ABSTRACT
BACKGROUND. Abdominal obesity, characterized by ectopic fat deposition in skeletal muscle and liver tissue, has been associated with insulin resistance and increased risk for type 2 diabetes mellitus. The aim of this study was to evaluate whether treatment with the angiotensin II type 1 (AT-1) receptor blocker telmisartan can reduce intramyocellular lipid (IMCL) and hepatic fat storage, thereby improving insulin sensitivity among individuals with abdominal obesity. METHODS. Ninety-five adults with abdominal obesity (body mass index ≥ 30 kg/m(2) and waist circumference > 102 cm in men and > 88 cm in women) were randomized to double-blind treatment with telmisartan or placebo for 24 weeks. Following 4 weeks of 80 mg telmisartan per day, the dose was increased to 160 mg telmisartan for the duration of the study. Soleus muscle IMCL and liver fat content were assessed by (1)H-magnetic resonance imaging ((1)H-MRI) spectroscopy. Secondary outcomes included changes in body composition, plasma lipids, glucose profiles, insulin sensitivity, beta-cell function and total adiponectin levels. RESULTS. There was no significant effect of telmisartan in abdominally obese individuals consuming either a low or high glycemic diet, on IMCL content (5.73 ± 1.11 vs 6.11 ± 1.11; p = 0.13) or liver fat (0.08 ± 0.05 vs 0.09 ± 0.05; p = 0.60). Body composition, lipid and glucose profiles, insulin sensitivity and adiponectin were likewise unaffected. Beta-cell function, as determined by the insulinogenic index (IGI), improved significantly (19.3 ± 13.7 vs 22.5 ± 17.6; p = 0.03; 16.5% increase from baseline in the telmisartan group). CONCLUSIONS. Telmisartan increased beta-cell function but did not decrease IMCL or liver fat content or other metabolic parameters among individuals with abdominal obesity.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Benzimidazoles/therapeutic use , Benzoates/therapeutic use , Obesity, Abdominal/drug therapy , Obesity, Abdominal/metabolism , Adiponectin/metabolism , Adult , Aged , Female , Humans , Insulin Resistance , Lipid Metabolism/drug effects , Male , Middle Aged , Prospective Studies , Single-Blind Method , TelmisartanABSTRACT
Endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) have been implicated in a number of complications associated with diabetes mellitus including micro- and macrovascular dysfunction. In this study we examine ER stress levels in blood cells isolated from human subjects with metabolic syndrome and in healthy controls. Total RNA and protein were isolated from leukocytes and the levels of specific ER stress markers were quantified by real-time-PCR and immunoblot analysis. Our results indicate that, compared to healthy controls, individuals with metabolic syndrome have elevated mRNA levels of genes indicative of ER stress; including spliced XBP-1 (sXBP-1), Grp78, and CHOP. Induced ER stress levels correlate with blood glucose but not plasma lipid concentration. Furthermore, in healthy individuals, a standard 75 g oral glucose challenge produced a significant elevation in spliced XBP-1 (1.3 fold), Grp78 (2.0 fold), and calreticulin (3.5 fold) mRNA 60 min post challenge and a significant increase in Grp78 (2.0 fold), calreticulin (2.7 fold) protein levels 2 h postchallenge, relative to fasting levels. The UPR was also activated ex vivo, in human leukocytes cultured in the presence of 15 mmol/l glucose, supporting a specific role for glucose. The oral glucose challenge was associated with a significant increase in the expression of inflammatory cytokines, including interleukin (IL)-1α/ß, IL-6, and IL-8, that may result from ER stress. These findings suggest that there is an association between both acute and chronic dysglycemia and ER stress in humans.