Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 μM RSG increased ( P < 0.05) AMPKα1 activity and phosphorylation of AMPK (Thr172). In addition, acetyl-CoA carboxylase (Ser218) phosphorylation and palmitate oxidation were increased ( P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 μl/100 g body mass), or 3 mg/kg RSG. AMPKα1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKα2 activity was ∼25% lower in obese vs. lean animals ( P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity ( P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

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Contractile activity restores insulin responsiveness in skeletal muscle of obese Zucker rats

Biochemical Journal ◽

10.1042/bj2890423 ◽

1993 ◽

Vol 289 (2) ◽

pp. 423-426 ◽

Cited By ~ 24

Author(s):

P L Dolan ◽

E B Tapscott ◽

P J Dorton ◽

G L Dohm

Keyword(s):

Skeletal Muscle ◽

Glucose Transport ◽

Contractile Activity ◽

Clinical Importance ◽

Zucker Rats ◽

Insulin Resistant ◽

Significant Difference ◽

Obese Rats ◽

Obese Zucker Rats ◽

Insulin Responsiveness

Both insulin and contraction stimulate glucose transport in skeletal muscle. Insulin-stimulated glucose transport is decreased in obese humans and rats. The aims of this study were (1) to determine if contraction-stimulated glucose transport was also compromised in skeletal muscle of genetically obese insulin-resistant Zucker rats, and (2) to determine whether the additive effects of insulin and contraction previously observed in muscle from lean subjects were evident in muscle from the obese animals. To measure glucose transport, hindlimbs from lean and obese Zucker rats were perfused under basal, insulin-stimulated (0.1 microM), contraction-stimulated (electrical stimulation of the sciatic nerve) and combined insulin-(+)contraction-stimulated conditions. One hindlimb was stimulated to contract while the contralateral leg served as an unstimulated control. 2-Deoxyglucose transport rates were measured in the white gastrocnemius, red gastrocnemius and extensor digitorum longus muscles. As expected, the insulin-stimulated glucose transport rate in each of the three muscles was significantly slower (P < 0.05) in obese rats when compared with lean animals. When expressed as fold stimulation over basal, there was no significant difference in contraction-induced muscle glucose transport rates between lean and obese animals. Insulin-(+)contraction-stimulation was additive in skeletal muscle of lean animals, but synergistic in skeletal muscle of obese animals. Prior contraction increased insulin responsiveness of glucose transport 2-5-fold in the obese rats, but had no effect on insulin responsiveness in the lean controls. This contraction-induced improvement in insulin responsiveness could be of clinical importance to obese subjects as a way to improve insulin-stimulated glucose uptake in resistant skeletal muscle.

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Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00628.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. E207-E213 ◽

Cited By ~ 26

Author(s):

Betsy B. Dokken ◽

Erik J. Henriksen

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Transport ◽

Glycogen Synthase ◽

Whole Body ◽

Zucker Rats ◽

Oral Glucose ◽

Insulin Resistant ◽

Obese Zucker Rats

Increasing evidence supports a negative role of glycogen synthase kinase-3 (GSK-3) in regulation of skeletal muscle glucose transport. We assessed the effects of chronic treatment of insulin-resistant, prediabetic obese Zucker ( fa/ fa) rats with a highly selective GSK-3 inhibitor (CT118637) on glucose tolerance, whole body insulin sensitivity, plasma lipids, skeletal muscle insulin signaling, and in vitro skeletal muscle glucose transport activity. Obese Zucker rats were treated with either vehicle or CT118637 (30 mg/kg body wt) twice per day for 10 days. Fasting plasma insulin and free fatty acid levels were reduced by 14 and 23% ( P < 0.05), respectively, in GSK-3 inhibitor-treated animals compared with vehicle-treated controls. The glucose response during an oral glucose tolerance test was reduced by 18% ( P < 0.05), and whole body insulin sensitivity was increased by 28% ( P < 0.05). In vivo insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (50%) and IRS-1-associated phosphatidylinositol-3′ kinase (79%) relative to fasting plasma insulin levels were significantly elevated ( P < 0.05) in plantaris muscles of GSK-3 inhibitor-treated animals. Whereas basal glucose transport in isolated soleus and epitrochlearis muscles was unaffected by chronic GSK-3 treatments, insulin stimulation of glucose transport above basal was significantly enhanced (32–60%, P < 0.05). In summary, chronic treatment of insulin-resistant, prediabetic obese Zucker rats with a specific GSK-3 inhibitor enhances oral glucose tolerance and whole body insulin sensitivity and is associated with an amelioration of dyslipidemia and an improvement in IRS-1-dependent insulin signaling in skeletal muscle. These results provide further evidence that selective targeting of GSK-3 in muscle may be an effective intervention for the treatment of obesity-associated insulin resistance.

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Effects of a unique conjugate of α-lipoic acid and γ-linolenic acid on insulin action in obese Zucker rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.2.r453 ◽

2000 ◽

Vol 278 (2) ◽

pp. R453-R459 ◽

Cited By ~ 17

Author(s):

J. Anthony Peth ◽

Tyson R. Kinnick ◽

Erik B. Youngblood ◽

Hans J. Tritschler ◽

Erik J. Henriksen

Keyword(s):

Fatty Acid ◽

Essential Fatty Acid ◽

Glucose Transport ◽

Lipoic Acid ◽

Insulin Action ◽

Whole Body ◽

Zucker Rats ◽

Additive Effects ◽

Insulin Resistant ◽

Obese Zucker Rats

The purpose of this study was to assess the individual and interactive effects of the antioxidant α-lipoic acid (LPA) and the n-6 essential fatty acid γ-linolenic acid (GLA) on insulin action in insulin-resistant obese Zucker rats. LPA, GLA, and a unique conjugate consisting of equimolar parts of LPA and GLA (LPA-GLA) were administered for 14 days at 10, 30, or 50 mg ⋅ kg body wt− 1 ⋅ day− 1. Whereas LPA was without effect at 10 mg/kg, at 30 and 50 mg/kg it elicited 23% reductions ( P < 0.05) in the glucose-insulin index (the product of glucose and insulin areas under the curve during an oral glucose tolerance test and an index of peripheral insulin action) that were associated with significant increases in insulin-mediated (2 mU/ml) glucose transport activity in isolated epitrochlearis (63–65%) and soleus (33–41%) muscles. GLA at 10 and 30 mg/kg caused 21–25% reductions in the glucose-insulin index and 23–35% improvements in insulin-mediated glucose transport in epitrochlearis muscle. The beneficial effects of GLA disappeared at 50 mg/kg. At 10 and 30 mg/kg, the LPA-GLA conjugate elicited 29 and 38% reductions in the glucose-insulin index. These LPA-GLA-induced improvements in whole body insulin action were accompanied by 28–63 and 38–57% increases in insulin-mediated glucose transport in epitrochlearis and soleus muscles and resulted from the additive effects of LPA and GLA. At 50 mg/kg, the metabolic improvements due to LPA-GLA were substantially reduced. In summary, these results indicate that the conjugate of the antioxidant LPA and the n-6 essential fatty acid GLA elicits significant dose-dependent improvements in whole body and skeletal muscle insulin action on glucose disposal in insulin-resistant obese Zucker rats. Moreover, these actions of LPA-GLA are due to the additive effects of its individual components.

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Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats

Nephron Experimental Nephrology ◽

10.1159/000254567 ◽

2010 ◽

Vol 114 (2) ◽

pp. e61-e68 ◽

Cited By ~ 11

Author(s):

Jie Liao ◽

Zohreh Soltani ◽

Philip Ebenezer ◽

Angel A. Isidro-Carrión ◽

Rubin Zhang ◽

...

Keyword(s):

Renal Injury ◽

Receptor Agonist ◽

Zucker Rats ◽

Peroxisome Proliferator ◽

Metabolic Abnormalities ◽

Peroxisome Proliferator Activated Receptor ◽

Obese Zucker Rats

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The effect of insulin and exercise on c-Cbl protein abundance and phosphorylation in insulin-resistant skeletal muscle in lean and obese Zucker rats

Diabetologia ◽

10.1007/s00125-003-1322-2 ◽

2004 ◽

Vol 47 (3) ◽

pp. 412-419 ◽

Cited By ~ 10

Author(s):

G. D. Wadley ◽

C. R. Bruce ◽

N. Konstantopoulos ◽

S. L. Macaulay ◽

K. F. Howlett ◽

...

Keyword(s):

Skeletal Muscle ◽

Zucker Rats ◽

Protein Abundance ◽

Insulin Resistant ◽

Obese Zucker Rats ◽

Cbl Protein

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Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00547.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. E1188-E1194 ◽

Cited By ~ 63

Author(s):

Betsy B. Dokken ◽

Julie A. Sloniger ◽

Erik J. Henriksen

Keyword(s):

Skeletal Muscle ◽

Tyrosine Phosphorylation ◽

Glucose Transport ◽

Insulin Signaling ◽

Insulin Action ◽

Glycogen Synthase ◽

Serine Phosphorylation ◽

Zucker Rats ◽

Type I ◽

Insulin Resistant

Glycogen synthase kinase-3 (GSK3) has been implicated in the multifactorial etiology of skeletal muscle insulin resistance in animal models and in human type 2 diabetic subjects. However, the potential molecular mechanisms involved are not yet fully understood. Therefore, we determined if selective GSK3 inhibition in vitro leads to an improvement in insulin action on glucose transport activity in isolated skeletal muscle of insulin-resistant, prediabetic obese Zucker rats and if these effects of GSK3 inhibition are associated with enhanced insulin signaling. Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 μM CT118637, Ki < 10 nM for GSK3α and GSK3β). Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. GSK3 inhibition enhanced ( P <0.05) basal glycogen synthase activity and insulin-stimulated glucose transport in obese epitrochlearis (81 and 24%) and soleus (108 and 20%) muscles. GSK3 inhibition did not modify insulin-stimulated tyrosine phosphorylation of IR β-subunit in either muscle type. However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3β serine phosphorylation (39%). Substantially smaller GSK3 inhibitor-mediated enhancements of insulin action on these insulin signaling factors were observed in obese epitrochlearis. These results indicate that selective GSK3 inhibition enhances insulin action in insulin-resistant skeletal muscle of the prediabetic obese Zucker rat, at least in part by relieving the deleterious effects of GSK3 action on post-IR insulin signaling. These effects of GSK3 inhibition on insulin action are greater in type I muscle than in type IIb muscle from these insulin-resistant animals.

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Peroxisome Proliferator-Activated Receptors and Hepatitis C Virus-Induced Insulin Resistance

PPAR Research ◽

10.1155/2009/483485 ◽

2009 ◽

Vol 2009 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Francesco Negro

Keyword(s):

Insulin Resistance ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Insulin Signalling ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Resistant ◽

Peroxisome Proliferator Activated Receptors ◽

Chronic Hepatitis C Patients

Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a), insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator-activated receptorγ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.

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Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00448.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. R137-R142 ◽

Cited By ~ 19

Author(s):

Elizabeth M. Marchionne ◽

Maggie K. Diamond-Stanic ◽

Mujalin Prasonnarong ◽

Erik J. Henriksen

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Transport ◽

Insulin Action ◽

Whole Body ◽

Zucker Rats ◽

Obese Zucker Rats ◽

Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

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Effects of exercise training and antioxidant R-ALA on glucose transport in insulin-sensitive rat skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.000617.2001 ◽

2002 ◽

Vol 92 (1) ◽

pp. 50-58 ◽

Cited By ~ 24

Author(s):

Vitoon Saengsirisuwan ◽

Felipe R. Perez ◽

Tyson R. Kinnick ◽

Erik J. Henriksen

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Training ◽

Glucose Transport ◽

Insulin Action ◽

Treadmill Running ◽

Protein Carbonyls ◽

Zucker Rats ◽

Oral Glucose ◽

Insulin Resistant

We have recently demonstrated (Saengsirisuwan V, Kinnick TR, Schmit MB, and Henriksen EJ, J Appl Physiol 91: 145–153, 2001) that exercise training (ET) and the antioxidant R-(+)-α-lipoic acid ( R-ALA) interact in an additive fashion to improve insulin action in insulin-resistant obese Zucker ( fa/fa) rats. The purpose of the present study was to assess the interactions of ET and R-ALA on insulin action and oxidative stress in a model of normal insulin sensitivity, the lean Zucker ( fa/−) rat. For 6 wk, animals either remained sedentary, received R-ALA (30 mg · kg body wt−1 · day−1), performed ET (treadmill running), or underwent both R-ALA treatment and ET. ET alone or in combination with R-ALA significantly increased ( P < 0.05) peak oxygen consumption (28–31%) and maximum run time (52–63%). During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose response (17–36%) at 15 min relative to R-ALA alone and of the insulin response (19–36%) at 15 min compared with sedentary controls. Insulin-mediated glucose transport activity was increased by ET alone in isolated epitrochlearis (30%) and soleus (50%) muscles, and this was associated with increased GLUT-4 protein levels. Insulin action was not improved by R-ALA alone, and ET-associated improvements in these variables were not further enhanced with combined ET and R-ALA. Although ET and R-ALA caused reductions in soleus protein carbonyls (an index of oxidative stress), these alterations were not significantly correlated with insulin-mediated soleus glucose transport. These results indicate that the beneficial interactive effects of ET and R-ALA on skeletal muscle insulin action observed previously in insulin-resistant obese Zucker rats are not apparent in insulin-sensitive lean Zucker rats.

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