MicroRNA-106b regulates skeletal muscle insulin sensitivity and glucose homeostasis by targeting mitofusion-2

Several studies showed an increased risk for diabetes with statin treatment. PGC-1α is an important regulator of muscle energy metabolism and mitochondrial biogenesis. Since statins impair skeletal muscle PGC-1α expression and reduced PGC-1α expression has been observed in diabetic patients, we investigated the possibility that skeletal muscle PGC1α expression influences the effect of simvastatin on muscle glucose metabolism. Mice with muscle PGC-1α knockout (KO) or PGC-1α overexpression (OE), and wild-type (WT) mice were investigated. Mice were treated orally for 3 weeks with simvastatin (5 mg/kg/day) and investigated by intraperitoneal glucose tolerance (iGTT), in vivo skeletal muscle glucose uptake, muscle glycogen content, and Glut4 and hexokinase mRNA and protein expression. Simvastatin impaired glucose metabolism in WT mice, as manifested by increased glucose blood concentrations during the iGTT, decreased skeletal muscle glucose uptake and glycogen stores. KO mice showed impaired glucose homeostasis with increased blood glucose concentrations during the iGTT already without simvastatin treatment and simvastatin induced a decrease in skeletal muscle glucose uptake. In OE mice, simvastatin treatment increased blood glucose and insulin concentrations during the iGTT, and increased skeletal muscle glucose uptake, glycogen stores, and Glut4 and hexokinase protein expression. In conclusion, simvastatin impaired skeletal muscle insulin sensitivity in WT mice, while KO mice exhibited impaired skeletal muscle insulin sensitivity already in the absence of simvastatin. In OE mice, simvastatin augmented muscular glucose uptake but impaired whole-body insulin sensitivity. Thus, simvastatin affected glucose homeostasis depending on PGC-1α expression.

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Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans

Metabolism ◽

10.1016/j.metabol.2006.08.006 ◽

2006 ◽

Vol 55 (12) ◽

pp. 1658-1663 ◽

Cited By ~ 20

Author(s):

Dominic N. Reeds ◽

Charles A. Stuart ◽

Obed Perez ◽

Samuel Klein

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Acanthosis Nigricans ◽

Obese Subjects ◽

Skeletal Muscle Insulin Sensitivity

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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.

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Age-Related Decline of Skeletal Muscle Insulin Sensitivity in Rats: Effect of Sex and Muscle Type

Rejuvenation Research ◽

10.1089/rej.2010.1107 ◽

2011 ◽

Vol 14 (2) ◽

pp. 153-161 ◽

Cited By ~ 14

Author(s):

Yolanda Gómez-Pérez ◽

Magdalena Gianotti ◽

Ana M. Proenza ◽

Isabel Lladó

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Muscle Type ◽

Age Related ◽

Skeletal Muscle Insulin Sensitivity

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Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides

International Journal of Molecular Sciences ◽

10.3390/ijms21041514 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1514 ◽

Cited By ~ 4

Author(s):

Paul T. Reidy ◽

Ziad S. Mahmassani ◽

Alec I. McKenzie ◽

Jonathan J. Petrocelli ◽

Scott A. Summers ◽

...

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Muscle Contraction ◽

Contractile Activity ◽

Skeletal Muscle Insulin Resistance ◽

Ceramide Content ◽

Subcellular Compartmentalization ◽

Skeletal Muscle Insulin Sensitivity

Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity.

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Enhanced skeletal muscle insulin sensitivity after acute resistance-type exercise is upregulated by rapamycin-sensitive mTOR complex 1 inhibition

Scientific Reports ◽

10.1038/s41598-020-65397-z ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Kohei Kido ◽

Kohei Sase ◽

Takumi Yokokawa ◽

Satoshi Fujita

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Skeletal Muscle Insulin Sensitivity ◽

Mtor Complex 1

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Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00189.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. E124-E133 ◽

Cited By ~ 85

Author(s):

Rodrigo P. A. Barros ◽

Chiara Gabbi ◽

Andrea Morani ◽

Margaret Warner ◽

Jan-Åke Gustafsson

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

White Adipose Tissue ◽

Glucose Transporter ◽

Wild Type ◽

Glut4 Expression ◽

Glucose Challenge ◽

Fasting Hypoglycemia

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.

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Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Journal of Endocrinology ◽

10.1530/joe-13-0177 ◽

2013 ◽

Vol 219 (2) ◽

pp. 173-182 ◽

Cited By ~ 28

Author(s):

P Brandimarti ◽

J M Costa-Júnior ◽

S M Ferreira ◽

A O Protzek ◽

G J Santos ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Secretion ◽

Alternative Splicing ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Clearance ◽

Cafeteria Diet ◽

Mrna Levels ◽

Insulin Degrading Enzyme ◽

Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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