1.
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.
2.
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.