Mechanism of induction of muscle protein loss by hyperglycaemia
ABSTRACT Treatment of murine myotubes with high glucose concentrations (10 and 25 mM) stimulated protein degradation through the ubiquitin–proteasome pathway, and also caused activation (autophosphorylation) of PKR (double-stranded-RNA-dependent protein kinase) and eIF2α (eukaryotic initiation factor 2α). Phosphorylation of PKR and eIF2α was also seen in the gastrocnemius muscle of diabetic ob/ob mice. High glucose levels also inhibited protein synthesis. The effect of glucose on protein synthesis and degradation was not seen in myotubes transfected with a catalytically inactive variant (PKRΔ6). High glucose also induced an increased activity of both caspase-3 and -8, which led to activation of PKR, since this was completely attenuated by the specific caspase inhibitors. Activation of PKR also led to activation of p38MAPK (mitogen activated protein kinase), leading to ROS (reactive oxygen species) formation, since this was attenuated by the specific p38MAPK inhibitor SB203580. ROS formation was important in protein degradation, since it was completely attenuated by the antioxidant butylated hydroxytoluene. These results suggest that high glucose induces muscle atrophy through the caspase-3/-8 induced activation of PKR, leading to phosphorylation of eIF2α and depression of protein synthesis, together with PKR-mediated ROS production, through p38MAPK and increased protein degradation.
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ABSTRACT: Objective In insulin-resistant states, resistance of protein anabolism occurs concurrently with that of glucose, but can be compensated for by abundant amino acid (AA) provision. This effect and its mechanism were sought in obesity.Methods Pancreatic clamps were performed in 8 lean and 11 obese men, following 5-h postabsorptive, 3-h infusions of octreotide, basal glucagon, and growth hormone, with clamped postprandial-level insulin, glucose, and AA. Whole-body [1-13C]-leucine and [3-3H]-glucose kinetics, skeletal muscle protein (2H5-phenylalanine) fractional synthesis rates, and insulin signaling were determined.ResultsClamp Δ insulin and Δ branched-chain AA did not differ; fasting glucagon and growth hormone were maintained. Glucose uptake was 20% less in obese concurrent with less AktSer473, but also less IRS-1Ser636/639 phosphorylation. Stimulation of whole-body, myofibrillar, and sarcoplasmic protein synthesis was similar. Whole-body protein catabolism suppression tended to be less (P=0.06), resulting in lesser net balance (1.09 ± 0.07 vs. 1.31 ± 0.08 μmol [kg FFM−1] min−1, P = 0.048). Increments in muscle S6K1Thr389 phosphorylation were less in the obese, but 4E-BP1Ser65 did not differ.Conclusions Hyperaminoacidemia with hyperinsulinemia stimulated protein synthesis (possibly via nutrient signaling) normally in obesity, but suppression of proteolysis may be compromised. Whether long-term high protein intakes could compensate for the insulin resistance of protein anabolism remains to be determined.Obesity 11/2014; · 4.39 Impact Factor
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ABSTRACT: Pancreatic β-cell function is of critical importance in the regulation of fuel homeostasis, and metabolic dysregulation is a hallmark of diabetes mellitus (DM). The β-cell is an intricately designed cell type that couples metabolism of dietary sources of carbohydrates, amino acids, and lipids to insulin secretory mechanisms, such that insulin release occurs at appropriate times to ensure efficient nutrient uptake and storage by target tissues. However, chronic exposure to high nutrient concentrations results in altered metabolism that impacts negatively on insulin exocytosis, insulin action, and may ultimately lead to development of DM. Reduced action of insulin in target tissues is associated with impairment of insulin signalling and contributes to insulin resistance (IR), a condition often associated with obesity, and a major risk factor for DM. The altered metabolism of nutrients by insulin sensitive target tissues (muscle, adipose, and liver) can result in high circulating levels of glucose and various lipids, which further impact on pancreatic β-cell function, IR, and progression of the metabolic syndrome. Here, we have considered the role played by the major nutrient groups, carbohydrates, amino acids, and lipids, in mediating β-cell insulin secretion, while also exploring the interplay between amino acids and insulin action in muscle. We also focus on the effects of altered lipid metabolism in adipose and liver resulting from activation of inflammatory processes commonly observed in DM pathophysiology. The aim of this review is to describe commonalities and differences in metabolism related to insulin secretion and action, pertinent to the development of DM.Journal of Endocrinology 03/2014; · 3.59 Impact Factor
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ABSTRACT: Stress-induced hyperglycemia has been considered an adaptive mechanism to stress up to the first intensive insulin therapy trial, which showed a 34% reduction in relative risk of in-hospital mortality when normalizing blood glucose levels. Further trials had conflicting results and, at present, stress-induced hyperglycemia management remains non-consensual. These findings could be explained by discrepancies in trials, notably regarding the approach to treat hyperglycemia: high versus restrictive caloric intake. Stress-induced hyperglycemia is a frequent complication during intensive care unit stay and is associated with a higher mortality. It results from an imbalance between insulin and counter-regulatory hormones, increased neoglucogenesis, and the cytokine-induced insulin-resistant state of tissues. In this review, we summarize detrimental effects of hyperglycemia on organs in the critically ill (peripheric and central nervous, liver, immune system, kidney, and cardiovascular system). Finally, we show clinical and experimental evidence of potential benefits from glucose and insulin administration, notably on metabolism, immunity, and the cardiovascular system.Critical care (London, England) 07/2014; 18(4):232. · 5.04 Impact Factor