Acute hyperaminoacidemia does not suppress insulin-mediated glucose turnover in healthy young men

Elevated circulating amino acid (AA) concentrations are purported to cause insulin resistance (IR) in humans. To quantify hyperaminoacidemia effects on insulin-mediated glucose turnover in healthy men, we performed two-stage pancreatic clamps using octreotide with glucagon and growth hormone replacement. In the basal stage, insulin was infused to maintain euglycemia at postabsorptive levels. During the clamp stage, insulin was raised to postprandial levels, glycemia clamped at 5.5 mmol/L by glucose infusion and branched-chain AA (BCAA) maintained at either postabsorptive (Hyper1; n=8) or postprandial (Hyper2; n=7) by AA infusion. Glucose turnover was measured by D-3-[3H]glucose dilution. Octreotide suppressed C-peptide; glucagon, growth hormone and glycemia were maintained at postabsorptive levels throughout. Insulin did not differ at postabsorptive (72±5 vs. 60±5 pmol/L; Hyper1 vs. Hyper2) and increased to similar concentrations at basal (108±11 vs. 106±14) and clamp stages (551±23 vs. 540±25). Postabsorptive BCAA were maintained during Hyper1 and increased >2-fold (830±26 µmol/L) during Hyper2. Endogenous glucose production was similarly suppressed (0.95±0.16 vs. 1.37±0.23 mg/kg lean body mass/min; Hyper1 vs. Hyper2) and basal glucose disposal (3.44±0.12 vs. 3.67±0.14) increased to similar levels (10.89±0.56 vs. 11.11±1.00) during the clamp. Thus, acute physiological elevation of AA did not cause IR in healthy men. NOVELTY • A two-step pancreatic clamp was used to quantify the effect of amino acids on insulin sensitivity in humans. • Acute physiological elevation of circulating amino acids does not cause insulin resistance in healthy men.

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Influence of growth hormone on glucose-glucose 6-phosphate cycle and insulin action in normal humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.5.e980 ◽

1992 ◽

Vol 263 (5) ◽

pp. E980-E987 ◽

Cited By ~ 1

Author(s):

R. D. Neely ◽

D. P. Rooney ◽

P. M. Bell ◽

N. P. Bell ◽

B. Sheridan ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Insulin Action ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Glucose Disposal ◽

Impaired Insulin ◽

Increased Activity ◽

P Cycle

Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action.

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Growth hormone signaling and action in obese versus lean human subjects

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00431.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. E333-E344 ◽

Cited By ~ 5

Author(s):

Morten Lyng Høgild ◽

Ann Mosegaard Bak ◽

Steen Bønløkke Pedersen ◽

Jørgen Rungby ◽

Jan Frystyk ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Human Subjects ◽

Glucose Production ◽

Relative Increase ◽

Antagonistic Effect ◽

Endogenous Glucose Production ◽

Metabolic Adaptation ◽

Igf I

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, −66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

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Chronic Dietary Branched-Chain Amino Acids Induced Lipid Oxidation and Blunted Insulin-Stimulated Glucose Production in Mice With NAFLD

Current Developments in Nutrition ◽

10.1093/cdn/nzab041_044 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 529-529

Author(s):

Chaitra Surugihalli ◽

Vaishna Muralidaran ◽

Kruti Patel ◽

Tabitha Gregory ◽

Nishanth Sunny

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Lipid Oxidation ◽

Glucose Production ◽

Branched Chain Amino Acids ◽

Hepatic Insulin Resistance ◽

High Fat ◽

Branched Chain

Abstract Objectives Elevated circulating branched-chain amino acids (BCAAs) during insulin resistance are strong predictors of type 2 diabetes mellitus onset. Defects in BCAA degradation are evident in several tissues during insulin resistance and non-alcoholic fatty liver disease (NAFLD). Furthermore, alterations in BCAA metabolism are associated with changes in several aspects lipid metabolism, including lipogenesis, ketogenesis and mitochondrial TCA cycle activity. Considering the crosstalk between BCAAs and lipid metabolism, we hypothesized that chronic supplementation of BCAAs will modulate hepatic insulin resistance and mitochondrial lipid oxidation during NAFLD. Methods Mice (C57BL/6N) were reared on either a low-fat (LF; 10% fat kcal), high-fat (HF; 60% fat kcal or high-fat diet supplemented with BCAA (HFBA; 150% BCAA) for 24 weeks. Metabolic profiling was conducted under fed or overnight fasted (14–16 hrs) conditions. A subset of overnight fasted mice from the HF and HFBA groups were subjected to hyperinsulinemic euglycemic clamps, following implantation of jugular vein catheters. Results Feeding HF and HFBA diets resulted in NAFLD. Circulating BCAAs were higher in ‘fed’ mice consuming HFBA diet (e.g., Valine, µM ± SEM; 311 ± 38 in HF, 432 ± 34 in HFBA, P ≤ 0.05). Overnight fasting significantly reduced BCAA levels in all groups, but the fasting levels of BCAAs remained similar between groups. Fed-to-fasted fold changes in blood glucose, serum insulin and c-peptide were higher in HFBA mice (P ≤ 0.05). Insulin stimulated suppression of glucose production (% ± SEM; HF = 38 ± 11, HFBA = 16 ± 16) was blunted in HFBA mice. Furthermore, fed-to-fasted expression of hepatic genes involved in lipid oxidation, including LCAD, MCAD, PPARa and CPT1a were significantly higher (P ≤ 0.05) in the HFBA mice. Conclusions In summary, chronic BCAA supplementation induced hepatic lipid oxidation gene expression, without any apparent improvements in insulin sensitivity. In conclusion, while the induction of lipid oxidation by BCAAs could explain certain beneficial effects associated with their supplementation, the longer-term impact of the BCAAs on insulin sensitivity need to be further explored. Funding Sources National Institutes of Health (NIH) grant RO1-DK-112865

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Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0378 ◽

2009 ◽

Vol 94 (9) ◽

pp. 3297-3305 ◽

Cited By ~ 13

Author(s):

Burak Salgin ◽

Maria L. Marcovecchio ◽

Rachel M. Williams ◽

Sarah J. Jackson ◽

Leslie J. Bluck ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Growth Hormone ◽

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Endogenous Glucose

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D. Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit. Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity. Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis. Growth hormone decreases insulin sensitivity through increases in free fatty acid levels.

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Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

Acta Endocrinologica ◽

10.1530/acta.0.1180125 ◽

1988 ◽

Vol 118 (1) ◽

pp. 125-134 ◽

Cited By ~ 18

Author(s):

Ole Schmitz

Keyword(s):

Insulin Resistance ◽

Insulin Infusion ◽

Serum Insulin ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Glucose Disposal ◽

Peripheral Tissues ◽

Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

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Influence of dietary fat on postprandial glucose metabolism (exogenous and endogenous) using intrinsically 13C-enriched durum wheat

British Journal Of Nutrition ◽

10.1079/bjn2001359 ◽

2001 ◽

Vol 86 (1) ◽

pp. 3-11 ◽

Cited By ~ 45

Author(s):

Sylvie Normand ◽

Yadh Khalfallah ◽

Corinne Louche-Pelissier ◽

Christiane Pachiaudi ◽

Jean-Michel Antoine ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Glucose Production ◽

Postprandial Glucose ◽

Endogenous Glucose Production ◽

Glucose Turnover ◽

Exogenous Glucose ◽

Esterified Fatty Acids ◽

Secondary Recovery ◽

Total Glucose

The present study evaluates the influence of different amounts of fat added to starch on postprandial glucose metabolism (exogenous and endogenous). Nine women (24 (SE 2) YEARS OLD, BMI 20·4 (se 0·7) kg/m2) ingested 1 week apart 75 g glucose equivalent of 13C-labelled starch in the form of pasta without (low fat; LF) or with 15 (medium fat; MF) or 40 (high fat; HF) g sunflower oil. During the 7 h following meal consumption, plasma glucose, non-esterified fatty acids, triacylglycerols (TG) and insulin concentrations, and endogenous (using [6,6-2H2]glucose) and exogenous glucose turnover were determined. With MF and HF meals, a lower postprandial glucose peak was observed, but with a secondary recovery. A decrease in exogenous glucose appearance explained lower glycaemia in HF. At 4 h after the HF meal the insulin, insulin:glucose and postprandial blood TG were higher than those measured after the LF and MF meals. Despite higher insulinaemia, total glucose disappearance was similar and endogenous glucose production was suppressed less than after the LF and MF meals, suggesting insulin resistance. Thus, the addition of a large amount of fat appears to be unfavourable to glucose metabolism because it leads to a feature of insulin resistance. On the contrary, the MF meal did not have these adverse effects, but it was able to decrease the initial glycaemic peak.

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Site of Insulin Resistance after Surgery: The Contribution of Hypocaloric Nutrition and Bed Rest

Clinical Science ◽

10.1042/cs0930137 ◽

1997 ◽

Vol 93 (2) ◽

pp. 137-146 ◽

Cited By ~ 71

Author(s):

Jonas Nygren ◽

Anders Thorell ◽

Suad Efendic ◽

K. Sree Nair ◽

Olle Ljungqvist

Keyword(s):

Insulin Resistance ◽

Glucose Oxidation ◽

Glucose Utilization ◽

Glucose Production ◽

Bed Rest ◽

Endogenous Glucose Production ◽

Whole Body ◽

Glucose Disposal ◽

Before And After ◽

Endogenous Glucose

1. Insulin resistance after surgery has been shown to be related to several important derangements in protein and fat metabolism. However, mechanisms of impaired glucose tolerance after surgery remain ill-defined. 2. Insulin sensitivity and glucose kinetics (6,62H2-glucose) were studied in seven patients before and after elective surgery (surgery group), by two step-hyperinsulinaemic (0.3 and 0.8 munits kg−1 min−1), normoglycaemic (4.5 mmol/l) clamps. Six healthy subjects were studied, using the same protocol, before and after a similar period of bed rest and hypocaloric nutrition (fast/bed rest group) to delineate the effects of surgery per se. 3. Basal endogenous glucose production and whole-body glucose disposal was higher after surgery (P < 0.001), whereas no change was found after fast/bed rest. During glucose clamps, the glucose infusion rates required to maintain normoglycaemia and whole-body glucose disposal decreased (P < 0.001) after surgery, while endogenous glucose production increased (P < 0.001). In the control subjects, levels of endogenous glucose production remained unchanged after fast/bed rest. In contrast, glucose infusion rates and whole-body glucose disposal during glucose clamps also decreased after fast/bed rest (P < 0.01). However, the relative decrease in both these parameters was greater after surgery compared with after fast/bed rest (P < 0.01). 4. After surgery, energy expenditure and fat oxidation increased (P < 0.001), whereas glucose oxidation decreased (P < 0.05). No significant change was found in glucose utilization postoperatively. After fast/bed rest, no change was found in energy expenditure. However, fat oxidation increased (P < 0.01), whereas glucose oxidation and glucose utilization decreased (P < 0.05). 5. In conclusion, impaired glucose tolerance develops after surgery as a result of decreased insulin-stimulated whole-body glucose disposal as well as increased endogenous glucose release. Despite the increase in endogenous glucose production, the reduction in endogenous glucose production with each elevation of insulin was unaffected by surgery. Perioperative bed rest and/or hypocaloric nutrition contribute to the decrease in insulin-stimulated whole-body glucose disposal in the postoperative state, whereas these factors have no effects on endogenous glucose production.

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Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Journal of Endocrinology ◽

10.1530/joe-14-0373 ◽

2014 ◽

Vol 223 (3) ◽

pp. R49-R62 ◽

Cited By ~ 96

Author(s):

Alex Rafacho ◽

Henrik Ortsäter ◽

Angel Nadal ◽

Ivan Quesada

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Cell Function ◽

Insulin Signalling ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucose Disposal ◽

Β Cells ◽

Glucocorticoid Treatment ◽

Long Term Treatment

Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

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Metabolomics analysis reveals altered metabolites in lean compared with obese adolescents and additional metabolic shifts associated with hyperinsulinaemia and insulin resistance in obese adolescents: a cross-sectional study

Metabolomics ◽

10.1007/s11306-020-01759-y ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Elisabeth Müllner ◽

Hanna E. Röhnisch ◽

Claudia von Brömssen ◽

Ali A. Moazzami

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Glucose Tolerance ◽

Insulin Response ◽

Oral Glucose ◽

Response Level ◽

Metabolic Alterations ◽

Obese Adolescents ◽

Branched Chain ◽

Metabolomics Analysis

Abstract Introduction Hyperinsulinaemia and insulin resistance (IR) are strongly associated with obesity and are forerunners of type 2 diabetes. Little is known about metabolic alterations separately associated with obesity, hyperinsulinaemia/IR and impaired glucose tolerance (IGT) in adolescents. Objectives To identify metabolic alterations associated with obesity, hyperinsulinaemia/IR and hyperinsulinaemia/IR combined with IGT in obese adolescents. Methods 81 adolescents were stratified into four groups based on body mass index (lean vs. obese), insulin responses (normal insulin (NI) vs. high insulin (HI)) and glucose responses (normal glucose tolerance (NGT) vs. IGT) after an oral glucose tolerance test (OGTT). The groups comprised: (1) healthy lean with NI and NGT, (2) obese with NI and NGT, (3) obese with HI and NGT, and (4) obese with HI and IGT. Targeted nuclear magnetic resonance-based metabolomics analysis was performed on fasting and seven post-OGTT plasma samples, followed by univariate and multivariate statistical analyses. Results Two groups of metabolites were identified: (1) Metabolites associated with insulin response level: adolescents with HI (groups 3–4) had higher concentrations of branched-chain amino acids and tyrosine, and lower concentrations of serine, glycine, myo-inositol and dimethylsulfone, than adolescents with NI (groups 1–2). (2) Metabolites associated with obesity status: obese adolescents (groups 2–4) had higher concentrations of acetylcarnitine, alanine, pyruvate and glutamate, and lower concentrations of acetate, than lean adolescents (group 1). Conclusions Obesity is associated with shifts in fat and energy metabolism. Hyperinsulinaemia/IR in obese adolescents is also associated with increased branched-chain and aromatic amino acids.

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Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.3.e430 ◽

1991 ◽

Vol 260 (3) ◽

pp. E430-E435 ◽

Cited By ~ 10

Author(s):

I. Raz ◽

A. Katz ◽

M. K. Spencer

Keyword(s):

Glycogen Synthase ◽

Glucose Production ◽

High Energy ◽

Endogenous Glucose Production ◽

Fat Free Mass ◽

Glucose Disposal ◽

High Energy Phosphates ◽

Before And After ◽

Glucose Tolerant ◽

Femoris Muscle

The effect of epinephrine (E) infusion on insulin-mediated glucose metabolism in humans has been studied. Eight glucose-tolerant men were studied on two separate occasions: 1) during 120 min of euglycemic hyperinsulinemia (UH, approximately 5 mM; 40 mU.m-2.min-1); and 2) during UH while E was infused (UHE, 0.05 microgram.kg-1.min-1). Biopsies were taken from the quadriceps femoris muscle before and after each clamp. Glucose disposal, correcting for endogenous glucose production, was 36 +/- 3 and 18 +/- 2 (SE) mumol.kg fat-free mass (FFM)-1.min-1 during the last 40 min of UH and UHE, respectively (P less than 0.001). Nonoxidative glucose disposal (presumably glycogenesis) averaged 23.0 +/- 3.0 and 4.0 +/- 1.1 (P less than 0.001), whereas carbohydrate oxidation (which is proportional to glycolysis) averaged 13.1 +/- 1.4 and 15.3 +/- 1.1 mumol.kg FFM-1.min-1 (P less than 0.05) during UH and UHE, respectively. UHE resulted in significantly higher contents of UDP-glucose, hexose monophosphates, postphosphofructokinase intermediates, and glucose 1,6-bisphosphate (G-1,6-P2) in muscle (P less than 0.05-0.001), but there were no significant differences in high-energy phosphates or fructose 2,6-bisphosphate (F-2,6-P2) between treatments. Fractional activities of phosphorylase increased (P less than 0.01), and glycogen synthase decreased (P less than 0.001) during UHE. It is concluded that E inhibits insulin-mediated glycogenesis because of an inactivation of glycogen synthase and an activation of glycogenolysis. E also appears to inhibit insulin-mediated glucose utilization, at least partly, because of an increase in G-6-phosphate (which inhibits hexokinase) and enhances glycolysis by G-1,6-P2-, fructose 6-phosphate-, and F-1,6-P2-mediated activation of PFK.

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