scholarly journals Activation of the Hexosamine Signaling Pathway in Adipose Tissue Results in Decreased Serum Adiponectin and Skeletal Muscle Insulin Resistance

Endocrinology ◽  
2004 ◽  
Vol 145 (5) ◽  
pp. 2118-2128 ◽  
Author(s):  
Mark Hazel ◽  
Robert C. Cooksey ◽  
Deborah Jones ◽  
Glendon Parker ◽  
John L. Neidigh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
Serum Adiponectin ◽  
Glucose Disposal ◽  
Mrna Levels ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

Abstract Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and β-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-d-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNFα and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor γ decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.

scholarly journals Irisin and Myonectin Regulation in the Insulin Resistant Muscle: Implications to Adipose Tissue: Muscle Crosstalk

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Luis Gamas ◽  
Paulo Matafome ◽  
Raquel Seiça
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Current Knowledge ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Vicious Cycle ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

Myokines are peptides produced and secreted by the skeletal muscle, with autocrine, paracrine, and endocrine actions. Many of them are overexpressed during physical exercise and appear to contribute to the benefits of exercise to metabolic homeostasis. Irisin, resulting from the cleavage of the membrane protein FNDC5, was shown to induce adipocyte browning, with increased lipid oxidation and thermogenesis. Myonectin was only recently discovered and initial studies revealed a role in fatty acid uptake and oxidation in adipose tissue and liver. However, the mechanisms of their regulation by exercise are not entirely established. Impaired secretion and action of myokines, such as irisin and myonectin, may have a role in the establishment of insulin resistance. On the other hand, several studies have shown that insulin resistance in the skeletal muscle may change myokines expression and secretion. This may have consequences on lipid and glucose metabolism in adipose tissue and lead to a vicious cycle between impaired myokines production and insulin resistance. This review summarizes the current knowledge about the influence of skeletal muscle insulin resistance on the secretion of irisin and myonectin, as well as its impact on adipose tissue metabolism.

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.

scholarly journals Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle

2018 ◽  
Vol 314 (2) ◽  
pp. R181-R190 ◽  
Author(s):  
Jacob T. Mey ◽  
Brian K. Blackburn ◽  
Edwin R. Miranda ◽  
Alec B. Chaves ◽  
Joan Briller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Expression ◽  
Enzyme System ◽  
Vastus Lateralis ◽  
Negative Regulator ◽  
Glucose Disposal ◽  
Carbonyl Stress ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m2) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m2). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m−2·min−1)–euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (−78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (−31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

scholarly journals Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans

2010 ◽  
Vol 298 (6) ◽  
pp. E1161-E1169 ◽  
Author(s):  
Cédric Dray ◽  
Cyrille Debard ◽  
Jennifer Jager ◽  
Emmanuel Disse ◽  
Danièle Daviaud ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Receptor Expression ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
Type 2 Diabetic

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/ db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/ db mice. APJ expression was decreased in both HF-fed and db/ db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.

scholarly journals Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0154119 ◽  
Author(s):  
Cacylde Amouzou ◽  
Cyril Breuker ◽  
Odile Fabre ◽  
Annick Bourret ◽  
Karen Lambert ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Obese Women ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia

2000 ◽  
Vol 278 (3) ◽  
pp. E563-E569 ◽  
Author(s):  
Roland Buettner ◽  
Christopher B. Newgard ◽  
Christopher J. Rhodes ◽  
Robert M. O'Doherty
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Plasma Glucose ◽  
Metabolic Abnormalities ◽  
High Fat ◽  
Human Obesity ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance ◽  
Plasma Leptin

Human obesity and high fat feeding in rats are associated with the development of insulin resistance and perturbed carbohydrate and lipid metabolism. It has been proposed that these metabolic abnormalities may be reversible by interventions that increase plasma leptin. Up to now, studies in nongenetic animal models of obesity and in human obesity have concentrated on multiple injection therapy with mixed results. Our study sought to determine whether a sustained, moderate increase in plasma leptin, achieved by administration of a recombinant adenovirus containing the leptin cDNA (AdCMV-leptin) would be effective in reversing the metabolic abnormalities of the obese phenotype. Wistar rats fed a high-fat diet (HF) were heavier ( P< 0.05), had increased fat mass and intramuscular triglycerides (mTG), and had elevated plasma glucose, insulin, triglyceride, and free fatty acids compared with standard chow-fed (SC) control animals (all P < 0.01). HF rats also had impaired glucose tolerance and were markedly insulin resistant, as demonstrated by a 40% reduction in insulin-stimulated muscle glucose uptake ( P < 0.001). Increasing plasma leptin levels to 29.0 ± 1.5 ng/ml (from 7.0 ± 1.4 ng/ml, P < 0.001) for a period of 6 days decreased adipose mass by 40% and normalized plasma glucose and insulin levels. In addition, insulin-stimulated skeletal muscle glucose uptake was normalized in hyperleptinemic rats, an effect that correlated closely with a 60% ( P < 0.001) decrease in mTG. Importantly, HF rats that received a control adenovirus containing the β-galactosidase cDNA and were calorically matched to AdCMV-leptin-treated animals remained hyperglycemic, hyperinsulinemic, insulin resistant, and maintained elevated mTG. We conclude that a gene-therapeutic intervention that elevates plasma leptin moderately for a sustained period reverses diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance, and that these improvements are tightly linked to leptin-induced reductions in mTG.

scholarly journals Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans

2019 ◽  
Vol 316 (5) ◽  
pp. E866-E879 ◽  
Author(s):  
Stephan Sachs ◽  
Simona Zarini ◽  
Darcy E. Kahn ◽  
Kathleen A. Harrison ◽  
Leigh Perreault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Matrix Proteins ◽  
Muscle Insulin Resistance ◽  
Intermuscular Adipose Tissue ◽  
Skeletal Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Sensitivity

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

scholarly journals Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner

2015 ◽  
Vol 308 (8) ◽  
pp. E662-E669 ◽  
Author(s):  
Lisette A. Maddison ◽  
Kaitlin E. Joest ◽  
Ryan M. Kammeyer ◽  
Wenbiao Chen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Fasting Blood Glucose ◽  
Β Cells ◽  
Β Cell ◽  
Muscle Insulin Resistance ◽  
Insulin Resistant ◽  
Skeletal Muscle Insulin Resistance

Insulin resistance creates an environment that promotes β-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of β-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the β-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the β-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.

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