Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp

Myers, S. R.; Diamond, Michael P.; Adkins-Marshall, Bess A.; Williams, Phillip E.; Stinsen, Randy; Cherrington, Alan D.

doi:10.1016/0026-0495(91)90194-2

Cited by 38 publications

(29 citation statements)

References 33 publications

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“…This is in agreement with studies suggesting that peripheral effects of insulin are responsible for suppression of hepatic glucose production by restricting gluconeogenic substrate availability [32][33]. The gluconeogenic process would be facilitated by the increased circulating plasma glucagon levels [34][35][36] and by the increased availability of gluconeogenic amino acids, particularly alanine and glycine, to the liver. Unfortunately, most of the amino acid solutions currently available for clinical use in the United States have an inappropriately high content of these two amino acids which are used as "nitrogen fillers".…”

Section: Discussionsupporting

confidence: 90%

“…When the data derived by indirect calorimetry are combined with those derived isotopically, it becomes clear that the availability of amino acids resulted in decreased oxidation as well as decreased storage of glucose, indicating that the defect is exerted on both glycogen deposition as well as on the rate of glycolysis. While the exact mechanism of these changes remains unclear, it can be speculated that the splanchnic tissues would play only a minor role as it is well established that in the post-absorptive period, glucose utilization by the liver accounts for only 15-20 % of whole body rate of glucose utilization [34,35,42]. Therefore, the major effect of amino acids would appear to be exerted on skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1992

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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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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

et al. 1992

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“…Therefore, even small changes in glucagon (48,49), which may not be detected with significance in immunoassays, might still be significant at the level of the liver. The lack of correlation between suppression of GP and suppression ofglucagon could also be explained in terms of variability of the immunoassay.…”

Section: Discussionmentioning

confidence: 99%

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

Giacca¹,

Fisher²,

Shi³

et al. 1992

J. Clin. Invest.

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It is generally believed that glucose production (GP) cannot be adequately suppressed in insulin-treated diabetes because the portal-peripheral insulin gradient is absent. To determine whether suppression of GP in diabetes depends on portal insulin levels, we performed 3-h glucose and specific activity clamps in moderately hyperglycemic (10 mM) depancreatized dogs, using three protocols: (a) 54 pmols kg-' bolus + 5.4 pmol* kg-' -min' portal insulin infusion (a = 7; peripheral insulin = 170±51 pM); (b) an equimolar peripheral infusion (a = 7; peripheral insulin = 294±28 pM, P < 0.001); and (c) a half-dose peripheral infusion (a = 7), which gave comparable (157±13 pM) insulinemia to that seen in protocol 1. Glucose production, use (GU) and cycling (GC) were measured using HPLC-purified 6-13Hj-and 2-13Hjglucose. Consistent with the higher peripheral insulinemia, peripheral infusion was more effective than equimolar portal infusion in increasing GU. Unexpectedly, it was also more potent in suppressing GP (73±7 vs. 55±7% suppression between 120 and 180 min, P < 0.001). At matched peripheral insulinemia (protocols 2 and 3), not only stimulation of GU, but also suppression of GP was the same (55±7 vs. 63±4%). In the diabetic dogs at 10 mM glucose, GC was threefold higher than normal but failed to decrease with insulin infusion by either route. Glycerol, alanine, FFA, and glucagon levels decreased proportionally to peripheral insulinemia. However, the decrease in glucagon was not significantly greater in protocol 2 than in 1 or 3. When we combined all protocols, we found a correlation between the decrements in glycerol and FFAs and the decrease in GP (r = 0.6, P < 0.01). In conclusion, when suprabasal insulin levels in the physiological postprandial range are provided to moderately hyperglycemic depancreatized dogs, suppression of GP appears to be more dependent on peripheral than portal insulin concentrations and may be mainly mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and by the suppressive effect of insulin on glucagon secretion. These results suggest that a portal-peripheral insulin gradient might not be necessary to effectively suppress postprandial GP in insulin-treated diabetics. (J. Clin. Invest. 1992. 90:1769-1777

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“…It is the most important hyperglycaemic hormone in animals and man [1,2]. Glucagon increases plasma glucose by promoting hepatic glycogenolysis.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of glucagon secretion in mouse and human pancreatic alpha cells by protein kinase C (PKC) involves intracellular trafficking of PKCα and PKCδ

et al. 2009

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Aims/hypothesis Protein kinase C (PKC) regulates exocytosis in various secretory cells. Here we studied intracellular translocation of the PKC isoenzymes PKCα and PKCδ, and investigated how activation of PKC influences glucagon secretion in mouse and human pancreatic alpha cells. Methods Glucagon release from intact islets was measured in static incubations, and the amounts released were determined by RIA. Exocytosis was monitored as increases in membrane capacitance using the patch-clamp technique.

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Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp

Cited by 38 publications

References 33 publications

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

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

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

Enhancement of glucagon secretion in mouse and human pancreatic alpha cells by protein kinase C (PKC) involves intracellular trafficking of PKCα and PKCδ

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