Hyperaminoacidaemia reduces insulin-mediated glucose disposal in healthy man

Abstract

Summary.To determine whether hyperaminoacidaemia may modify insulin-mediated glucose disposal, normal subjects were studied with the euglycaemic glucose-clamp technique, with or without an amino acid infusion, at a rate sufficient to duplicate the plasma concentration of most amino acids. Steady-state glucose infusion rates to maintain euglycaemia were 36% lower during hyperaminoacidaemia (7.3 + 1.0 versus 11.4 _+ 0.8 mg. kg-1. rain-2, p < 0.01) at comparable insulin concentrations (92 + 6 versus 93 + 7 mU/1 respectively). Thus, under conditions of hyperinsulinaemia, amino acids could compete with glucose as metabolic fuels.Key words: Hyperaminoacidaemia, euglycaemic hyperinsulinaemic clamp, glucose disposal.During an euglycaemic, hyperinsulinaemic clamp, insulin-sensitivity is often expressed as the glucose infusion rate necessary to maintain euglycaemia [1]. However, many other metabolic changes occur under hyperinsulinaemic conditions. Among them, plasma free fatty acid, ketone body and amino acid concentrations decrease markedly. Since competition between substrates as metabolic fuels may occur [2], glucose uptake in vivo could be indirectly enhanced by the concomitant decrease in concentration and utilization of other substrates. Therefore, "insulin sensitivity", measured with the euglycaemic, hyperinsulinaemic clamp technique, could be modified by preventing the fall and/or increasing the concentrations of the substrates suppressed by insulin.Recently, increased plasma free fatty acid concentrations have been shown to reduce insulin-mediated glucose disposal [3]. However, it is not known whether in vivo increments in plasma amino acid concentrations may also affect glucose disposal rates. Therefore, the aim of the present study was to evaluate the effect ofhyperaminoacidaemia on insulin-mediated glucose utilization in postabsorptive normal subjects. Subjects and methodsHealthy subjects (aged 21-57 years) were studied in the post-absorptive state. All subjects had normal body weight, and consumed their usual weight-maintaining diet ( -30 kcal/kg per day, containing 50% of total calories as carbohydrates, 20% as protein and 30% as fat) for at least 3 days prior to the study. The details and the potential risks of the study were explained, and each subject signed an informed written consent before the initiation of the study. The subjects were divided into two groups. In group A, (five males, one female, age: 28 + 3 years, body mass index: 22.9+0.8), an euglycaemic-hyperinsulinaemic clamp was performed for 180 rain, as previously described [4]. Insulin was infused by means of a Harvard Pump (Harvard Apparatus, Millis, MA, USA), at the rate of 0.05 U.m 2-' .min -1. Blood glucose concentration was maintained by means of the Biostator (Miles Laboratories, Elkhart, IN, USA) [4] at 4.72 + 0.11 mmol/1 (coefficient of variation: ~11%). In group B (four males, one female, age: 35 + 5 years, body mass index: 22.0 + 0.7) the subjects were studied as for group A, with the addition of an amino acid infusion for the sam...

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

“…In euglycemic somatostatin clamps with insulin at 430 pmol/l, lower muscle glucose uptake by the supraphysiological elevation of AA (vs. hypoaminoacidemia) was termed "insulin resistance" (27,47). Although not always found, this effect has been reported previously (1,42,44). Our data are compatible with an alternative interpretation: rather than resistance to insulin, a physiological response to concurrent glucose and AA provision.…”

“…Nevertheless, despite 77% higher insulin in Hyper-3 glucose R d was not significantly different. This indicates that physiological hyperaminoacidemia restrains the increase of insulin-mediated glucose uptake (14,44), as does even greater hyperaminoacidemia (27,47). Furthermore, hyperglycemic, hyperinsulinemic clamps (that would cause hypoaminoacidemia) increase glucose R d more than with euglycemia (32).…”

Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle

“…A large majority, but not all 6, 7 , of these studies have shown that increasing blood amino acid availability resulted in an inhibition of glucose disposal at the whole body level and across the forearm [8][9][10][11][12][13][14][15] . It is now proposed that increased amino acid availability induces insulin resistance by inhibiting insulin signaling within muscle cells.…”

Role of substrate competition in the pathogenesis of insulin resistance in man

“…Infusions of branched chain amino acids were shown to decrease whole body and forearm uptakes of glucose during hyperinsulinemic, euglycemic clamps (27). Infusions of mixtures of amino acids also decreased the rate of glucose infusion required to maintain euglycemia during insulin infusions (28,29). This could, however, be largely explained by stimulation of endogenous glucose production which occurs during hyperaminoacidemia (Fig.…”