scholarly journals Skeletal Muscle-Specific CPT1 Deficiency Elevates Lipotoxic Intermediates but Preserves Insulin Sensitivity

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Wanchun Shi ◽  
Siping Hu ◽  
Wenhua Wang ◽  
Xiaohui Zhou ◽  
Wei Qiu
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Skeletal Muscles ◽  
Glucose Transporter ◽  
Tolerance Test ◽  
Acid Oxidation ◽  
Pyruvate Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Phosphorylated Akt

Objective. By specific knockout of carnitine palmitoyl transferase 1b (CPT1b) in skeletal muscles, we explored the effect of CPT1b deficiency on lipids and insulin sensitivity.Methods. Mice with specific knockout of CPT1b in skeletal muscles (CPT1b M−/−) were used for the experiment group, with littermate C57BL/6 as controls (CPT1b). General and metabolic profiles were measured and compared between groups. mRNA expression and CPT1 activity were measured in skeletal muscle tissues and compared between groups. Mitochondrial fatty acid oxidation (FAO), triglycerides (TAGs), diglycerides (DAGs), and ceramides were examined in skeletal muscles in two groups. Phosphorylated AKT (pAkt) and glucose transporter 4 (Glut4) were determined with real-time polymerase chain reaction (RT-PCR). Insulin tolerance test, glucose tolerance test, and pyruvate oxidation were performed in both groups.Results. CPT1b M−/− model was successfully established, with impaired muscle CPT1 activity. Compared with CPT1b mice, CPT1b M−/− mice had similar food intake but lower body weight or fat mass and higher lipids but similar glucose or insulin levels. Their mitochondrial FAO of skeletal muscles was impaired. There were lipids accumulations (TAGs, DAGs, and ceramides) in skeletal muscle. However, pAkt and Glut4, insulin sensitivity, glucose tolerance, and pyruvate oxidation were preserved.Conclusion. Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity.

scholarly journals Chronic Central Leptin Decreases Food Intake and Improves Glucose Tolerance in Diet-Induced Obese Mice Independent of Hypothalamic Malonyl CoA Levels and Skeletal Muscle Insulin Sensitivity

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4127-4137 ◽  
Author(s):  
Wendy Keung ◽  
Arivazhagan Palaniyappan ◽  
Gary D. Lopaschuk
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Tolerance Test ◽  
Acid Oxidation ◽  
Obese Mice ◽  
Malonyl Coa ◽  
Skeletal Muscle Insulin Sensitivity

Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice.

PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivityThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 307-314 ◽  
Author(s):  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Metabolic Effects ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Exercise Induced

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1α, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1α. Indeed, PGC-1α overexpression, like exercise training, increases exercise performance. PGC-1α reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1α mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1α overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1α, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1α was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1α-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1α overexpression, but not physiologic PGC-1α overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1α.

scholarly journals A Novel EPO Receptor Agonist Improves Glucose Tolerance via Glucose Uptake in Skeletal Muscle in a Mouse Model of Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Michael S. Scully ◽  
Tatiana A. Ort ◽  
Ian E. James ◽  
Peter J. Bugelski ◽  
Dorie A. Makropoulos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Receptor Agonist ◽  
Glucose Tolerance Test ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Class Effect ◽  
Epo Receptor ◽  
Insulin Resistant

Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of -2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-αand darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men

1991 ◽  
Vol 261 (4) ◽  
pp. E437-E443 ◽  
Author(s):  
J. A. Houmard ◽  
P. C. Egan ◽  
P. D. Neufer ◽  
J. E. Friedman ◽  
W. S. Wheeler ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Transporter ◽  
Exercise Bout ◽  
Tolerance Test ◽  
Whole Body ◽  
Oral Glucose ◽  
Middle Aged ◽  
Glut 4

Exercise training has been proposed to improve whole body insulin sensitivity through a postreceptor adaptation in skeletal muscle. This study examined if levels of the insulin-responsive muscle glucose transporter protein (GLUT-4) were associated with improved insulin sensitivity in trained vs. sedentary middle-aged individuals. Muscle GLUT-4 levels and oral glucose tolerance test (OGTT) responses were obtained in age-matched trained and sedentary men (n = 11). Plasma insulin levels during the OGTT were significantly lower (P less than 0.01) in the trained men, whereas no differences were seen in plasma glucose responses. GLUT-4 protein content was approximately twofold higher in the trained men (2.41 +/- 0.17 vs. 1.36 +/- 0.11 micrograms standard, P less than 0.001). OGTT responses and GLUT-4 levels were not altered 15-18 h after a standard exercise bout in six representative sedentary subjects. These data suggest that GLUT-4 levels are increased in conjunction with insulin sensitivity in chronically exercise-trained middle-aged men. This finding suggests a possible mechanism for the improved insulin sensitivity observed with exercise training in humans.

scholarly journals Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

2015 ◽  
Vol 309 (3) ◽  
pp. E233-E245 ◽  
Author(s):  
Stefan R. Hargett ◽  
Natalie N. Walker ◽  
Syed S. Hussain ◽  
Kyle L. Hoehn ◽  
Susanna R. Keller
Keyword(s):  
Skeletal Muscle ◽  
Cell Surface ◽  
Glucose Uptake ◽  
Skeletal Muscles ◽  
Energy Homeostasis ◽  
Glucose Transporter ◽  
Whole Body ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Male And Female

Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling.

Exercise training prevents maturation-induced decrease in insulin sensitivity

1996 ◽  
Vol 80 (6) ◽  
pp. 1963-1967 ◽  
Author(s):  
N. Nakai ◽  
Y. Shimomura ◽  
N. Ohsaki ◽  
J. Sato ◽  
Y. Oshida ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Infusion Rate ◽  
Glucose Transporter ◽  
Euglycemic Clamp ◽  
Glut 4 ◽  
Hindlimb Muscle ◽  
Female Wistar Rats ◽  
Sensitivity Improvement

We examined the effects of exercise training initiated before maturation or after maturation on insulin sensitivity and glucose transporter GLUT-4 content in membrane fractions of skeletal muscle. Female Wistar rats (4 wk of age) were divided into sedentary and exercise-trained groups. At 12 wk of age, a subset of the trained animals (Tr) was killed along with a subset of sedentary controls (Sed). One-half of the remaining sedentary animals remained sedentary (Sed-Sed) while the other half began exercise training (Sed-Tr). The remaining rats in the original trained group continued to train (Tr-Tr). Euglycemic clamp (insulin infusion rate at 6 mU.kg body wt-1. min-1) was performed at 4, 12, and 27 wk. After euglycemic clamp in all animals except the 4-wk-old, hindlimb (gastrocnemius and part of quadriceps) muscles were removed for preparation of membrane fractions. In sedentary rats, glucose infusion rate (GIR) during euglycemic clamp was decreased from 15.9 mg.kg-1.min-1 at 4 wk of age to 9.8 mg.kg-1.min-1 at 12 wk of age and 9.1 mg.kg-1.min-1 at 27 wk of age. In exercise-trained rats, the GIR was not significantly decreased by maturation (at 12 wk) and further aging (at 27 wk). Initiation of exercise after maturation restored the GIR at 27 wk of age to the same levels as these for the corresponding exercise-trained rats. GLUT-4 content in plasma and intracellular membrane fractions of hindlimb muscle obtained just after euglycemic clamp showed the same trend as the results of GIR. These results suggest that exercise training prevented the maturation-induced decrease in insulin sensitivity. Improvement of insulin sensitivity caused by exercise training was attributed, at least in part, to the increase in insulin-sensitive GLUT-4 on the plasma membrane in skeletal muscle.

scholarly journals Direct Measurements of the Permeability Surface Area for Insulin and Glucose in Human Skeletal Muscle

2003 ◽  
Vol 88 (10) ◽  
pp. 4559-4564 ◽  
Author(s):  
Soffia Gudbjörnsdóttir ◽  
Mikaela Sjöstrand ◽  
Lena Strindberg ◽  
John Wahren ◽  
Peter Lönnroth
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Tolerance ◽  
Plasma Insulin ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Permeability Surface ◽  
One Step

Abstract To elucidate mechanisms regulating capillary transport of insulin and glucose, we directly calculated the permeability surface (PS) area product for glucose and insulin in muscle. Intramuscular microdialysis in combination with the forearm model and blood flow measurements was performed in healthy males, studied during an oral glucose tolerance test or during a one-step or two-step euglycemic hyperinsulinemic clamp. PS for glucose increased significantly from 0.29 ± 0.1 to 0.64 ± 0.2 ml/min·100 g after oral glucose tolerance test, and glucose uptake increased from 1.2 ± 0.4 to 2.6 ± 0.6 μmol/min·100 g (P < 0.05). During one-step hyperinsulinemic clamp (plasma insulin, 1.962 pmol/liter), PS for glucose increased from 0.2 ± 0.1 to 2.3 ± 0.9 ml/min·100 g (P < 0.05), and glucose uptake increased from 0.6 ± 0.2 to 5.0 ± 1.4 μmol/min·100 g (P < 0.05). During the two-step clamp (plasma insulin, 1380 ± 408 and 3846 ± 348 pmol/liter), the arterial-interstitial difference and PS for insulin were constant. The PS for glucose tended to increase (P = not significant), whereas skeletal muscle blood flow increased from 4.4 ± 0.7 to 6.2 ± 0.8 ml/min·100 ml (P < 0.05). The present data show that PS for glucose is markedly increased by oral glucose, whereas a further vasodilation exerted by high insulin concentrations may not be physiologically relevant for capillary delivery of either glucose or insulin in resting muscle.

scholarly journals Beneficial Effect of Diazoxide in Obese Hyperinsulinemic Adults1

1998 ◽  
Vol 83 (6) ◽  
pp. 1911-1915 ◽  
Author(s):  
Ramin Alemzadeh ◽  
Gina Langley ◽  
Lori Upchurch ◽  
Pam Smith ◽  
Alfred E. Slonim
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Body Fat ◽  
Therapeutic Potential ◽  
Controlled Trial ◽  
Insulin Response ◽  
Tolerance Test ◽  
Fat Free Mass ◽  
Zucker Rats ◽  
Significant Difference

Hyperinsulinemia, insulin resistance, and increased adipose tissue are hallmarks of the obesity state in both humans and experimental animals. The role of hyperinsulinemia as a possible preceding event in the development of obesity has been proposed. We previously demonstrated that administration of diazoxide (DZ), an inhibitor of insulin secretion, to obese hyperinsulinemic Zucker rats resulted in less weight gain, enhanced insulin sensitivity, and improved glucose tolerance. Assuming that hyperinsulinemia plays a major role in the development of human obesity, then its reversal should have therapeutic potential. To test this hypothesis, we conducted a randomized placebo-controlled trial in 24 hyperinsulinemic adults [body mass index (BMI) > 30 kg/m2]. All subjects were placed on a low-calorie (1260 for females and 1570 for males) Optifast (Sandoz, Minneapolis, MN) diet. After an initial 1-week lead-in period, 12 subjects (mean ± se for age and BMI, 31 ± 1 and 40 ± 2, respectively) received DZ (2 mg/kg BW·day; maximum, 200 mg/day, divided into 3 doses) for 8 weeks; and 12 subjects (mean± se for age and BMI, 28 ± 1 and 43 ± 1, respectively) received placebo. Compared with the placebo group, DZ subjects had greater weight loss (9.5 ± 0.69% vs. 4.6 ± 0.61%, P < 0.001), greater decrease in body fat (P < 0.01), greater increase in fat-free mass to body fat ratio (P < 0.01), and greater attenuation of acute insulin response to glucose (P < 0.01). However, there was no significant difference in insulin sensitivity and glucose effectiveness, as determined by the insulin-modified iv glucose tolerance test (Bergman’s minimal model) and no significant difference in glycohemoglobin values. Conclusion: 8 weeks treatment with DZ had a significant antiobesity effect in hyperinsulinemic obese adults without inducing hyperglycemia.

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