Short-term regulation of insulin-mediated glucose utilization in four-day fasted human volunteers: role of amino acid availability

Abstract

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...

Direct and indirect effects of amino acids on hepatic glucose metabolism in humans

“…One previous report suggested that AA infusion could increase EGP by stimulating GNG in humans [47]. However, plasma glucagon concentrations were not controlled and remained consistently high during AA delivery in that study [47,48] so it cannot be ruled out that stimulation of GNG by glucagon was responsible or at least contributed to the metabolic AA effect. Our study also aimed to compare the direct AA action on EGP and GNG with that of a selective rise in plasma glucagon concentrations (GLUC+S).…”

Mechanism of Amino Acid-Induced Skeletal Muscle Insulin Resistance in Humans

“…Studies in humans, however, revealed controversial results. Infusion of AAs decreased forearm and whole-body glucose disposal in some (12)(13)(14)(15), but not all (16,17), studies. Moreover, endogenous release of insulin (18) and glucagon (19) induced by plasma AA elevation might have obscured possible direct effects of AAs in those studies.…”

“…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 ϳ2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01).…”

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.…”