scholarly journals Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle

2012 ◽  
Vol 303 (6) ◽  
pp. E798-E805 ◽  
Author(s):  
Michael J. Boden ◽  
Amanda E. Brandon ◽  
Jennifer D. Tid-Ang ◽  
Elaine Preston ◽  
Donna Wilks ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Insulin Action ◽  
Manganese Superoxide Dismutase ◽  
Whole Body ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Manganese Superoxide

Elevated mitochondrial reactive oxygen species have been suggested to play a causative role in some forms of muscle insulin resistance. However, the extent of their involvement in the development of diet-induced insulin resistance remains unclear. To investigate, manganese superoxide dismutase (MnSOD), a key mitochondrial-specific enzyme with antioxidant modality, was overexpressed, and the effect on in vivo muscle insulin resistance induced by a high-fat (HF) diet in rats was evaluated. Male Wistar rats were maintained on chow or HF diet. After 3 wk, in vivo electroporation (IVE) of MnSOD expression and empty vectors was undertaken in right and left tibialis cranialis (TC) muscles, respectively. After one more week, insulin action was evaluated using hyperinsulinemic euglycemic clamp, and tissues were subsequently analyzed for antioxidant enzyme capacity and markers of oxidative stress. MnSOD mRNA was overexpressed 4.5-fold, and protein levels were increased by 70%, with protein detected primarily in the mitochondrial fraction of muscle fibers. This was associated with elevated MnSOD and glutathione peroxidase activity, indicating that the overexpressed MnSOD was functionally active. The HF diet significantly reduced whole body and TC muscle insulin action, whereas overexpression of MnSOD in HF diet animals ameliorated this reduction in TC muscle glucose uptake by 50% ( P < 0.05). Decreased protein carbonylation was seen in MnSOD overexpressing TC muscle in HF-treated animals (20% vs. contralateral control leg, P < 0.05), suggesting that this effect was mediated through an altered redox state. Thus interventions causing elevation of mitochondrial antioxidant activity may offer protection against diet-induced insulin resistance in skeletal muscle.

scholarly journals Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3158-3164 ◽  
Author(s):  
Bronwyn D. Hegarty ◽  
Stuart M. Furler ◽  
Nicholas D. Oakes ◽  
Edward W. Kraegen ◽  
Gregory J. Cooney
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
High Fat

Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P &lt; 0.01). This improvement in insulin action was associated with decreased diglyceride (P &lt; 0.05) and long chain acyl coenzyme A (P &lt; 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P &lt; 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P &lt; 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats

2001 ◽  
Vol 281 (1) ◽  
pp. E62-E71 ◽  
Author(s):  
Charles Lavigne ◽  
Frédéric Tremblay ◽  
Geneviève Asselin ◽  
Hélène Jacques ◽  
André Marette
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Amino Acids ◽  
Glucose Uptake ◽  
Soy Protein ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-d-[3H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-α in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.

Abstract T P114: Insulin Resistance in Skeletal Muscle of Chronic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alice S Ryan ◽  
Heidi Ortmeyer ◽  
Frederick Ivey ◽  
Charlene Hafer-Macko
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Chronic Stroke ◽  
Whole Body ◽  
Wide Range

Risk of glucose intolerance and diabetes increases in chronic stroke. The purpose of this study was to assess insulin sensitivity and glycogen synthase (GS), a known benchmark index of insulin action in skeletal muscle, and to compare the activity of this important regulatory enzyme between paretic (P) and non-paretic (NP) skeletal muscle in chronic stroke. We measured insulin sensitivity (M) and bilateral GS fractional activity (ratio of independent to total activity), in lyophilized microdissected muscle samples obtained after an overnight fast and 2 hrs into a 3-hr 80 mU . m -2. min -1 hyperinsulinemic-euglycemic clamp in 21 stroke survivors (n=15 men, n=6 women) (age: 59±2 yrs, BMI: 31±2 kg/m 2 , X±SEM). All had hemiparetic gait after ischemic stroke (>6 months), low aerobic capacity (VO 2 peak, 19.7±1.3 ml/kg/min), and wide range of %body fat (11-48%). Leg lean mass was lower in P than NP (9.3±0.5 vs. 10.0±0.5 kg, P<0.001). Subjects had either normal glucose tolerance (n=7), impaired glucose tolerance (n=7), or diabetes (n=7) and insulin resistance (M: 38.5±2.6 umol/kgFFM/min). Insulin robustly increased GS fractional activity (basal vs. insulin) in P (2.8±0.4 vs.7.5±0.8%, P<0.00001) and NP (2.7±0.4 vs. 9.1±1.1%, P<0.00001) muscle. The %change was greater in NP than P (213±32 vs. 296±36%, P=0.04). The effect of in vivo insulin to increase GS fractional activity was associated with M in P and NP muscle (r=0.59 and r=0.49, P<0.05). In conclusion, muscle atrophy and a reduction in insulin action in paretic muscle likely contribute to whole body insulin resistance in chronic stroke.

A potent in vivo effect of ciglitazone on muscle insulin resistance induced by high fat feeding of rats

Metabolism ◽  
1989 ◽  
Vol 38 (11) ◽  
pp. 1089-1093 ◽  
Author(s):  
E.W. Kraegen ◽  
D.E. James ◽  
A.B. Jenkins ◽  
D.J. Chisholm ◽  
L.H. Storlien
Keyword(s):  
Insulin Resistance ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Fat Feeding

scholarly journals Modeling insulin resistance in rodents by alterations in diet: what have high-fat and high-calorie diets revealed?

2018 ◽  
Vol 314 (3) ◽  
pp. E251-E265 ◽  
Author(s):  
Lewin Small ◽  
Amanda E. Brandon ◽  
Nigel Turner ◽  
Gregory J. Cooney
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Insulin Action ◽  
Whole Body ◽  
Dietary Energy ◽  
High Fat ◽  
Large Heterogeneity ◽  
Simple Carbohydrates ◽  
Almost All ◽  
High Calorie

For over half a century, researchers have been feeding different diets to rodents to examine the effects of macronutrients on whole body and tissue insulin action. During this period, the number of different diets and the source of macronutrients employed have grown dramatically. Because of the large heterogeneity in both the source and percentage of different macronutrients used for studies, it is not surprising that different high-calorie diets do not produce the same changes in insulin action. Despite this, diverse high-calorie diets continue to be employed in an attempt to generate a “generic” insulin resistance. The high-fat diet in particular varies greatly between studies with regard to the source, complexity, and ratio of dietary fat, carbohydrate, and protein. This review examines the range of rodent dietary models and methods for assessing insulin action. In almost all studies reviewed, rodents fed diets that had more than 45% of dietary energy as fat or simple carbohydrates had reduced whole body insulin action compared with chow. However, different high-calorie diets produced significantly different effects in liver, muscle, and whole body insulin action when insulin action was measured by the hyperinsulinemic-euglycemic clamp method. Rodent dietary models remain an important tool for exploring potential mechanisms of insulin resistance, but more attention needs to be given to the total macronutrient content and composition when interpreting dietary effects on insulin action.

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