DHEA and Glucose Metabolism in Skeletal Muscle

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

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Lack of skeletal muscle IL-6 influences hepatic glucose metabolism in mice during prolonged exercise

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00373.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. R626-R636 ◽

Cited By ~ 5

Author(s):

Lærke Bertholdt ◽

Anders Gudiksen ◽

Camilla L. Schwartz ◽

Jakob G. Knudsen ◽

Henriette Pilegaard

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Prolonged Exercise ◽

Hepatic Glycogen ◽

Glucose Content ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose ◽

Single Bout ◽

Substrate Choice

The liver is essential in maintaining and regulating glucose homeostasis during prolonged exercise. IL-6 has been shown to be secreted from skeletal muscle during exercise and has been suggested to signal to the liver. Therefore, the aim of this study was to investigate the role of skeletal muscle IL-6 on hepatic glucose regulation and substrate choice during prolonged exercise. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice (age, 12–14 wk) and littermate lox/lox (Control) mice were either rested (Rest) or completed a single bout of exercise for 10, 60, or 120 min, and the liver was quickly obtained. Hepatic IL-6 mRNA was higher at 60 min of exercise, and hepatic signal transducer and activator of transcription 3 was higher at 120 min of exercise than at rest in both genotypes. Hepatic glycogen was higher in IL-6 MKO mice than control mice at rest, but decreased similarly during exercise in the two genotypes, and hepatic glucose content was lower in IL-6 MKO than control mice at 120 min of exercise. Hepatic phosphoenolpyruvate carboxykinase mRNA and protein increased in both genotypes at 120 min of exercise, whereas hepatic glucose 6 phosphatase protein remained unchanged. Furthermore, IL-6 MKO mice had higher hepatic pyruvate dehydrogenase (PDH)Ser232 and PDHSer300 phosphorylation than control mice at rest. In conclusion, hepatic gluconeogenic capacity in mice is increased during prolonged exercise independent of muscle IL-6. Furthermore, Skeletal muscle IL-6 influences hepatic substrate regulation at rest and hepatic glucose metabolism during prolonged exercise, seemingly independent of IL-6 signaling in the liver.

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Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism

Circulation Research ◽

10.1161/res.113.suppl_1.a112 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Masataka YOKOYAMA ◽

Yoshio KOBAYASHI ◽

Tohru MINAMINO

Keyword(s):

Skeletal Muscle ◽

Endothelial Cell ◽

Glucose Metabolism ◽

Endothelial Function ◽

Mitochondrial Biogenesis ◽

Glucose Transporter ◽

Diabetic Patients ◽

Glucose Transporter 1 ◽

P53 Activation

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.

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Increased concentrations of glycogen synthase protein in skeletal muscle of patients with NIDDM

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.1.e27 ◽

1995 ◽

Vol 269 (1) ◽

pp. E27-E32 ◽

Cited By ~ 1

Author(s):

M. Lofman ◽

H. Yki-Jarvinen ◽

M. Parkkonen ◽

J. Lindstrom ◽

L. Koranyi ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Protein Concentration ◽

Glycogen Synthase ◽

Glycogen Metabolism ◽

Dependent Diabetes Mellitus ◽

Euglycemic Hyperinsulinemic Clamp ◽

Control Subjects ◽

Significant Difference ◽

Glycogen Synthase Activity

To examine whether changes in the glycogen synthase protein concentration contribute to impaired insulin-stimulated glycogen metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM), muscle biopsies were taken before and after a 4-h euglycemic hyperinsulinemic clamp to measure glycogen synthase activity and glycogen synthase protein concentrations in 14 patients with NIDDM and in 17 control subjects. Nonoxidative glucose metabolism was reduced by 64% in patients with NIDDM compared with control subjects and correlated with insulin-stimulated glycogen synthase activity (r = 0.55, P < 0.05). The concentration of glycogen synthase protein in skeletal muscle was higher in patients with NIDDM than in control subjects (6.75 +/- 0.88 vs. 4.41 +/- 0.50 counts.min-1.micrograms protein-1, P < 0.05), whereas there was no significant difference in glycogen synthase mRNA concentration between the two groups. The glycogen synthase protein concentration correlated inversely with the rate of nonoxidative glucose metabolism (r = -0.63, P < 0.05). These findings indicate that the amount of glycogen synthase protein is increased in skeletal muscle of patients with NIDDM. The increase in the glycogen synthase protein may serve to compensate for a functional defect in the activation of the enzyme by insulin.

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Insulin action in growth hormone-deficient and age-matched control rats: effect of growth hormone treatment

Journal of Endocrinology ◽

10.1677/joe.0.1600127 ◽

1999 ◽

Vol 160 (1) ◽

pp. 127-135 ◽

Cited By ~ 13

Author(s):

◽

JL Laustsen ◽

BS Hansen ◽

EA Richter

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Glucose Metabolism ◽

Recombinant Human Growth Hormone ◽

Normal Weight ◽

Lower Amount ◽

Control Group ◽

Muscle Fibre Size ◽

Igf I

The isolated effect of growth hormone on carbohydrate metabolism in rat skeletal muscle was studied in growth hormone-deficient dwarf rats (dw/dw) treated with either recombinant human growth hormone or saline for 10 days. In addition, age-matched heterozygous (DW/dw) (normal weight and plasma IGF-I) control rats were treated with saline. Growth hormone increased weight gain from 0.1+/-0.1 (s.e.m) to 3.6+/-0.1 g/day and plasma IGF-I concentration from 364+/-23 to 451+/-32 ng/ml. Glucose metabolism in skeletal muscle perfused with basal, submaximal and maximal concentrations (0, 600 and 60 000 pmol/l respectively) of insulin was not changed by growth hormone. No change could be detected in the total number of glucose transporters (GLUT1 and GLUT4) in the skeletal muscles, except from a lower amount of GLUT4 in the soleus muscle in the heterozygous control group. However, at submaximal insulin concentrations, skeletal muscle glucose uptake and transport were significantly lower in the heterozygous control group compared with the growth hormone-deficient group. This could indicate either a direct long-term effect of growth hormone or more likely a secondary effect attributable to the difference in body weight (205.2+/-3.1 vs 361. 6+/-5.9 g for dwarf rats and heterozygous controls respectively), and thereby muscle fibre size, between the groups probably resulting in lower average interstitial insulin and glucose concentrations at a given plasma concentration in the heterozygous rats. It is concluded that restoration of subnormal growth hormone concentrations for 10 days has no effect on insulin-stimulated glucose metabolism in skeletal muscle in vitro.

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