Glucose transport: locus of muscle insulin resistance in obese Zucker rats

1988 ◽  
Vol 255 (3) ◽  
pp. E374-E382 ◽  
Author(s):  
W. M. Sherman ◽  
A. L. Katz ◽  
C. L. Cutler ◽  
R. T. Withers ◽  
J. L. Ivy
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glycogen Synthase ◽  
Fiber Type ◽  
Zucker Rats ◽  
Muscle Insulin Resistance ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Fast Twitch

The purposes of this study were to determine whether the muscle insulin resistance of the obese rat is due to a defect in the glucose transport process and whether the insulin resistance is fiber-type specific. The hindlimbs of fasted, 14-wk-old obese (fa/fa) and lean (fa/?) Zucker rats were perfused with perfusate containing 8 mM glucose and no insulin or 8 mM glucose and either a physiological (0.15 mU/ml), a submaximal (1.50 mU/ml), or a maximal (15.0 mU/ml) insulin concentration. Glucose uptake was determined after which the initial rate of glucose transport was determined using 3-O-methyl-D-glucose (3-OMG). Glucose uptake of the obese rats was depressed by 40, 33, 42, and 47% in the absence of insulin and in the presence of the physiological, submaximal, and maximal insulin concentrations, respectively, when compared with lean littermates. Glucose transport in the absence and in the presence of the three insulin concentrations was significantly lower in the soleus (slow-twitch, oxidative fibers), red quadriceps (fast-twitch, oxidative, glycolytic fibers), and gastrocnemius (mixed fibers) of the obese rats when compared with lean rats. Glucose transport in the white quadriceps (fast-twitch, glycolytic fibers) was significantly lower in the obese rats in the absence of insulin and in the presence of the submaximal and maximal insulin concentrations. The glycogen concentration and the activity of hexokinase were the same and the glycogen synthase activity was higher in the muscles for the obese rats when compared to lean rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle glucose transport in obese Zucker rats after exercise training

1989 ◽  
Vol 66 (6) ◽  
pp. 2635-2641 ◽  
Author(s):  
J. L. Ivy ◽  
J. T. Brozinick ◽  
C. E. Torgan ◽  
G. M. Kastello
Keyword(s):  
Insulin Resistance ◽  
Glucose Transport ◽  
Transport Process ◽  
Fiber Type ◽  
Zucker Rat ◽  
Muscle Insulin Resistance ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Muscle Glucose Transport ◽  
Fast Twitch

Exercise training has been found to reduce the muscle insulin resistance of the obese Zucker rat (fa/fa). The purpose of the present study was to determine whether this reduction in muscle insulin resistance was associated with an improvement in the glucose transport process and if it was fiber-type specific. Rats were randomly assigned to a sedentary or training group. Training consisted of treadmill running at 18 m/min up an 8% grade, 1.5 h/day, 5 days/wk, for 6–8 wk. The rate of muscle glucose transport was assessed in the absence of insulin and in the presence of a physiological (0.15 mU/ml), a submaximal (1.50 mU/ml), and a maximal (15.0 mU/ml) insulin concentration by determining the rate of 3-O-methyl-D-glucose (3-OMG) accumulation during hindlimb perfusion. The average 3-OMG transport rate of the red gastrocnemii (fast-twitch oxidative-glycolytic fibers) was significantly higher in the trained compared with the sedentary obese rats in the absence of insulin and in the presence of the three insulin concentrations. Significant improvements in 3-OMG transport were also observed in the plantarii (mixed fibers) of trained obese rats in the presence of 0, 0.15, and 15.0 mU/ml insulin. Training appeared to have little effect on the insulin-stimulated 3-OMG transport of the soleus (slow-twitch oxidative fibers) or white gastrocnemius (fast-twitch glycolytic fibers). The results suggest that the improvement in the muscle insulin resistance of the obese Zucker rat after moderate endurance training was associated with an improvement in the glucose transport process but that it was fiber-type specific.

Contraction-activated glucose uptake is normal in insulin-resistant muscle of the obese Zucker rat

1992 ◽  
Vol 73 (1) ◽  
pp. 382-387 ◽  
Author(s):  
J. T. Brozinick ◽  
G. J. Etgen ◽  
B. B. Yaspelkis ◽  
J. L. Ivy
Keyword(s):  
Muscle Contraction ◽  
Glucose Uptake ◽  
Fiber Type ◽  
Zucker Rats ◽  
Fiber Types ◽  
Glut 4 ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Fast Twitch ◽  
White Gastrocnemius

The rates of muscle glucose uptake of lean and obese Zucker rats were assessed via hindlimb perfusion under basal conditions (no insulin), in the presence of a maximal insulin concentration (10 mU/ml), and after electrically stimulated muscle contraction in the absence of insulin. The perfusate contained 28 mM glucose and 7.5 microCi/mmol of 2-deoxy-D-[3H-(G)]glucose. Glucose uptake rates in the soleus (slow-twitch oxidative fibers), red gastrocnemius (fast-twitch oxidative-glycolytic fibers), and white gastrocnemius (fast-twitch glycolytic fibers) under basal conditions and after electrically stimulated muscle contraction were not significantly different between the lean and obese rats. However, the rate of glucose uptake during insulin stimulation was significantly lower for obese than for lean rats in all three fiber types. Significant correlations were found for insulin-stimulated glucose uptake and glucose transporter protein isoform (GLUT-4) content of soleus, red gastrocnemius, and white gastrocnemius of lean (r = 0.79) and obese (r = 0.65) rats. In contrast, the relationships between contraction-stimulated glucose uptake and muscle GLUT-4 content of lean and obese rats were negligible because of inordinately low contraction-stimulated glucose uptakes by the solei. These results suggest that maximal skeletal muscle glucose uptake of obese Zucker rats is resistant to stimulation by insulin but not to contractile activity. In addition, the relationship between contraction-stimulated glucose uptake and GLUT-4 content appears to be fiber-type specific.

scholarly journals Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites

1980 ◽  
Vol 186 (2) ◽  
pp. 525-534 ◽  
Author(s):  
Marco Crettaz ◽  
Marc Prentki ◽  
Daniel Zaninetti ◽  
Bernard Jeanrenaud
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Insulin Binding ◽  
Zucker Rats ◽  
Maximal Response ◽  
Endogenous Fatty Acid ◽  
Lipid Utilization ◽  
Obese Rats ◽  
Obese Zucker Rats

1. The effect of insulin upon glucose transport and metabolism in soleus muscles of genetically obese (fa/fa) and heterozygote lean Zucker rats was investigated at 5–6 weeks and 10–11 weeks of age. Weight-standardized strips of soleus muscles were used rather than the intact muscle in order to circumvent problems of diffusion of substrates. 2. In younger obese rats (5–6 weeks), plasma concentrations of immunoreactive insulin were twice those of controls, whereas their circulating triacylglycerol concentrations were normal. Insulin effects upon 2-deoxyglucose uptake and glucose metabolism by soleus muscles of these rats were characterized by both a decreased sensitivity and a decrease in the maximal response of this tissue to the hormone. 3. In older obese rats (10–11 weeks), circulating concentrations of insulin and triacylglycerols were both abnormally elevated. A decrease of 25–35% in insulin-binding capacity to muscles of obese rats was observed. The soleus muscles from the older obese animals also displayed decreased sensitivity and maximal response to insulin. However, at a low insulin concentration (0.1m-i.u./ml), 2-deoxyglucose uptake by muscles of older obese rats was stimulated, but such a concentration was ineffective in stimulating glucose incorporation into glycogen, and glucose metabolism by glycolysis. 4. Endogenous lipid utilization by muscle was calculated from the measurements of O2 consumption, and glucose oxidation to CO2. The rate of utilization of fatty acids was normal in muscles of younger obese animals, but increased in those of the older obese rats. Increased basal concentrations of citrate, glucose 6-phosphate and glycogen were found in muscles of older obese rats and may reflect intracellular inhibition of glucose metabolism as a result of increased lipid utilization. 5. Thus several abnormalities are responsible for insulin resistance of muscles from obese Zucker rats among which we have observed decreased insulin binding, decreased glucose transport and increased utilization of endogenous fatty acid which could inhibit glucose utilization.

Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats

1997 ◽  
Vol 273 (1) ◽  
pp. E59-E67 ◽  
Author(s):  
T. Kolter ◽  
I. Uphues ◽  
J. Eckel
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Zucker Rats ◽  
Glut 4 ◽  
Ventricular Cardiomyocytes ◽  
Obese Rats ◽  
Glut 4 Translocation ◽  
Obese Zucker Rats

Isolated ventricular cardiomyocytes obtained from lean and genetically (fa/fa) obese Zucker rats were used to correlate alterations of insulin-induced glucose transport activation and GLUT-4 translocation to possible defects of the insulin signaling cascade. Maximal stimulation with insulin was found to produce an unaltered translocation of GLUT-4 to the plasma membrane (4.2- and 3.7-fold increase for lean and obese rats, respectively). However, a largely reduced sensitivity of 3-O-methylglucose transport could be detected in obese rats at physiological doses of insulin (completely unresponsive at 8 x 10(-11) M compared with 3-fold stimulation of glucose transport in lean controls). Tyrosine phosphorylation of the insulin receptor beta-subunit and the insulin receptor substrate 1 (IRS-1) was stimulated identically in cardiomyocytes from both lean and obese rats. Labeling of cells with [33P]orthophosphate revealed a marked increase in the serine and/or threonine phosphorylation of IRS-1 in the obese group (370% of lean controls), with a concomitant reduction in IRS-1 abundance (30-40%). The reduced sensitivity of glucose transport at 8 x 10(-11) M insulin was then found to correlate to a completely blunted response of IRS-1-associated phosphatidylinositol 3-kinase activity in cardiomyocytes from obese rats. Those data show that cardiac insulin resistance of obesity involves defective insulin signaling at low concentrations of the hormone, whereas GLUT-4 translocation is fully operative in the isolated cell. It is suggested that hyperphosphorylation of IRS-1 may significantly contribute to the pathogenesis of insulin resistance in the heart.

Muscle glucose uptake of obese Zucker rats trained at two different intensities

1991 ◽  
Vol 70 (1) ◽  
pp. 36-42 ◽  
Author(s):  
M. E. Willems ◽  
J. T. Brozinick ◽  
C. E. Torgan ◽  
M. Y. Cortez ◽  
J. L. Ivy
Keyword(s):  
Insulin Resistance ◽  
Exercise Training ◽  
Glucose Uptake ◽  
Exercise Bout ◽  
Zucker Rats ◽  
Muscle Insulin Resistance ◽  
Obese Zucker Rat ◽  
Training Response ◽  
Obese Zucker Rats ◽  
The Difference

Exercise training reduces the muscle insulin resistance of the obese Zucker rat. The purpose of the present study was to determine whether the magnitude of this training response is exercise intensity specific. Obese Zucker rats were randomly divided into sedentary (SED), low-intensity (LI), and high-intensity (HI) exercise groups. For the LI rats, exercise training consisted of running on a rodent treadmill at 18 m/min up an 8% grade for 90 min. Rats in the HI group ran at 24 m/min up an 8% grade for four 17-min bouts with 3 min between bouts. Both exercise groups performed the same amount of work and trained 5 days/wk for 7 wk. To evaluate muscle insulin resistance, rat hindlimbs were perfused for 30 min with perfusate containing 6 mM glucose (0.15 mu Ci of D-[14C(U)] glucose/ml) and either a maximal (10.0 mU/ml) or a submaximal (0.50 mU/ml) insulin concentration. Perfusions were performed 48–56 h after the last exercise bout and a 12-h fast. In the presence of 0.5 mU/ml insulin, the rate of muscle glucose uptake was found to be significantly faster for the HI (9.56 +/- 0.66 mumol.h-1.g-1) than for the LI (7.72 +/- 0.65 mumol.h-1.g-1) and SED (6.64 +/- 0.44 mumol.h-1.g-1) rats. The difference in glucose uptake between the LI and SED rats was not significant. In the presence of 10.0 mU/ml insulin, the rate of glucose uptake was significantly faster for the HI (16.43 +/- 1.02 mumol.h-1.g-1) than for the LI rats (13.76 +/- 0.84 mumol.h-1.g-1) and significantly faster for the LI than for the SED rats (11.02 +/- 0.35 mumol.h-1.g-1).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

Effect of insulin and contraction on glycogen synthase phosphorylation and kinetic properties in epitrochlearis muscles from lean and obese Zucker rats

2012 ◽  
Vol 302 (10) ◽  
pp. C1539-C1547 ◽  
Author(s):  
Fang Chin Lin ◽  
Astrid Bolling ◽  
Jorid T. Stuenæs ◽  
Kristoffer T. Cumming ◽  
Ada Ingvaldsen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Glycogen Synthase ◽  
Zucker Rats ◽  
Kinetic Properties ◽  
Physiological Concentration ◽  
Obese Rats ◽  
Obese Zucker Rats

In the present study, the effects of insulin and contraction on glycogen synthase (GS) kinetic properties and phosphorylation were investigated in epitrochlearis muscles from lean and obese Zucker rats. Total GS activity and protein expression were ∼15% lower in epitrochlearis from obese rats compared with lean rats. Insulin-stimulated GS fractional activity and affinity for UDP-glucose were lower (higher Km) in muscles from obese rats. GS Ser641 and Ser645,649,653,657 phosphorylation was higher in insulin-stimulated muscles from obese rats, which agreed with lower GS activation. Contraction-mediated GS dephosphorylation of Ser641, Ser641+645, Ser645,649,653,657, and Ser7+10 was normal in muscles from obese Zucker rats, and GS fractional activity increased to similar levels in epitrochlearis muscles from lean and obese rats. GS affinity for UDP glucose was ∼0.8, ∼0.4, and ∼0.1 mM with assay buffers containing 0, 0.17, and 12 mM glucose 6-phosphate, respectively. Contraction increased affinity for UDP-glucose (reduced Km) at a physiological concentration of glucose 6-phosphate (0.17 mM) to ∼0.2 mM in muscles from both lean and obese rats. Interestingly, in the absence of glucose 6-phosphate in the assay buffer, contraction (and insulin) did not influence GS affinity for UDP-glucose, indicating that affinity is regulated by sensitivity for glucose 6-phosphate. In conclusion, contraction-mediated activation and dephosphorylation of GS were normal in muscles from obese Zucker rats, whereas insulin-mediated GS activation and dephosphorylation were impaired.

scholarly journals Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

1984 ◽  
Vol 221 (3) ◽  
pp. 915-917 ◽  
Author(s):  
R A Challis ◽  
L Budohoski ◽  
B McManus ◽  
E A Newsholme
Keyword(s):  
Insulin Resistance ◽  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Zucker Rats ◽  
Adenosine Receptor Antagonist ◽  
Obese Rats ◽  
Obese Zucker Rats

The decreased sensitivity of glycolysis to insulin seen in isolated soleus muscles from genetically obese Zucker rats was abolished by addition of the adenosine-receptor antagonist 8-phenyltheophylline to the incubation medium; 8-phenyltheophylline had no effect on the sensitivity of glycogen synthesis to insulin. These findings suggest that changes in the sensitivity of glucose utilization by muscles of genetically obese rats may be explained, in part, by a modification in either the concentration of adenosine or the affinity of adenosine receptors in skeletal muscle.

scholarly journals Obesity-induced discrepancy between contractile and metabolic phenotypes in slow- and fast-twitch skeletal muscles of female obese Zucker rats

2017 ◽  
Vol 123 (1) ◽  
pp. 249-259 ◽  
Author(s):  
Luz M. Acevedo ◽  
Ana I. Raya ◽  
Rafael Ríos ◽  
Escolástico Aguilera-Tejero ◽  
José-Luis L. Rivero
Keyword(s):  
Muscle Mass ◽  
Skeletal Muscles ◽  
Fiber Type ◽  
Succinic Dehydrogenase ◽  
Zucker Rats ◽  
Fiber Types ◽  
Type Composition ◽  
Obese Zucker Rats ◽  
And Function ◽  
Fast Twitch

A clear picture of skeletal muscle adaptations to obesity and related comorbidities remains elusive. This study describes fiber-type characteristics (size, proportions, and oxidative enzyme activity) in two typical hindlimb muscles with opposite structure and function in an animal model of genetic obesity. Lesser fiber diameter, fiber-type composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of muscle fiber types were assessed in slow (soleus)- and fast (tibialis cranialis)-twitch muscles of obese Zucker rats and compared with age (16 wk)- and sex (females)-matched lean Zucker rats ( n = 16/group). Muscle mass and lesser fiber diameter were lower in both muscle types of obese compared with lean animals even though body weights were increased in the obese cohort. A faster fiber-type phenotype also occurred in slow- and fast-twitch muscles of obese rats compared with lean rats. These adaptations were accompanied by a significant increment in histochemical succinic dehydrogenase activity of slow-twitch fibers in the soleus muscle and fast-twitch fiber types in the tibialis cranialis muscle. Obesity significantly increased plasma levels of proinflammatory cytokines but did not significantly affect protein levels of peroxisome proliferator-activated receptors PPARγ or PGC1α in either muscle. These data demonstrate that, in female Zucker rats, obesity induces a reduction of muscle mass in which skeletal muscles show a diminished fiber size and a faster and more oxidative phenotype. It was noteworthy that this discrepancy in muscle's contractile and metabolic features was of comparable nature and extent in muscles with different fiber-type composition and antagonist functions. NEW & NOTEWORTHY This study demonstrates a discrepancy between morphological (reduced muscle mass), contractile (shift toward a faster phenotype), and metabolic (increased mitochondrial oxidative enzyme activity) characteristics in skeletal muscles of female Zucker fatty rats. It is noteworthy that this inconsistency was comparable (in nature and extent) in muscles with different structure and function.

Effects of clenbuterol on insulin resistance in conscious obese Zucker rats

2001 ◽  
Vol 280 (4) ◽  
pp. E554-E561 ◽  
Author(s):  
Shujia J. Pan ◽  
Joe Hancock ◽  
Zhenping Ding ◽  
Donovan Fogt ◽  
Mancheong Lee ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Chronic Administration ◽  
Abdominal Fat ◽  
Zucker Rats ◽  
Control Group ◽  
Obese Zucker Rats ◽  
Long Acting

The present study was conducted to determine the effect of chronic administration of the long-acting β2-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats ( fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin · kg−1 · min−1) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.

Sign in / Sign up

Export Citation Format

Share Document