Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle

1997 ◽  
Vol 273 (1) ◽  
pp. E185-E191 ◽  
Author(s):  
R. S. Streeper ◽  
E. J. Henriksen ◽  
S. Jacob ◽  
J. Y. Hokama ◽  
D. L. Fogt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Lipoic Acid ◽  
Glucose Oxidation ◽  
Glucose Transporter ◽  
Glycogen Synthesis ◽  
Racemic Mixture ◽  
Insulin Resistant ◽  
The Individual

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.

Insulin-Sensitive Phospholipid Signaling Systems and Glucose Transport. Update II

2001 ◽  
Vol 226 (4) ◽  
pp. 283-295 ◽  
Author(s):  
Robert V. Farese
Keyword(s):  
Protein Kinase ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Intracellular Signaling ◽  
Glucose Transporter ◽  
De Novo ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Cell Types ◽  
Biologically Active

Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidyicholine with subsequent increases in phosphatidic acid (PA) and diacyiglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.

Selective in vitro reversal of the insulin resistance of glucose transport in denervated rat skeletal muscle

1989 ◽  
Vol 257 (3) ◽  
pp. E418-E425 ◽  
Author(s):  
M. O. Sowell ◽  
S. L. Dutton ◽  
M. G. Buse
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Glycogen Synthesis ◽  
Insulin Response ◽  
Medium Composition ◽  
Insulin Resistant ◽  
Denervated Muscles

Denervation (24 h) of skeletal muscle causes severe postreceptor insulin resistance of glucose transport and glycogen synthesis that is demonstrable in isolated muscles after short (30 min) preincubations. After longer preincubations (2-4 h), the insulin response of glucose transport increased to normal, whereas glycogen synthesis remained insulin resistant. Basal and insulin-stimulated amino acid transport were significantly lower in denervated muscles than in controls after short or long incubations, although the percentage stimulation of transport by insulin was not significantly different. The development of glucose transport insulin resistance after denervation was not attributable to increased sensitivity to glucocorticoids or adenosine. The selective in vitro reversal of glucose transport insulin resistance was not dependent on medium composition, did not require protein or prostaglandin synthesis, and could not be attributed to release of a positive regulator into the medium. The data suggest 1) the insulin receptor in muscle stimulates glucose transport by a signaling pathway that is not shared by other insulin-sensitive effector systems, and 2) denervation may affect insulin receptor signal transduction at more than one site.

Effects of Insulin on Glucose Metabolism in Skeletal Muscle from Septic and Endotoxaemic Rats

1989 ◽  
Vol 77 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Brendan Leighton ◽  
George D. Dimitriadis ◽  
Mark Parry-Billings ◽  
Jane Bond ◽  
Paulo R. L. de Vasconcelos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Glycogen Synthesis ◽  
Dependent Manner ◽  
H 26 ◽  
Lactate Formation ◽  
Dose Dependent

1. The effects of non-lethal bacteraemia or endotoxaemia on insulin-stimulated glucose metabolism were studied in isolated, incubated soleus muscle of rats after 24 and 48 h. 2. The insulin-stimulated rates of lactate formation and glycogen synthesis were similar in muscles isolated from control and bacteraemic rats. 3. Endotoxaemia increased the rates of lactate formation, at all levels of insulin, both at 24 h (∼ 32%) and 48 h (∼ 26%). Endotoxaemia did not alter the sensitivity of glycolysis to insulin. 4. Endotoxaemia decreased the rates of glycogen synthesis at all concentrations of insulin both at 24 h (∼ 39%) and 48 h (∼ 23%). 5. The increase in the rate of glycolysis was related in a dose-dependent manner to the amount of endotoxin given to the animals. 6. Endotoxaemia decreased plasma tri-iodothyronine levels (41%). However, the effects of endotoxaemia (48 h) on glucose metabolism in muscle are similar to those caused by hyperthyroidism. In hypothyroid rats, endotoxin administration increased the rates of glycolysis in muscle in vitro. 7. It is concluded that there are enhanced basal and insulin-stimulated rates of glycolysis in soleus muscle from endotoxaemic rats. This may be due to both increased glucose transport and decreased glycogen synthesis.

Skeletal muscle glucose metabolism in obesity-prone and obesity-resistant rats

1993 ◽  
Vol 264 (6) ◽  
pp. R1224-R1228 ◽  
Author(s):  
M. J. Pagliassotti ◽  
K. A. Shahrokhi ◽  
J. O. Hill
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Weight Gain ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Glycogen Synthesis ◽  
Insulin Resistant ◽  
Wide Range

Ad libitum access to a high-fat (HF) diet produces a wide range of weight gain in rats. Rats most susceptible to weight gain on such a diet (obesity prone; OP) are more insulin resistant after 4-5 wk of diet exposure than are those most resistant (obesity resistant; OR) to weight gain. To investigate whether skeletal muscle glucose metabolism contributes to insulin resistance in this model, insulin-stimulated glucose metabolism was assessed in the perfused hindquarter of rats exposed to either a low-fat (LF, n = 6) or HF diet for 5 wk. Delineation of OP (n = 6) and OR (n = 6) rats was based on body weight gain. OP rats gained 60% more body weight while eating only 10% more energy than OR rats. Single-pass perfusions were carried out for 2 h in the presence of glucose, insulin, and [U-14C]glucose. Insulin-stimulated glucose uptake (mumol.100 g-1.min-1) was 14.2 +/- 0.9 in LF, 11.1 +/- 0.8 in OR, and 6.2 +/- 0.6 in OP. Glucose oxidation (mumol.100 g-1.min-1) was 1.7 +/- 0.3 and 1.2 +/- 0.3 in LF and OR, respectively, but was 0.2 +/- 0.1 in OP. Net glycogen synthesis was significantly reduced in OP compared with OR and LF despite similar glycogen synthase I activity. Muscle triglyceride concentration was not significantly different in OR and OP rats. These results demonstrate significant defects in skeletal muscle glucose uptake and disposal in rats most susceptible to HF diet-induced obesity. Clearly, the heterogeneous response to a HF diet involves not only body weight gain but also skeletal muscle fuel metabolism.

scholarly journals Peroxovanadates have full insulin-like effects on glycogen synthesis in normal and insulin-resistant skeletal muscle

1991 ◽  
Vol 276 (2) ◽  
pp. 289-292 ◽  
Author(s):  
B Leighton ◽  
G J S Cooper ◽  
C DaCosta ◽  
E A Foot
Keyword(s):  
Skeletal Muscle ◽  
Soleus Muscle ◽  
Wistar Rats ◽  
Glucose Oxidation ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Lactate Formation ◽  
Total Glucose ◽  
Synergistic Increase

1. The insulin-like effects of orthovanadate (10 mM) and peroxides of vanadate (peroxovanadates, at 1 mM) on rates of lactate formation, glucose oxidation and glycogen synthesis were measured in incubated soleus-muscle preparations isolated from non-obese Wistar rats and lean (fa/?) or insulin-resistant obese Zucker (fa/fa) rats. 2. The stimulation of the rates of lactate formation and glucose oxidation by either orthovanadate or peroxovanadates was of similar magnitude to the stimulation by a maximally effective concentration of insulin (1000 microunits/ml). 3. Peroxovanadates, but not orthovanadate, maximally stimulated the rate of glycogen synthesis in incubated soleus muscles isolated from Wistar rats. 4. When soleus-muscle preparations were incubated in the presence of both insulin (1000 microunits/ml) and peroxovanadates (1 mM), this did not result in a synergistic increase in the rate of total glucose utilization as compared with either agent alone. 5. Soleus muscles isolated from obese (fa/fa) Zucker rats exhibited a decrease in response to a physiologically relevant concentration of insulin (100 microunits/ml). Peroxovanadates, at 1 mM, maximally stimulated the rate of glycogen synthesis in soleus muscles isolated from obese (fa/fa) Zucker rats. 6. The findings indicate that peroxovanadates are useful and important agents for investigating the mechanism of action of insulin in skeletal muscle.

The Antioxidant  -Lipoic Acid Enhances Insulin-Stimulated Glucose Metabolism in Insulin-Resistant Rat Skeletal Muscle

Diabetes ◽  
1996 ◽  
Vol 45 (8) ◽  
pp. 1024-1029 ◽  
Author(s):  
S. Jacob ◽  
R. S. Streeper ◽  
D. L. Fogt ◽  
J. Y. Hokama ◽  
E. J. Henriksen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Lipoic Acid ◽  
Rat Skeletal Muscle ◽  
Insulin Resistant

scholarly journals Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle

1997 ◽  
Vol 321 (3) ◽  
pp. 707-712 ◽  
Author(s):  
George DIMITRIADIS ◽  
Brendan LEIGHTON ◽  
Mark PARRY-BILLINGS ◽  
Shlomo SASSON ◽  
Martin YOUNG ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Glucose Oxidation ◽  
Glycogen Synthesis ◽  
Total Content ◽  
Glucose Transporters ◽  
Lactate Formation

This study examines the mechanisms of glucocorticoid-induced insulin resistance in rat soleus muscle. Glucocorticoid excess was induced by administration of dexamethasone to rats for 5 days. Dexamethasone decreased the sensitivity of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation, glycogen synthesis and glucose oxidation to insulin. The total content of GLUT4 glucose transporters was not decreased by dexamethasone; however, the increase in these transporters in the plasma membrane in response to insulin (100 m-units/litre) was lessened. In contrast, the sensitivity of lactate formation to insulin was normal. The content of 2-deoxyglucose in the dexamethasone-treated muscle was decreased at 100 m-units/litre insulin, while the contents of glucose 6-phosphate and fructose 2,6-bisphosphate were normal at all concentrations of insulin studied. The maximal activity of hexokinase in the soleus muscle was not affected by dexamethasone; however, inhibition of this enzyme by glucose 6-phosphate was decreased. These results suggest the following. (1) Glucocorticoid excess causes insulin resistance in skeletal muscle by directly inhibiting the translocation of the GLUT4 glucose transporters to the plasma membrane in response to insulin; since the activity of hexokinase is not affected, the changes in the sensitivity of glucose phosphorylation to insulin seen under these conditions are secondary to those in glucose transport. (2) The sensitivity of glycogen synthesis and glucose oxidation to insulin is decreased, but that of glycolysis is not affected: a redistribution of glucose away from the pathway of glycogen synthesis and glucose oxidation could maintain a normal rate of lactate formation although the rate of glucose transport is decreased.

scholarly journals Glucose transport and GLUT4 protein distribution in skeletal muscle of GLUT4 transgenic mice

1996 ◽  
Vol 313 (1) ◽  
pp. 133-140 ◽  
Author(s):  
Joseph T. BROZINICK ◽  
Benedict B. YASPELKIS ◽  
Cindy M. WILSON ◽  
Kristen E. GRANT ◽  
E. Michael GIBBS ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Protein Concentration ◽  
Glucose Transporter ◽  
Protein Distribution ◽  
Transport Activity ◽  
Insulin Stimulation ◽  
Hind Limbs

The aim of the present investigation was to determine whether the subcellular distribution and insulin-stimulated translocation of the GLUT4 isoform of the glucose transporter are affected when GLUT4 is overexpressed in mouse skeletal muscle, and if the overexpression of GLUT4 alters maximal insulin-stimulated glucose transport and metabolism. Rates of glucose transport and metabolism were assessed by hind-limb perfusion in GLUT4 transgenic (TG) mice and non-transgenic (NTG) controls. Glucose-transport activity was determined under basal (no insulin), submaximal (0.2 m-unit/ml) and maximal (10 m-units/ ml) insulin conditions using a perfusate containing 8 mM 3-O-methyl-D-glucose. Glucose metabolism was quantified by perfusing the hind limbs for 25 min with a perfusate containing 8 mM glucose and 10 m-units/ml insulin. Under basal conditions, there was no difference in muscle glucose transport between TG (1.10±0.10 μmol/h per g; mean±S.E.M.) and NTG (0.93±0.16 μmol/h per g) mice. However, TG mice displayed significantly greater glucose-transport activity during submaximal (4.42±0.49 compared with 2.69±0.33 μmol/h per g) and maximal (11.68±1.13 compared with 7.53±0.80 μmol/h per g) insulin stimulation. Nevertheless, overexpression of the GLUT4 protein did not alter maximal rates of glucose metabolism. Membrane purification revealed that, under basal conditions, plasma-membrane (~ 12-fold) and intracellular-membrane (~ 4-fold) GLUT4 protein concentrations were greater in TG than NTG mice. Submaximal insulin stimulation did not increase plasma-membrane GLUT4 protein concentration whereas maximal insulin stimulation increased this protein in both NTG (4.1-fold) and TG (2.6-fold) mice. These results suggest that the increase in insulin-stimulated glucose transport following overexpression of the GLUT4 protein is limited by factors other than the plasma-membrane GLUT4 protein concentration. Furthermore, GLUT4 overexpression is not coupled to glucose-metabolic capacity.

Interactions of exercise training and α-lipoic acid on insulin signaling in skeletal muscle of obese Zucker rats

2004 ◽  
Vol 287 (3) ◽  
pp. E529-E536 ◽  
Author(s):  
Vitoon Saengsirisuwan ◽  
Felipe R. Perez ◽  
Julie A. Sloniger ◽  
Thomas Maier ◽  
Erik J. Henriksen
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Expression ◽  
Glucose Transport ◽  
Soleus Muscle ◽  
Lipoic Acid ◽  
Combination Treatment ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Resistant

We have shown previously (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ. J Appl Physiol 91: 145–153, 2001) that the antioxidant R-(+)-α-lipoic acid (R-ALA), combined with endurance exercise training (ET), increases glucose transport in insulin-resistant skeletal muscle in an additive fashion. The purpose of the present study was to investigate possible cellular mechanisms responsible for this interactive effect. We evaluated the effects of R-ALA alone, ET alone, or R-ALA and ET in combination on insulin-stimulated glucose transport, protein expression, and functionality of specific insulin-signaling factors in soleus muscle of obese Zucker ( fa/fa) rats. Obese animals remained sedentary, received R-ALA (30 mg·kg body wt−1·day−1), performed ET (daily treadmill running for ≤60 min), or underwent both R-ALA treatment and ET for 15 days. R-ALA or ET individually increased ( P < 0.05) insulin-mediated (5 mU/ml) glucose transport (2-deoxyglucose uptake) in soleus muscle by 45 and 68%, respectively, and this value was increased to the greatest extent (124%) in the combined treatment group. Soleus insulin receptor substrate (IRS)-1 protein was significantly increased by R-ALA alone (30%) or ET alone (31%), and a further enhancement (55%) was observed after the combination treatment in the obese animals. Enhanced levels of IRS-1 protein expression after individual or combined interventions were significantly correlated with insulin action on glucose transport activity ( r = 0.597, P = 0.0055). Similarly, insulin-mediated IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase was increased by R-ALA (317%) and ET (319%) and to the greatest extent (435%) (all P < 0.05) by the combination treatment. These results indicate that the improvements of insulin action in insulin-resistant skeletal muscle after R-ALA or ET, alone and in combination, were associated with increases in IRS-1 protein expression and IRS-1 associated with p85.

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