Myocardial insulin resistance does not always parallel skeletal muscle and whole body insulin resistance: A mini review&lt;br&gt;—Myocardial Insulin Resistance &lt;br&gt;

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.1.e62 ◽

2001 ◽

Vol 281 (1) ◽

pp. E62-E71 ◽

Cited By ~ 96

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.

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MON-647 Mechanisms of Insulin Resistance in Skeletal Muscle in Women with PCOS

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.773 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Alba Moreno-Asso ◽

Luke C McIlvenna ◽

Rhiannon K Patten ◽

Andrew J McAinch ◽

Raymond J Rodgers ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Reproductive Age ◽

Whole Body ◽

Dependent Manner ◽

Cultured Myotubes ◽

Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.

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Prolonged suppression of glucose metabolism causes insulin resistance in rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.272.2.e288 ◽

1997 ◽

Vol 272 (2) ◽

pp. E288-E296 ◽

Cited By ~ 6

Author(s):

J. K. Kim ◽

J. H. Youn

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Skeletal Muscles ◽

Glycogen Synthesis ◽

Whole Body ◽

Metabolic Fluxes ◽

Phosphate Inhibition ◽

Intracellular Glucose

To determine whether an impairment of intracellular glucose metabolism causes insulin resistance, we examined the effects of suppression of glycolysis or glycogen synthesis on whole body and skeletal muscle insulin-stimulated glucose uptake during 450-min hyperinsulinemic euglycemic clamps in conscious rats. After the initial 150 min to attain steady-state insulin action, animals received an additional infusion of saline, Intralipid and heparin (to suppress glycolysis), or amylin (to suppress glycogen synthesis) for up to 300 min. Insulin-stimulated whole body glucose fluxes were constant with saline infusion (n = 7). In contrast, Intralipid infusion (n = 7) suppressed glycolysis by approximately 32%, and amylin infusion (n = 7) suppressed glycogen synthesis by approximately 45% within 30 min after the start of the infusions (P < 0.05). The suppression of metabolic fluxes increased muscle glucose 6-phosphate levels (P < 0.05), but this did not immediately affect insulin-stimulated glucose uptake due to compensatory increases in other metabolic fluxes. Insulin-stimulated whole body glucose uptake started to decrease at approximately 60 min and was significantly decreased by approximately 30% at the end of clamps (P < 0.05). Similar patterns of changes in insulin-stimulated glucose fluxes were observed in individual skeletal muscles. Thus the suppression of intracellular glucose metabolism caused decreases in insulin-stimulated glucose uptake through a cellular adaptive mechanism in response to a prolonged elevation of glucose 6-phosphate rather than the classic mechanism involving glucose 6-phosphate inhibition of hexokinase.

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A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle

Journal of Diabetes Research ◽

10.1155/2016/6934937 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

R. W. A. Mackenzie ◽

P. Watt

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Control ◽

Direct Action ◽

Acute Hypoxia ◽

Whole Body ◽

Glucose Disposal ◽

Hypoxic Exposure ◽

Obstructive Sleep

Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control.

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Altered Skeletal Muscle Fiber Composition and Size Precede Whole-Body Insulin Resistance in Young Men with Low Birth Weight

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2360 ◽

2007 ◽

Vol 92 (4) ◽

pp. 1530-1534 ◽

Cited By ~ 93

Author(s):

Christine B. Jensen ◽

Heidi Storgaard ◽

Sten Madsbad ◽

Erik A. Richter ◽

Allan A. Vaag

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Birth Weight ◽

Capillary Density ◽

Whole Body ◽

Type I ◽

Normal Birth ◽

Fiber Composition ◽

Type I Fibers

Abstract Context: Low birth weight (LBW), a surrogate marker of an adverse fetal milieu, is linked to muscle insulin resistance, impaired insulin-stimulated glycolysis, and future risk of type 2 diabetes. Skeletal muscle mass, fiber composition, and capillary density are important determinants of muscle function and metabolism, and alterations have been implicated in the pathogenesis of insulin resistance. Objective: The aim of this study was to investigate whether an adverse fetal environment (LBW) induces permanent changes in skeletal muscle morphology, which may contribute to the dysmetabolic phenotype associated with LBW. Design and Subjects: Vastus lateralis muscle was obtained by percutaneous biopsy from 20 healthy 19-yr-old men with birth weights at 10th percentile or lower for gestational age (LBW) and 20 normal birth weight controls, matched for body fat, physical fitness, and whole-body glucose disposal. Myofibrillar ATPase staining was used to classify muscle fibers as type I, IIa, and IIx (formerly type IIb), and double immunostaining was performed to stain capillaries (LBW, n = 8; normal birth weight, n = 12). Results: LBW was associated with increased proportion of type IIx fibers (+66%; P = 0.03), at the expense of decreased type IIa fibers (−22%; P = 0.003). No significant change was observed in proportion of type I fibers (+16%; P = 0.11). In addition, mean area of type IIa fibers was increased (+29%; P = 0.01) and tended to be increased for type I fibers as well (+17%; P = 0.08). Capillary density was not significantly different between groups. Conclusion: Alterations in fiber composition and size may contribute to development of type 2 diabetes in individuals with LBW.

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Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00108.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. R290-R297 ◽

Cited By ~ 5

Author(s):

K. M. Fanning ◽

B. Pfisterer ◽

A. T. Davis ◽

T. D. Presley ◽

I. M. Williams ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Radiation Exposure ◽

Microvascular Density ◽

Whole Body ◽

Ecm Remodeling

Radiation exposure accelerates the onset of age-related diseases such as diabetes, cardiovascular disease, and neoplasia and, thus, lends insight into in vivo mechanisms common to these disorders. Fibrosis and extracellular matrix (ECM) remodeling, which occur with aging and overnutrition and following irradiation, are risk factors for development of type 2 diabetes mellitus. We previously demonstrated an increased incidence of skeletal muscle insulin resistance and type 2 diabetes mellitus in monkeys that had been exposed to whole body irradiation 5–9 yr prior. We hypothesized that irradiation-induced fibrosis alters muscle architecture, predisposing irradiated animals to insulin resistance and overt diabetes. Rhesus macaques ( Macaca mulatta, n = 7–8/group) grouped as nonirradiated age-matched controls (Non-Rad-CTL), irradiated nondiabetic monkeys (Rad-CTL), and irradiated monkeys that subsequently developed diabetes (Rad-DM) were compared. Prior radiation exposure resulted in persistent skeletal muscle ECM changes, including a relative overabundance of collagen IV and a trend toward increased transforming growth factor-β1. Preservation of microvascular markers differentiated the irradiated diabetic and nondiabetic groups. Microvascular density and plasma nitrate and heat shock protein 90 levels were lower in Rad-DM than Rad-CTL. These results are consistent with a protective effect of abundant microvasculature in maintaining glycemic control within radiation-induced fibrotic muscle.

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Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2012-0266 ◽

2013 ◽

Vol 38 (5) ◽

pp. 512-519 ◽

Cited By ~ 8

Author(s):

Andrea S. Cornford ◽

Alexander Hinko ◽

Rachael K. Nelson ◽

Ariel L. Barkan ◽

Jeffrey F. Horowitz

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Lipid Accumulation ◽

Rapid Development ◽

Insulin Response ◽

Whole Body ◽

Muscle Lipid ◽

Wet Weight

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

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Aging is associated with myocardial insulin resistance and mitochondrial dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00163.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. H3063-H3071 ◽

Cited By ~ 20

Author(s):

Siva Bhashyam ◽

Pratik Parikh ◽

Hakki Bolukoglu ◽

Alexander H. Shannon ◽

James H. Porter ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Insulin Action ◽

Left Ventricular ◽

Whole Body ◽

Acid Uptake ◽

Nonesterified Fatty Acids ◽

Left Circumflex Artery ◽

Mitochondrial Structure ◽

Myocardial Insulin Resistance

Aging is associated with insulin resistance, often attributable to obesity and inactivity. Recent evidence suggests that skeletal muscle insulin resistance in aging is associated with mitochondrial alterations. Whether this is true of the senescent myocardium is unknown. Twelve young (Y, 4 years old) and 12 old (O, 11 years old) dogs, matched for body mass, were instrumented with left-ventricular pressure gauges, aortic and coronary sinus catheters, and flow probes on left circumflex artery. Before surgery, all dogs participated in a 6-wk exercise program. Dogs underwent measurements of hemodynamics and plasma substrates before and during a 2-h hyperinsulinemic-euglycemic clamp to measure whole body and myocardial glucose and nonesterified fatty acid uptake. Following the protocol, myocardial and skeletal samples were obtained to measure components of the insulin-signaling cascade and mitochondrial structure. There was no difference in plasma glucose (Y, 90 ± 4 mg/dl; O, 87 ± 4 mg/dl), but old dogs had higher ( P < 0.02) nonesterified fatty acids (Y, 384 ± 48 μmol/l; O, 952 ± 97 μmol/l) and plasma insulin (Y, 39 ± 11 pmol/l; O, 108 ± 18 pmol/l). Old dogs had impaired total body glucose disposition (Y, 11.5 ± 1 mg·kg−1·min−1; O, 8.0 ± 0.5 mg·kg−1·min−1; P < 0.05) and insulin-stimulated myocardial glucose uptake (Y, 3.5 ± 0.3mg·min−1·g−1; O, 1.8 ± 0.3 mg·min−1·g−1; P < 0.05). The impaired insulin action was associated with altered insulin signaling and glucose transporter (GLUT4) translocation. There were myocardial mitochondrial structural changes observed in association with decreased expression of uncoupling protein-3. Aging is associated with both whole body and myocardial insulin resistance, independent of obesity and inactivity, but involving altered mitochondrial structure and impaired cellular insulin action.

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Improvement of insulin sensitivity by antagonism of the renin-angiotensin system

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00147.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R974-R980 ◽

Cited By ~ 80

Author(s):

Erik J. Henriksen

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Transport ◽

Renin Angiotensin System ◽

Whole Body ◽

Ang Ii ◽

Angiotensin System ◽

Skeletal Muscle Insulin Resistance

The reduced capacity of insulin to stimulate glucose transport into skeletal muscle, termed insulin resistance, is a primary defect leading to the development of prediabetes and overt type 2 diabetes. Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) produced from this system can act on ANG II type 1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of reactive oxygen species (ROS). Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole body and skeletal muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. Collectively, these findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with prediabetes and type 2 diabetes.

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