Høyt proteininntak og insulinresistens i muskelceller?

[Baahh]

Mechanism of amino acid-induced skeletal muscle insulin resistance in humans.

Krebs M, Krssak M, Bernroider E, Anderwald C, Brehm A, Meyerspeer M, Nowotny P, Roth E, Waldhausl W, Roden M.

Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Vienna, Austria.

Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.

http://diabetes.diabetesjournals.org/cgi/content/full/51/3/599

This study demonstrates that short-term elevation of plasma AAs induces skeletal muscle insulin resistance in healthy humans. At steady state, the reduction of whole-body glucose disposal by 25% along with complete suppression of EGP indicates diminished peripheral glucose uptake during plasma AA elevation. This finding is in contrast to a previous report (16), which concluded that the decrease in GIR during AA infusion was entirely attributable to increased EGP due to a combined elevation of plasma AA and glucagon concentrations. However, in that study, plasma insulin concentrations were up to twofold higher during AA infusion than during control studies, which likely counteracted the AA-dependent inhibition of glucose uptake.
Consistent with the findings of the present study, previous reports indicated that AAs might induce insulin resistance in human skeletal muscle (12?15). However, the mechanism responsible for impaired glucose uptake in vivo was not elucidated. In vitro studies showed that the availability of certain nutrients may play an important role in determining the cellular response to insulin stimulation. From studies in isolated rat muscle preparations, Randle et al. (34) concluded that FFAs reduce glucose uptake by substrate competition between FFAs and glucose for mitochondrial oxidation. Increased FFA oxidation would cause elevation of the intramitochondrial acetyl-CoA/CoA and NADH/NAD+ ratios, which decreases the activities of pyruvate dehydrogenase and phosphofructokinase. The subsequent reduction in glycolysis would give rise to intracellular G6P, which then decreases muscular glucose uptake by allosteric inhibition of hexokinase II. Because glycogen synthase is also under the allosteric control of G6P, high intramuscular concentrations of G6P would be expected to increase glycogen synthesis (34,35). Similar to FFAs, ketogenic AAs can be metabolized to acetyl-CoA and further oxidized by the tricarboxylic acid cycle. Therefore, substrate competition between AAs and glucose for mitochondrial oxidation might occur. Indeed AAs, particularly the branched-chain amino acids (valine, leucine, and isoleucine), decrease glucose oxidation by inhibition of pyruvate dehydrogenase secondary to a rise of the acetyl-CoA/CoA and NADH/NAD+ ratios in isolated rat skeletal muscle and liver cells (8,9,36).

To examine the mechanism by which AAs caused the impairment in insulin-stimulated whole-body glucose uptake, rates of skeletal muscle glycogen synthesis and intramuscular concentrations of G6P were measured. The rate of glycogen synthesis was reduced by 64% (P < 0.01) in the presence of plasma AA elevation. Because glycogen synthesis in skeletal muscle accounts for almost all glucose disposal under insulin-stimulated conditions (20), the observed decrease in rates of glycogen synthesis most likely accounted for the AA-induced reduction in whole-body glucose uptake. This decrease in skeletal muscle glycogen synthesis could have resulted from a reduction in glycogen synthase activity and/or inhibition of glucose transport/phosphorylation. G6P is an intermediate between glycogen synthesis and glucose transport/phosphorylation. Therefore, any isolated decline in the rate of net glycogen synthesis relative to glucose transport/phosphorylation would be expected to result in a rise of the G6P concentration (24). Furthermore, any reduction in glycolysis secondary to a possible AA-induced inhibition of pyruvate dehydrogenase would similarly give rise to G6P. In contrast to these assumptions, intramuscular G6P concentrations were lower during AA infusion than saline infusion studies, suggesting a direct inhibitory effect of AA on glucose transport/phosphorylation. Because intramuscular pH, PCr, and ADP did not change, allosteric effects of these mediators on glucose-metabolizing enzymes can be excluded. The small and transient increase in Pi during control studies is in line with previous observations (22,23). If anything, the lower intracellular concentrations of Pi, which is an allosteric inhibitor of hexokinase, observed during AA infusion would serve to underestimate the inhibitory effect of AA on glucose transport/phosphorylation (22).

Taken together, our data do not support the concept of substrate competition between AA and glucose. Likewise, recent in vitro studies showed that AA can interact with early steps of insulin signaling critical for glucose transport, resulting in impaired insulin-stimulated tyrosine phosphorylation of insulin receptor substrates with subsequent inhibition of insulin-stimulated phosphatidylinositol 3-kinase (11). Inhibition of insulin signaling could then impair insulin-stimulated glucose transport (10) and consecutively glycogen synthesis in skeletal muscle. Such mechanism of action is in line with that reported for insulin resistance typical for experimental hyperlipidemia (22,26,37), obesity (38), and type 2 diabetes (39).

Insulin-resistant states are also associated with increased plasma AA concentrations of particularly branched-chain AAs (1,2). Furthermore, a protein-enriched diet may impair glucose utilization (3?6). Thus, AAs might play a role in the development of insulin resistance typical for obesity and type 2 diabetes (20,39). The most marked increments after protein meals were observed for branched-chain AAs (leucine, isoleucine, and valine), which remained elevated for up to 8 h (40,41). From the present results, one cannot discern whether a single AA or a certain combination of AAs was responsible. Previous studies in vivo and in vitro (8,11?15,36), however, indicated that the branched-chain AAs, which are preferentially taken up by skeletal muscle (42), might be most important for the regulation of peripheral glucose metabolism.

Some limitations must be considered. First, the present study compared hyperaminoacidemic with moderately hypoaminoacidemic conditions. Total plasma AA concentrations achieved during AA infusion are comparable with those seen after ingestion of a large protein meal (40), whereas the moderate insulin-induced decrease in plasma AA of the control study is similar to what has been observed after a carbohydrate-rich meal (43). This suggests that short-term changes in plasma AAs within the physiologic range suffice to modify skeletal muscle glucose metabolism. Of note, the insulin-induced hypoaminoacidemia with low plasma concentrations of branched-chain AAs could have affected glucose kinetics and muscle glucose metabolites in control experiments of this and other studies (44). Thus, it cannot be ruled out that the differences observed between hyperaminoacidemic and hypoaminoacidemic conditions might be attenuated were fasting plasma AA concentrations present during the control study. Nevertheless, skeletal muscle G6P and glycogen concentrations previously reported for control conditions are in line with those of the present study (26,37). The lower rates of glycogen synthesis observed in this study could be due to the combined somatostatin/insulin/glucagon/growth hormone infusions, which have not been used in previous, otherwise comparable, studies (20,26,37,38).


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