Placental Restriction Reduces Insulin Sensitivity and Expression of Insulin Signaling and Glucose Transporter Genes in Skeletal Muscle, But Not Liver, in Young Sheep

Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (−43%, P < 0.001) and skeletal muscle expression of INSR (−36%), IRS1 (−28%), AKT2 (−44%), GLUT4 (−88%), GSK3α (−35%), and GYS1 (−31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.

Download Full-text

Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

10.21203/rs.3.rs-37586/v1 ◽

2020 ◽

Author(s):

Feifan Guo ◽

Yuguo Niu ◽

Haizhou Jiang ◽

Hanrui Yin ◽

Fenfen Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Neutralizing Antibodies ◽

Leptin Receptor ◽

Whole Body ◽

C2c12 Myotubes ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Sensitivity ◽

Pka Pathway

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.

Download Full-text

Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01185.2009 ◽

2011 ◽

Vol 300 (5) ◽

pp. H1637-H1644 ◽

Cited By ~ 34

Author(s):

Yukihiro Ohta ◽

Shintaro Kinugawa ◽

Shouji Matsushima ◽

Taisuke Ono ◽

Mochamad A. Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Diastolic Pressure ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Glucose Transporter 4

Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) ( 30 ). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

Download Full-text

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.

Download Full-text

(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. E503-E514 ◽

Cited By ~ 23

Author(s):

Arata Fukushima ◽

Shintaro Kinugawa ◽

Shingo Takada ◽

Shouji Matsushima ◽

Mochamad Ali Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Superoxide Production

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg−1·day−1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

Download Full-text

SUN-670 P300 and CBP Are Necessary for Skeletal Muscle Insulin-Stimulated Glucose Uptake

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1496 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Vitor Fernandes Martins ◽

Samuel LaBarge ◽

Kristoffer Svensson ◽

Jennifer M Cunliffe ◽

Dion Banoian ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Uptake ◽

Ex Vivo ◽

Binding Protein ◽

Whole Body ◽

Oral Glucose ◽

Skeletal Muscle Insulin Sensitivity

Abstract Introduction: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. Methods: We used Cre-LoxP methodology to generate mice with a tamoxifen-inducible, conditional knock out of Ep300 and/or Crebbp in skeletal muscle. At 13-15 weeks of age, the knockout was induced via oral gavage of tamoxifen and oral glucose tolerance, ex vivo skeletal muscle insulin sensitivity, and microarray and proteomics analysis were done. Results: Loss of both p300 and CBP in adult mouse skeletal muscle rapidly and severely impairs whole body glucose tolerance and skeletal muscle insulin sensitivity. Furthermore, giving back a single allele of either p300 or CBP rescues both phenotypes. Moreover, the severe insulin resistance in the p300/CBP double knockout mice is accompanied by significant changes in both mRNA and protein expression of transcript/protein networks critical for insulin signaling, GLUT4 trafficking, and metabolism. Lastly, in human skeletal muscle samples, p300 and CBP protein levels correlate significantly and negatively with markers of insulin resistance. Conclusions: p300 and CBP are jointly required for maintaining whole body glucose tolerance and insulin sensitivity in skeletal muscle.

Download Full-text

Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00448.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. R137-R142 ◽

Cited By ~ 19

Author(s):

Elizabeth M. Marchionne ◽

Maggie K. Diamond-Stanic ◽

Mujalin Prasonnarong ◽

Erik J. Henriksen

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Transport ◽

Insulin Action ◽

Whole Body ◽

Zucker Rats ◽

Obese Zucker Rats ◽

Renin Inhibition

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker ( fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser473 phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Download Full-text

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 ◽

10.1210/en.2004-0260 ◽

2004 ◽

Vol 145 (7) ◽

pp. 3158-3164 ◽

Cited By ~ 54

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 < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 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.

Download Full-text

Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

Journal of Endocrinology ◽

10.1677/joe-08-0534 ◽

2009 ◽

Vol 201 (1) ◽

pp. 49-58 ◽

Cited By ~ 11

Author(s):

Camilla Alexanderson ◽

Elias Eriksson ◽

Elisabet Stener-Victorin ◽

Malin Lönn ◽

Agneta Holmäng

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Uncoupling Protein ◽

Female Rats ◽

Whole Body ◽

Low Grade ◽

Expression Of Genes ◽

Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

Download Full-text

Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.5.e816 ◽

2001 ◽

Vol 280 (5) ◽

pp. E816-E824 ◽

Cited By ~ 45

Author(s):

Akira Oku ◽

Masao Nawano ◽

Kiichiro Ueta ◽

Takuya Fujita ◽

Itsuro Umebayashi ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Protein Kinase ◽

Insulin Receptor ◽

Soleus Muscle ◽

Insulin Signaling ◽

Skeletal Muscles ◽

Glucose Transporter ◽

Protein Kinase B ◽

Diabetic Rats

To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na+-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.

Download Full-text

Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle

AJP Advances in Physiology Education ◽

10.1152/advan.00080.2014 ◽

2014 ◽

Vol 38 (4) ◽

pp. 308-314 ◽

Cited By ~ 95

Author(s):

Kristin I. Stanford ◽

Laurie J. Goodyear

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Whole Body ◽

Metabolic Genes ◽

Increase Glucose Uptake ◽

Glucose Transporter Proteins

Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial function, increases mitochondrial biogenesis, and increases the expression of glucose transporter proteins and numerous metabolic genes. This review focuses on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle.

Download Full-text