142: Maternal bisphenol-A (BPA) exposure programs male offspring glucose tolerance and alters hepatic and skeletal muscle insulin signaling protein expression

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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AVE0991, a Nonpeptide Angiotensin 1-7 Receptor Agonist, Improves Glucose Metabolism in the Skeletal Muscle of Obese Zucker Rats: Possible Involvement of Prooxidant/Antioxidant Mechanisms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6372935 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Viktoria Dobrocsyova ◽

Miroslava Slamkova ◽

Katarina Krskova ◽

Lucia Balazova ◽

Maciej Suski ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Tolerance ◽

Insulin Signaling ◽

Receptor Agonist ◽

Colorimetric Assay ◽

Whole Body ◽

Zucker Rats ◽

Ros Generation ◽

Morbidly Obese ◽

Obese Zucker Rats

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

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Insulin signaling displayed a differential tissue-specific response to low-dose dihydrotestosterone in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. E353-E365 ◽

Cited By ~ 4

Author(s):

Stanley Andrisse ◽

Katelyn Billings ◽

Ping Xue ◽

Sheng Wu

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Energy Storage ◽

Protein Expression ◽

Insulin Signaling ◽

Low Dose ◽

Specific Response ◽

Pituitary Cells ◽

Reproductive Tissues ◽

Mrna And Protein Expression

Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

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Immobilization depresses insulin signaling in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.6.e1235 ◽

2000 ◽

Vol 279 (6) ◽

pp. E1235-E1241 ◽

Cited By ~ 38

Author(s):

Munetaka Hirose ◽

Masao Kaneki ◽

Hiroki Sugita ◽

Shingo Yasuhara ◽

J. A. Jeevendra Martyn

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Insulin Receptor ◽

Tyrosine Phosphorylation ◽

Glucose Transport ◽

Insulin Signaling ◽

Regulatory Subunit ◽

Protein Levels ◽

Essential Components ◽

Prolonged Immobilization

Prolonged immobilization depresses insulin-induced glucose transport in skeletal muscle and leads to a catabolic state in the affected areas, with resultant muscle wasting. To elucidate the altered intracellular mechanisms involved in the insulin resistance, we examined insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit (IR-β) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecule, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobilization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vein, and tibialis anterior muscles on both sides were extracted. Immobilization reduced insulin-stimulated tyrosine phosphorylation of IR-β and IRS-1. Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobilized hindlimb. Although IR-β and p85 protein levels were unchanged, IRS-1 protein expression was downregulated by immobilization. Thus prolonged immobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essential components of insulin signaling pathways.

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Resistance training and dietary protein: effects on glucose tolerance and contents of skeletal muscle insulin signaling proteins in older persons

American Journal of Clinical Nutrition ◽

10.1093/ajcn/85.4.1005 ◽

2007 ◽

Vol 85 (4) ◽

pp. 1005-1013 ◽

Cited By ~ 38

Author(s):

Heidi B Iglay ◽

John P Thyfault ◽

John W Apolzan ◽

Wayne W Campbell

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Glucose Tolerance ◽

Insulin Signaling ◽

Dietary Protein ◽

Older Persons ◽

Signaling Proteins

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Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00822.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. R1926-R1933 ◽

Cited By ~ 24

Author(s):

Xing-Hai Yao ◽

B. L. Grégoire Nyomba

Keyword(s):

Skeletal Muscle ◽

Glucose Tolerance ◽

Adult Female ◽

Insulin Signaling ◽

Glucose Transporter ◽

Female Offspring ◽

Female Rat ◽

Glucose Transporter 4 ◽

Insulin Resistant ◽

Rat Offspring

Adverse events during pregnancy, including prenatal ethanol (EtOH) exposure, are associated with insulin-resistant diabetes in male rat offspring, but it is unclear whether this is true for female offspring. We investigated whether prenatal EtOH exposure alters glucose metabolism in adult female rat offspring and whether this is associated with reduced in vivo insulin signaling in skeletal muscle. Female Sprague-Dawley rats were given EtOH, 4 g·kg−1·day−1 by gavage throughout pregnancy. Glucose tolerance test and hyperinsulinemic euglycemic clamp were performed, and insulin signaling was investigated in skeletal muscle, in adult female offspring. We gave insulin intravenously to these rats and determined the association of glucose transporter-4 with plasma membranes, as well as the phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1), Akt, and PKCζ. Although EtOH offspring had normal birth weight, they were overweight as adults and had fasting hyperglycemia, hyperinsulinemia, and reduced insulin-stimulated glucose uptake. After insulin treatment, EtOH-exposed rats had decreased membrane glucose transporter-4, PDK1, Akt, and PKCζ in the gastrocnemius muscle, compared with control rats. Insulin stimulation of PDK1, Akt, and PKCζ phosphorylation was also reduced. In addition, the expression of the protein tribbles-3 and the phosphatase enzyme activity of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which prevent Akt activation, were increased in muscle from EtOH-exposed rats. Female rat offspring exposed to EtOH in utero develop insulin-resistant diabetes in association with excessive PTEN and tribbles-3 signaling downstream of the phosphatidylinositol 3-kinase pathway in skeletal muscle, which may be a mechanism for the abnormal glucose tolerance.

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Calorie restriction initiated at middle age improved glucose tolerance without affecting age-related impairments of insulin signaling in rat skeletal muscle

Experimental Gerontology ◽

10.1016/j.exger.2006.06.055 ◽

2006 ◽

Vol 41 (9) ◽

pp. 837-845 ◽

Cited By ~ 14

Author(s):

Seongjoon Park ◽

Toshimitsu Komatsu ◽

Hiroko Hayashi ◽

Haruyoshi Yamaza ◽

Takuya Chiba ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Tolerance ◽

Calorie Restriction ◽

Insulin Signaling ◽

Middle Age ◽

Rat Skeletal Muscle ◽

Age Related

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. E529-E536 ◽

Cited By ~ 61

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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