different intimate mechanisms. [ABSTRACT FROM AUTHOR]

Background Plasma adiponectin is decreased in NASH patients and the mechanism(s) for histological improvement during thiazolidinedione treatment remain(s) poorly understood. Aim To evaluate the relationship between changes in plasma adiponectin following pioglitazone treatment and metabolic/histological improvement. Methods We measured in 47 NASH patients and 20 controls: (i) fasting glucose, insulin, FFA and adiponectin concentrations; (ii) hepatic fat content by magnetic resonance spectroscopy; and (iii) peripheral/hepatic insulin sensitivity (by double-tracer oral glucose tolerance test). Patients were then treated with pioglitazone (45 mg/day) or placebo and all measurements were repeated after 6 months. Results Patients with NASH had decreased plasma adiponectin levels independent of the presence of obesity. Pioglitazone increased 2.3-fold plasma adiponectin and improved insulin resistance, glucose tolerance and glucose clearance, steatosis and necroinflammation (all P < 0.01–0.001 vs. placebo). In the pioglitazone group, plasma adiponectin was significantly associated ( r = 0.52, P = 0.0001) with hepatic insulin sensitivity and with the change in both variables ( r = 0.44, P = 0.03). Increase in adiponectin concentration was related also to histological improvement, in particular, to hepatic steatosis ( r = −0.46, P = 0006) and necroinflammation ( r = −0.56, P < 0.0001) but importantly also to fibrosis ( r = −0.29, P = 0.03). Conclusions Adiponectin exerts an important metabolic role at the level of the liver, and its increase during pioglitazone treatment is critical to reverse insulin resistance and improve liver histology in NASH patients. [ABSTRACT FROM AUTHOR]

We have recently reported that pioglitazone (PIO) improved glucose metabolism and histology in 55 IGT/T2DM subjects with non-alcoholic steatohepatitis (NASH). Because insulin resistance OR) and abnormal lipid metabolism are important in the development of steatosis, we examined the role of adipose tissue IR and impact of PIO in these pts who were randomized (double-blind) to PIO (45mg/d) or placebo (Pbo) for 6 months. Before and after treatment pts underwent: 1) liver biopsy; 2) measurement of liver fat content by magnetic resonance (L-MRS); 3) a double-tracer 75gOGTT to assess glucose tolerance, production (EGP) and clearance (glu disposal/plasma glu), and to estimate indexes of IR in adipose tissue (Ad-IRI=fasting plasma FFAx insulin conc [FPI]) and liver (H-IRI=EGP x FPI). 15 control subjects (CON) were also studied in the same way (except for liver biopsy).Compared to CON, NASH pts had increased FFA (739±34 vs. CON 596±44 umol/l; p<0.001), impaired FFA suppression during OGTT (360±18 vs 240±19 umol/l; p<0.001), severe adipose-IR (12.1±1.3 vs. 2.7±0.6 mmol/l⋅mU/l, p<0.0003) and low adiponectin (7.0±1.6 vs. 13.2±2.1 mg/l p<0.001). L-MRS was ∼3-fold higher in NASH (p<0.001) and correlated positively with adipose-IR (r=0.35, p<0.05) and negatively with adiponectin (r=-0.31, p<0.03). Liver-IR was associated with both high fasting and OGTT FFA (r=0.30, p=0.02). Both H-IR and Ad-IR were associated with reduced glucose clearance both fasting and during OGTT (r=0.37-0.44, all p<0.002). PIP improved H-IR, glu tolerance and clearance, steatosis and necro-inflammation (p<0.01-0.001 vs. Pbo). FFA decreased by ∼15% with PIP (p<0.02), L-MRS by ∼50% (p<0.001) and adipose-IR by 40% (13<0.05). L-MRS decrease was associated with improved adipose-IR and OGTT glu clearance (r=0.43 and r=0.55, both p<0.02). Adiponectin increased ∼3-fold (p<0.001), correlating with a decrease in L-MRS (r=-0.57, p<0.001), liver- and adipose-IR (r=-0.37 & r=-0.54, p<0.01) and enhanced OGTT glu clearance (r=0.44, p<0.004). Conclusion: Severe adipose-IR is an important clinical feature of pts with IGT/T2DM and NASH, being associated with elevated liver fat, low adiponectin and hepatic and peripheral insulin resistance. Enhanced adipose tissue function (i.e., improved insulin sensitivity/incr. adiponectin) by PIO plays a key role in the metabolic (i.e., hepatic/peripheral IR) and histologic (i.e., lower liver fat) improvements associated with treatment. [ABSTRACT FROM AUTHOR]