Metabolism: clinical and experimental
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Burn injury is associated with inflammatory responses and metabolic alterations including insulin resistance. Impaired insulin receptor substrate-1 (IRS-1)-mediated insulin signal transduction is a major component of insulin resistance in skeletal muscle following burn injury. To further investigate molecular mechanisms that underlie burn injury-induced insulin resistance, we study a role of inducible nitric oxide synthase (iNOS), a major mediator of inflammation, on burn-induced muscle insulin resistance in iNOS-deficient mice. ⋯ Unexpectedly, however, blood glucose levels were depressed in both wild-type and iNOS-deficient mice after burn injury. Gene disruption of iNOS ameliorated the effect of burn on IRS-1-mediated insulin signaling in skeletal muscle of mice. These findings indicate that iNOS plays a significant role in burn injury-induced skeletal muscle insulin resistance.
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Randomized Controlled Trial
High-dose insulin administration is associated with hypoaminoacidemia during cardiac surgery.
Although the effects of insulin on glucose homeostasis are well recognized in surgical patients, its effect on perioperative protein metabolism has received little attention. The purpose of this study was to examine the effect of high-dose insulin therapy on the plasma concentrations of amino acids (AAs) in patients undergoing coronary artery bypass grafting surgery. We studied 20 nondiabetic patients scheduled for elective coronary artery bypass grafting surgery. ⋯ Plasma concentrations of all AAs decreased in the insulin group, with 15 of 22 AAs, including all branched-chain AAs, being significantly lower at sternal closure when compared with the control group. At the end of surgery, plasma glucose concentration was significantly lower in the insulin group (4.2 ± 0.6 vs 7.3 ± 1.0 mmol/L, P = .0001), whereas plasma cortisol levels did not show any difference between groups. High-dose insulin therapy resulted in a significant reduction in plasma AAs, particularly branched-chain AAs, during cardiac surgery.
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Clinical Trial
Short-term increase of plasma free fatty acids does not interfere with intrinsic mitochondrial function in healthy young men.
Free fatty acid (FFA)- and obesity-induced insulin resistance has been associated with disturbed mitochondrial function. Elevated plasma FFA can impair insulin-induced increase of adenosine triphosphate synthesis and downregulate the expression of genes important in the biogenesis of mitochondria in human skeletal muscle. Whether FAs have a direct effect on intrinsic mitochondrial capacity remains to be established. ⋯ Peripheral glucose uptake (rate of disappearance) was significantly lower during infusion of the lipid emulsion compared with the control saline infusion (68 μmol/kg·min [saline] vs 40 μmol/kg·min [lipid], P = .008). However, adenosine diphosphate-stimulated and maximal carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone-stimulated uncoupled respiration rates were not different in permeabilized skeletal muscle fibers after exposure to high levels of FFA compared with the control condition. We conclude that short-term elevation of FFA within the physiological range induces insulin resistance but does not affect intrinsic mitochondrial capacity in skeletal muscle in humans.
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Randomized Controlled Trial
Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women.
Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (metreleptin) for a long period improves BMD and BMC remains unknown. ⋯ The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone remodeling milieu to favor bone accretion. Results from this pilot study should be confirmed by future, larger clinical trials and need to be extended by studying bone microarchitecture and fracture risk.
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Skeletal muscle biopsy studies have consistently shown a decreased oxidative phenotype in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Limited information is available regarding potential adaptations or abnormalities in anaerobic metabolism and glucose homeostasis. Whole-body glucose production was assessed at rest and during exercise in COPD patients with moderate disease severity (forced expiratory volume in 1 second, 52% ± 3%), prestratified into normal-weight (n = 7; body mass index [BMI], 27.5 ± 0.9 kg·m(-2)) and underweight subjects (n = 6; BMI, 20.6 ± 0.7 kg·m(-2)), and in 8 healthy controls matched for age and BMI with the normal-weight COPD group. ⋯ In normal-weight patients, there was evidence for decreased insulin sensitivity assessed by homeostatic modeling technique. Whole-body glucose production is increased in underweight COPD patients with normal glucose tolerance. It is hypothesized that lowered body weight in COPD has unique effects on glucose uptake despite reduced skeletal muscle oxidative capacity, relative hypoxemia, and sympathetic activation.