Differential regulation of amino acid exchange and protein dynamics across splanchnic and skeletal muscle beds by insulin in healthy human subjects.

Meek, Shon; Persson, Mai; Ford, G. C.; Nair, K. S.

doi:10.2337/diabetes.47.12.1824

Cited by 112 publications

(123 citation statements)

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“…The increased circulating insulin levels on 11 days of insulin treatment substantially reduced fasting glucose levels but had little impact on circulating amino acid concentrations and amino acid kinetics, reflecting protein turnover. Previous studies in nondiabetic people demonstrated that leucine carbon flux declined progressively in a dose-dependent manner on intravenous insulin infusion (31,49,50). However, these dose-dependent effects clearly showed that the near-maximal insulin effect was achieved when insulin was infused at a dose of 1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 (31).…”

Section: Discussionmentioning

confidence: 78%

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

et al. 2002

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Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO 2max . We investigated the effect of 11 days of intensive insulin treatment (T 2 D؉) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T 2 D؊) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T 2 D؊. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.

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Section: Discussionmentioning

confidence: 78%

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

et al. 2002

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“…It is well recognized that increased availability of mitochondrial protein is associated with increased respiration (13,35). By increasing mitochondrial protein synthesis and possibly decreasing protein breakdown (36)(37)(38), insulin may increase mitochondrial protein content and could thus enhance mitochondrial respiration. Previous studies have meticulously revealed many of the subcellular mechanisms by which insulin stimulates muscle protein synthesis, most involving the up-regulation of translational steps (39,40).…”

Section: Discussionmentioning

confidence: 99%

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

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Bigelow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

419

369

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Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits͞kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164 -180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16 -26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels.cytochrome c oxidase ͉ NADH dehydrogenase subunit IV ͉ amino acids ͉ citrate synthase

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“…Hyperinsulinemia, as was present in our subjects with NASH, has been shown to differentially inhibit hepatic protein synthesis and degradation. [54][55][56] Although our primary goal was to determine the relative expression of genes involved in the mitochondrial function and glucose and lipid metabolism, the finding that several mediators of inflammation were expressed differentially also merits consideration. Hepatocyte-derived fibrinogen-related protein 1, complement compo-nent C3, and ␣-1 antitrypsin, all acute phase reactants, also were relatively overexpressed in subjects with NASH.…”

Section: Discussionmentioning

confidence: 99%

Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

et al. 2003

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Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high-density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap-frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic-stage NASH (n ‫؍‬ 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n ‫؍‬ 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n ‫؍‬ 6), and (4) healthy controls (n ‫؍‬ 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic-stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6-phospatase, alcohol dehydrogenase, elongation factor-TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte-derived fibrinogen-related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings. (HEPATOLOGY 2003;38:244-251.)

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Differential regulation of amino acid exchange and protein dynamics across splanchnic and skeletal muscle beds by insulin in healthy human subjects.

Cited by 112 publications

References 0 publications

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

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