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The control by insulin of amino acid accumulation in muscle.

ABSTRACT: 1. The capacity of insulin to enhance the accumulation by muscle of several amino acids was studied. Reports that threonine uptake is enhanced by insulin were not confirmed, despite its enhanced incorporation into protein. Uptake of beta-alanine and gamma-aminobutyric acid also did not respond to the hormone. A stimulation of accumulation of alanine, histidine and ethionine was observed. 2. The capacity of inhibitors of protein synthesis to reveal a stimulation by insulin of accumulation of several amino acids, hitherto considered unresponsive to insulin in the absence of inhibitor, was confirmed. Cycloheximide was as effective as puromycin. However, two of these amino acids, alanine and histidine, here showed response to insulin in the absence of inhibitor. The presence of cycloheximide was found to enhance uptake of cycloleucine, ethionine and threonine; in its presence insulin enhanced uptake of beta-alanine and alpha-methyltyrosine. 3. It is concluded that the influence of inhibitors of protein synthesis on amino acid accumulation and the response of amino acid accumulation to insulin are not adequately explained on the basis of inhibition of protein synthesis allowing amino acids to accumulate more readily. 4. The technical problems of whether linear rates of incorporation of amino acids into protein really indicate more than one cell pool are discussed and safeguards suggested. That initial rates of incorporation of label into protein are likely to be non-linear is shown.

SUBMITTER: Manchester KL

PROVIDER: S-EPMC1178947 | biostudies-other | 1970 Apr

REPOSITORIES: biostudies-other

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Project description:ObjectiveA branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obesity-related metabolic dysfunction, we studied the impact of BCAA restriction in a rodent model of obesity in which BCAA metabolism is perturbed in ways that mirror the human condition.MethodsZucker-lean rats (ZLR) and Zucker-fatty rats (ZFR) were fed either a custom control, low fat (LF) diet, or an isonitrogenous, isocaloric LF diet in which all three BCAA (Leu, Ile, Val) were reduced by 45% (LF-RES). We performed comprehensive metabolic and physiologic profiling to characterize the effects of BCAA restriction on energy balance, insulin sensitivity, and glucose, lipid and amino acid metabolism.ResultsLF-fed ZFR had higher levels of circulating BCAA and lower levels of glycine compared to LF-fed ZLR. Feeding ZFR with the LF-RES diet lowered circulating BCAA to levels found in LF-fed ZLR. Activity of the rate limiting enzyme in the BCAA catabolic pathway, branched chain keto acid dehydrogenase (BCKDH), was lower in liver but higher in skeletal muscle of ZFR compared to ZLR and was not responsive to diet in either tissue. BCAA restriction had very little impact on metabolites studied in liver of ZFR where BCAA content was low, and BCKDH activity was suppressed. However, in skeletal muscle of LF-fed ZFR compared to LF-fed ZLR, where BCAA content and BCKDH activity were increased, accumulation of fatty acyl CoAs was completely normalized by dietary BCAA restriction. BCAA restriction also normalized skeletal muscle glycine content and increased urinary acetyl glycine excretion in ZFR. These effects were accompanied by lower RER and improved skeletal muscle insulin sensitivity in LF-RES fed ZFR as measured by hyperinsulinemic-isoglycemic clamp.ConclusionsOur data are consistent with a model wherein elevated circulating BCAA contribute to development of obesity-related insulin resistance by interfering with lipid oxidation in skeletal muscle. BCAA-dependent lowering of the skeletal muscle glycine pool appears to contribute to this effect by slowing acyl-glycine export to the urine.

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The control by insulin of amino acid accumulation in muscle.

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