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

1993 ◽  
Vol 289 (2) ◽  
pp. 423-426 ◽  
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.

Modulation of noradrenaline-induced vasoconstriction in isolated perfused mesenteric arterial beds from obese Zucker rats in the presence and absence of insulin

2002 ◽  
Vol 80 (3) ◽  
pp. 171-179 ◽  
Author(s):  
Yi He ◽  
Kathleen M MacLeod
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Receptor Antagonist ◽  
Vascular Reactivity ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Significant Difference ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Presence And Absence

The genetically obese Zucker rat (fa/fa) is an insulin-resistant animal model with early-onset severe hyperinsulinemia that eventually develops mild hypertension. Thus, it represents a model in which the effect of hyperinsulinemia – insulin resistance associated with hypertension on vascular reactivity can be examined. The purpose of this study was to investigate the contribution of endogenous nitric oxide (NO) and prostaglandins to reactivity to noradrenaline (NA) in the presence and absence of insulin in mesenteric arterial beds (MAB) from 25-week-old obese Zucker rats and their lean, gender-matched littermates. In the absence of insulin, bolus injection of NA (0.9–90 nmol) produced a dose-dependent increase in perfusion pressure in MAB from both lean and obese rats. Although there was no significant difference in NA pD2 (–log ED50) values, the maximum response of MAB from obese rats to NA was slightly but significantly reduced compared with that of MAB from lean rats. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 µM) enhanced and indomethacin (20 µM) inhibited pressor responses to NA in MAB from both obese and lean rats. Perfusion with insulin (200 mU/L, a level similar to that in obese rats in vivo) potentiated only the responses of the obese MAB to the two lowest doses of NA tested (0.9 and 3 nmol). In the presence of L-NMMA, insulin further potentiated the NA response in MAB from obese rats. Indomethacin, the prostaglandin H2/thromboxane A2 receptor antagonist SQ 29548 (0.3 µM), and the nonselective endothelin-1 (ET-1) receptor antagonist bosentan (3 µM) all abolished insulin potentiation of the NA response in obese MAB. These data suggest that concurrent release of NO and vasoconstrictor cyclooxygenase product(s) in MAB from both obese and lean Zucker rats normally regulates NA-induced vasoconstrictor responses. Furthermore, insulin increases the release of contracting cyclooxygenase product(s) and enhances reactivity to low doses of NA in MAB from obese rats. The effects of insulin may be partially mediated by ET-1 via ET receptors and are buffered to some extent by concomitant NO release. This altered action of insulin may play a role in hypertension in this hyperinsulinemic – insulin-resistant model.Key words: hyperinsulinemia, insulin resistance, hypertensive Zucker obese rat, mesenteric arterial bed, noradrenaline.

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

2006 ◽  
Vol 291 (2) ◽  
pp. E207-E213 ◽  
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.

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

2000 ◽  
Vol 278 (2) ◽  
pp. R453-R459 ◽  
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.

scholarly journals 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 ◽  
2004 ◽  
Vol 47 (3) ◽  
pp. 412-419 ◽  
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

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

2005 ◽  
Vol 288 (6) ◽  
pp. E1188-E1194 ◽  
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.

Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. E251-E257 ◽  
Author(s):  
Sarah J. Lessard ◽  
Zhi-Ping Chen ◽  
Matthew J. Watt ◽  
Michael Hashem ◽  
Julianne J. Reid ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zucker Rats ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Palmitate Oxidation ◽  
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.

scholarly journals Failure of insulin-regulated recruitment of the glucose transporter GLUT4 in cardiac muscle of obese Zucker rats is associated with alterations of small-molecular-mass GTP-binding proteins

1995 ◽  
Vol 311 (1) ◽  
pp. 161-166 ◽  
Author(s):  
I Uphues ◽  
T Kolter ◽  
B Goud ◽  
J Eckel
Keyword(s):  
Plasma Membranes ◽  
Microsomal Fraction ◽  
Glucose Transporter ◽  
Zucker Rats ◽  
Gtp Binding Protein ◽  
Insulin Resistant ◽  
Gtp Binding ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Glucose Transporter Glut4

Cardiac ventricular tissue of lean and genetically obese (fa/fa) Zucker rats was used to study the expression, subcellular distribution and insulin-induced recruitment of the glucose transporter GLUT4 and to elucidate possible molecular alterations of the translocation process. Hearts were removed from basal and insulin-treated (20 min) lean and obese Zucker rats, and processed for subcellular fractionation and Western blotting of proteins. In obese rats, the total GLUT4 content in a crude membrane fraction was reduced to 75 +/- 8% (P = 0.019) of lean controls. In contrast, GLUT4 abundance in plasma membranes was not significantly different between lean and obese rats with a concomitant decrease (47 +/- 3%) in the microsomal fraction of obese animals. In plasma membranes of lean animals insulin was found to increase the GLUT4 abundance to 294 +/- 43% of control with a significantly (P = 0.009) reduced effect in the obese group (139 +/- 10% of control). In these animals insulin failed to recruit GLUT4 from the microsomal fraction, whereas the hormone induced a significant decrease (41 +/- 4%) of microsomal GLUT4 in lean controls. In GLUT4-enriched membrane vesicles, obtained from cardiac microsomes of lean rats, a 24 kDa GTP-binding protein could be detected, whereas no significant labelling of this species was observed in GLUT4 vesicles prepared from obese animals. In addition to the translocation of GLUT4, insulin was found to promote the movement of the small GTP-binding protein rab4A from the cytosol (decrease to 61 +/- 13% of control) to the plasma membrane (increase to 177 +/- 19% of control) in lean rats with no effect of the hormone on rab4A redistribution in the obese group. In conclusion, cardiac glucose uptake of insulin-resistant obese Zucker rats is subject to multiple cellular abnormalities involving a reduced expression, altered redistribution and defective recruitment of GLUT4. We show here an association of the latter defect with alterations at the level of small GTP-binding proteins possibly leading to an impaired trafficking of GLUT4 in the insulin-resistant state.

Impaired Insulin-Induced Attenuation of Noradrenaline-Mediated Vasoconstriction in Insulin-Resistant Obese Zucker Rats

1997 ◽  
Vol 93 (3) ◽  
pp. 235-241 ◽  
Author(s):  
A. B. Walker ◽  
J. Dores ◽  
R. E. Buckingham ◽  
M. W. Savage ◽  
G. Williams
Keyword(s):  
Underlying Mechanism ◽  
Zucker Rats ◽  
Insulin Resistant ◽  
Obese Zucker Rat ◽  
Maximal Tension ◽  
Impaired Insulin ◽  
Obese Rats ◽  
Significant Impairment ◽  
Obese Zucker Rats ◽  
L 13

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (≈ 220 μm diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 ± 3%, P < 0.05; 500 m-units/l: 13 ± 3%, P < 0.02; 5000 m-units/l: 13 ± 2%, P < 0.02). 3. Vessels from obese rats failed to show any such response to insulin (2 ± 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of l-arginine (3 mmol/l). 4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 × 10−8−10−4 mol/l) (obese: 64.1 ± 3.7% relaxation; lean: 77.3 ± 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 ± 10.6% relaxation; lean: 79.1 ± 9.7% relaxation; not significant). 5. Systolic blood pressure was not significantly different in lean (126 ± 8 mmHg) and obese (127 ± 7 mmHg) rats at the time of study (not significant). 6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.

Direct effect of CNS on insulin hypersecretion in obese Zucker rats: involvement of vagus nerve

1989 ◽  
Vol 256 (3) ◽  
pp. E439-E444 ◽  
Author(s):  
H. C. Lee ◽  
D. L. Curry ◽  
J. S. Stern
Keyword(s):  
Nervous System ◽  
Insulin Secretion ◽  
Vagus Nerve ◽  
Parasympathetic Nervous System ◽  
Zucker Rats ◽  
Parasympathetic Innervation ◽  
Pancreas Perfusion ◽  
Significant Difference ◽  
Obese Rats ◽  
Obese Zucker Rats

It is hypothesized that the vagus nerve makes a major contribution to pancreatic insulin hypersecretion in the genetically obese rat (fa/fa) via direct pancreatic innervation. An in situ brain-pancreas perfusion model with intact pancreatic central nervous system (CNS) innervation was used in these studies. The dynamics of insulin secretion in response to a 40-min glucose stimulus (200 mg/dl) was investigated in CNS intact (INT), bilateral cervical vagotomized (VGX), and CNS functionally ablated (ABL) 11- to 12-wk-old homozygous lean (Fa/Fa) and obese (fa/fa) female Zucker rats. The overall pattern of insulin secretory dynamics from obese and lean rats was similar. However, insulin released during the entire 40-min perfusion period by pancreata from obese rats was significantly greater than in lean rats. In lean rats, there was no significant difference in insulin secretion from pancreata of CNS-INT, VGX, and ABL rats. In obese rats, CNS-INT pancreata secreted almost twice as much insulin as pancreata from obese ABL rats and four times as much insulin as CNS-INT lean rats. This demonstrates that hypersecretion of insulin in obese Zucker rats is comprised of a significant direct CNS component. Although vagotomy had little effect on CNS-INT lean rats, it reversed the CNS component of hypersecretion present in CNS-INT obese rats. Because insulin secretion in CNS-INT obese rats was lowered by vagotomy to that equivalent to values of CNS-ABL obese rats, this demonstrates a significant contribution by the parasympathetic nervous system to the hyperinsulinemia seen in the Zucker obese rat that is attributed to direct parasympathetic innervation of the pancreas.

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