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Background: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). Results: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. Conclusion: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus is a metabolic disorder characterized by insulin resistance. Previous studies in patients demonstrated that plasma levels of cathepsin D (CTSD), which is optimally active in the acidic environment of lysosomes, correlate with insulin resistance. As plasma pH is slightly reduced in type 2 diabetic patients and we have previously shown that plasma CTSD activity is causally linked to insulin levels in vivo , it is likely that the activity of CTSD in plasma will be increased in type 2 diabetes compared to healthy individuals. However, so far the interaction between CTSD activity and levels to postprandial metabolic derangements in type 2 diabetes is not known. Methods: Eighteen type 2 diabetes and 16 age-matched healthy males were given 2 consecutive standardized mixed meals, after which blood samples were collected. Plasma metabolic parameters as well as CTSD levels and activity were measured, and changes in plasma pH was assessed. Results: In line with the elevation of plasma free fatty acids (FFA) levels in male type 2 diabetics patients, plasma pH in type 2 diabetic individuals was decreased compared to male healthy individuals. While plasma CTSD levels were similar, plasma CTSD activity was increased in male type 2 diabetic compared to male healthy individuals. Besides, plasma CTSD activity rather than levels significantly correlated with indicators of type 2 diabetes (HbA1c, HOMA-IR and glucose). Furthermore, FFA was also independently associated with plasma CTSD activity (standardized β = 0.493, p = 0.007). Conclusions: Despite similar plasma CTSD levels, type 2 diabetic male individuals showed increased plasma CTSD activity compared to healthy males, which was independently linked to plasma FFA levels. Our data therefore point toward plasma CTSD as a metabolic regulator in male type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article provides information on a study that examined whether exposure to consecutive high-fat mixed meals during a 24-hour period will disclose type 2 diabetic patients' compromised metabolism and subsequent endothelial dysfunction. Plasma glucose, triglyceride, and insulin concentrations rose postprandially in patients, relative to baseline and healthy control subjects. At baseline, flow-mediated dilation was decreased in patients versus control subjects, and deteriorated postprandially in both groups

In insulin resistant states, increased lipolysis in adipose tissue and unsuppressed hepatic VLDL-triglyceride output lead to a high exposure of non-adipose tissues to lipids. Experimental and autopsy data indicate that fatty infiltration of pancreatic islets may also contribute to β-cell dysfunction, but whether this phenomenon occurs in humans in vivo is unknown. Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of β-cell function in 12 insulin-naïve type 2 diabetic and 24 age- and BMI-matched non-diabetic males. Patients versus controls had higher HbA1c, fasting plasma glucose, insulin and triglyceride levels, lower HDL-C, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients was 20.4(13.4-43.6) and 9.7(7.0-20.2)% in controls (P=0.032). Pancreatic fat correlated negatively with β-cell function parameters, including insulinogenic index adjusted for insulin resistance, early phase insulin secretion, β-cell glucose sensitivity, rate sensitivity (all P<0.05), but not potentiation. The interaction of pancreatic fat with the diabetic state significantly affected the association. Separate analyses showed a significant association of pancreatic fat with β-cell dysfunction in the non-diabetic group only (all P<0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat may account for further β-cell function decline. In controls, the association of pancreatic fat and β-cell dysfunction remained significant after correction for BMI, fasting plasma glucose and triglycerides (P=0.006). These findings indicate that pancreatic lipid content may contribute to β-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (DM2) and the metabolic syndrome (MetS) are conditions associated with a high risk of coronary artery disease (CAD) and congestive heart failure (CHF). Although CAD contributes to diastolic dysfunction and left ventricular (LV) stiffness, the interaction between CAD, DM2 and the MetS, is largely unknown. We studied the impact of CAD, DM2 and the MetS on LV function and stiffness in patients who underwent a diagnostic coronary angiography. Sixty patients (n=22 with and n=21 without the MetS and n=17 with DM2; n=38 males were studied. Only subjects with LV ejection fraction >40% were included to avoid the confounding of post myocardial infarction remodeling. CAD severity was determined according to the number of the vessels with >50% stenosis. Thus, 26 patients had no CAD, 14 had 1, 9 had 2, 11 had 3 vessel disease. Hemodynamic and echocardiographic data were collected and combined to calculate percent LV wall thickening (LVWT%), a measure of systolic function, as well as LV end-diastolic wall thickness (LVWTed) and myocardial stiffness modulus, both variables of diastolic function. LVWT% did not differ among groups. DM2 subjects and those with the MetS had higher LVWTed than controls (P=0.019), but LV stiffness was not increased. Patients with vs those without CAD had higher LVWTed (P=0.022) and lower LVWT% (P=0.031). A trend for increased LV stiffness in CAD patients was observed (P=0.158). LV stiffness worsened according to the number of vessels involved (P=0.044). Multivariate analyses revealed CAD as an independent determinant of LV stiffness, after correction for age, gender and fasting glucose, in patients with MetS and DM2 (P=0.002), but not in controls (P=0.895). In conclusion, increased LVWTed was observed in subjects with the MetS and DM2, vs controls, and in patients with relative to those without CAD. We show that the contribution of CAD to LV stiffness depends on the presence of dysmetabolic conditions including the MetS and DM2. These findings implicate that strategies aiming early detection and treatment of CAD in people with MetS and DM2 may prevent future development of CHF. [ABSTRACT FROM AUTHOR]