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Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.
Ellis, KL, Zhou, Y, Rodriguez-Murillo, L, Beshansky, JR, Ainehsazan, E, Selker, HP, Huggins, GS, Cupples, LA, Peter, I
The pharmacogenomics journal. 2017;(1):76-83
Abstract
Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.
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The effects of long-term valsartan treatment on skeletal muscle fatty acid handling in humans with impaired glucose metabolism.
Moors, CC, Blaak, EE, van der Zijl, NJ, Diamant, M, Goossens, GH
The Journal of clinical endocrinology and metabolism. 2013;(5):E891-6
Abstract
CONTEXT Blocking the renin-angiotensin system reduces the incidence of type 2 diabetes mellitus in humans with impaired glucose metabolism (IGM). Nevertheless, underlying mechanisms remain to be established. OBJECTIVE The purpose of this study was to investigate the effects of the angiotensin II type 1 receptor blocker valsartan (VAL) on skeletal muscle fatty acid (FA) handling in subjects with IGM. DESIGN/SETTING This was a randomized, double-blind placebo-controlled trial at Maastricht University Medical Center. INTERVENTION/MAIN OUTCOMES/PARTICIPANTS Fasting and postprandial skeletal muscle FA handling were assessed at baseline and after 26 weeks of treatment with VAL or placebo in 26 subjects with IGM. Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm balance technique with stable isotopes of palmitate. [²H₂]-Palmitate was infused iv to label endogenous triacylglycerol (TAG) and free fatty acid (FFA) in the circulation, and [U-¹³C]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61% energy from fat) to label chylomicron TAG. Muscle biopsy samples were taken to determine im TAG, diacylglycerol (DAG), FFA, and phospholipid contents, their fractional synthetic rates and degree of saturation, and mRNA expression of oxidative genes. RESULTS VAL decreased saturation of im TAG and DAG fractions but did not affect net muscle uptake of [²H₂]-palmitate, very low-density lipoprotein ([²H₂])-TAG and chylomicron ([U-¹³C])-TAG, and muscle mRNA expression. VAL decreased FA spillover, as estimated by circulating [U-¹³C]-palmitate, and FFA rate of appearance and tended to decrease chylomicron TAG concentrations. CONCLUSIONS VAL treatment for 26 weeks decreased saturation of skeletal muscle TAG and DAG stores, suggesting altered intramuscular lipid partitioning of FA. The VAL-induced reduction in postprandial FA spillover, endogenous lipolysis, and chylomicron TAG concentrations indicate improved adipose tissue lipid buffering capacity.
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Does rimonabant independently affect free fatty acid and glucose metabolism?
Triay, J, Mundi, M, Klein, S, Toledo, FG, Smith, SR, Abu-Lebdeh, H, Jensen, M
The Journal of clinical endocrinology and metabolism. 2012;(3):819-27
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Abstract
CONTEXT Endocannabinoid receptor 1 blockade is proposed to improve metabolic complications of obesity via central and peripheral effects. OBJECTIVE Our objective was to test whether rimonabant improves insulin regulation of free fatty acid and glucose metabolism after controlling for fat loss. DESIGN This was a double-blind, placebo-controlled substudy of the visceral fat reduction assessed by computed tomography scan on rimonabant (VICTORIA) trial. PARTICIPANTS AND SETTING Sixty-seven abdominally obese, metabolic syndrome volunteers age 35-70 yr participated at academic medical center general clinical research centers. INTERVENTION Intervention included a 12-month lifestyle weight management program plus rimonabant 20 mg/d or placebo. MAIN OUTCOME MEASURES Body composition and two-step euglycemic, hyperinsulinemic clamp before and after intervention were performed. Insulin sensitivity was assessed as insulin concentration needed to suppress by 50% palmitate concentration [IC50(palmitate)], flux [IC50(palmitate)f], and hepatic glucose output [IC50(HGO)] and as insulin-stimulated glucose disposal (Δ glucose disappearance per Δ insulin concentration--glucose slope). RESULTS Body fat decreased by 4.5±2.9% (SD) in the rimonabant and 1.9±4.5% in the placebo group (P<0.005). The primary [improvement in IC50(palmitate) and IC50(palmitate)f] and secondary [improvement in IC50(HGO) and glucose slope] outcomes were not significantly different between the rimonabant and placebo groups. Post hoc analyses revealed that 1) changes in body mass index (BMI) and IC50(palmitate) were correlated (P=0.005) in the rimonabant group; this relationship was not significantly different from placebo when controlling for greater BMI loss (P=0.5); 2) insulin-regulated glucose disposal improved in both groups (P=0.002) and correlated with changes in BMI. CONCLUSIONS Improvements observed in insulin regulation of free fatty acid and glucose metabolism with rimonabant treatment in humans was not greater than that predicted by weight loss alone.
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Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes.
van Wijk, JP, de Koning, EJ, Castro Cabezas, M, Rabelink, TJ
Diabetes care. 2005;(4):844-9
Abstract
OBJECTIVE Increased postprandial lipemia is part of diabetic dyslipidemia and is associated with accelerated atherosclerosis. We investigated the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on postprandial lipemia in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A randomized, 8-week, crossover, placebo-controlled, double-blind trial was performed in which rosiglitazone at 4 mg was administrated twice daily in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. Postprandial curves were calculated as the total area under the curve (AUC) and the incremental area under the curve (dAUC). RESULTS Rosiglitazone did not change fasting plasma triglycerides compared with placebo (1.97 +/- 0.22 vs. 1.88 +/- 0.20 mmol/l, respectively) but decreased postprandial triglyceride levels, leading to significantly lower triglyceride dAUC (-37%, P < 0.05), without changing total triglyceride AUC. Significant postprandial triglyceride reductions in the chylomicron fraction (Svedberg flotation rate [Sf] >400) were achieved with rosiglitazone, which resulted in a significant lower triglyceride AUC (-22%) in this fraction. The postprandial triglyceride increase in VLDL1 (Sf 60-400) was also lower after rosiglitazone (-27%), but this did not result in a significant lower triglyceride AUC. In VLDL2 (Sf 20-60), there were no significant differences in triglyceride AUC and triglyceride dAUC between rosiglitazone and placebo. Rosiglitazone decreased free fatty acid (FFA) AUC (-12%) and FFA dAUC (-18%) compared with placebo. CONCLUSIONS Rosiglitazone improves the metabolism of large triglyceride-rich lipoproteins and decreases postprandial FFA concentrations in type 2 diabetes. This may have clinical implications, as these effects may contribute to cardiovascular risk reduction.