Summary. Glucose homeostasis in men fasted for 84 h was assessed using isotopes, indirect calorimetry and forearm balance techniques during a basal period and three sequential hyperinsulinaemic euglycaemic clamps each lasting for 150 min. Two protocols (n = 12 in each) were used: subjects were either allowed to develop hypoaminoacidaemia or received a commercial solution of L-amino acids while maintaining near-basal plasma leucine levels. Insulin infusions resulted in 3-, 35-and 650-fold increases in plasma insulin levels in both protocols. The infusion of amino acids produced a rightward shift in the dose-response curve of insulin's effect on suppressing hepatic glucose production, indicating decreased sensitivity in addition to blunting of the maximal responsiveness. Total body glucose rate of disappearance was progressively increased with escalating insulin doses, but was 22 % lower at the intermediate and highest insulin doses in the group that was infused with amino acids (3.44 + 0.53 vs 4.82 + 0.71 and 7.72 + 1.01 vs 10.36 + 1.08 mg. kg i. rain-1, respectively; p < 0.05). Forearm balance data confirmed the isotopic data, since amino acid infusions blunted the insulinmediated increase in net forearm glucose utilization (by 50-83 %). Furthermore, the infusion of amino acids resulted in marked reductions in the rate of carbohydrate oxidation and storage as assessed by indirect calorimetry. The data indicate that the amino acid-mediated suppression of glucose utilization and carbohydrate oxidation is exerted on the responsive component of insulin action.Key words: Insulin responsiveness, insulin sensitivity, glucose utilization, glucose production, hyperinsulinaemic euglycaemic clamp.Extended fasting and uncontrolled diabetes are characterized by alterations in glucose regulatory hormones, elevated non-esterified fatty acids, increased plasma amino acids and increased resistance to insulin-mediated glucose utilization. The cause of this insulin resistance has been the focus of considerable research aimed at improving treatment of diabetes, post-surgical trauma and infection-related stress. Elevated plasma non-esterified fatty acids have been shown to decrease glucose utilization and as a result have been implicated as a major factor contributing to increased insulin resistance [1]. Additionally, the increases in circulating levels of plasma cortisol [2], epinephrine [3], growth hormone [4] and glucagon [5], singly or in combination, have been demonstrated to enhance resistance to insulin-mediated glucose disposal.The role that the elevated levels of amino acids play in modulating insulin's action on glucose homeostasis during fasting is not well defined. Several studies have indicated that high protein diets promoted glucose intolerance in rats [6-9] and humans [10][11][12]. A previous study from our laboratory [13] and another by Tessari et al. [14] have established that during repeated insulin clamps in overnight fasted volunteers, the amount of exogenous glucose infused to maintain euglycaemia was considera...

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Patients with isolated closed-head injuries are characterized by excessive nitrogen loss, hyperglycemia, and increased caloric demand. However, the relative contributions of specific metabolic events such as protein breakdown and synthesis or glucose production and utilization to the physiological changes prevalent during isolated closed-head injury remains unestablished. By use of isotopic dilutions of L-[1-13C]leucine and D-[3-3H]glucose, components of protein and glucose metabolism were examined in patients with isolated closed-head injury (n = 7). Normal overnight-fasted volunteers (n = 8) were also studied as a reference point for comparison. Despite prevailing hyperinsulinemia (29 +/- 5 microU/ml), head-injured patients had elevated plasma leucine concentrations (183 +/- 22 vs. 144 +/- 8 mumol/l), whole body proteolysis (331 +/- 44 vs. 150 +/- 7 mg.kg-1.h-1), protein synthesis (248 +/- 38 vs. 126 +/- 11 mg.kg-1.h-1), and amino acid oxidation (84 +/- 11 vs. 23 +/- 3 mg.kg-1.h-1). Therefore nitrogen loss normally associated with isolated closed-head injury is primarily due to an increase in the rate of whole body proteolysis, with a greater proportion of the resultant amino acids being oxidized for energy. Furthermore, head-injured patients were hyperglycemic (6.7 +/- 0.3 mumol/l) with increased rates of glucose turnover (an estimate of production and utilization) compared with the controls (4.0 +/- 0.7 vs. 2.5 +/- 0.2 mg.kg-1.min-1). Hence, these data suggest that head injury, even in the absence of peripheral trauma, induces a physiological state of accelerated metabolism associated with resistance to insulin action.

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