Ectopic Lipid Deposition Is Associated With Insulin Resistance in Postmenopausal Women

Abstract Context Menopause is associated with an increased incidence of insulin resistance and diabetes. Objective The aim of this study was to explore the lipid deposition in liver and skeletal muscle and investigate the association with insulin sensitivity in postmenopausal and premenopausal women. Design and Setting Single-center cross-sectional study of 55 healthy women between 45 and 60 years of age. We measured lipid deposition in the liver with magnetic resonance spectroscopy, intramuscular and intra-abdominal lipid deposition with MRI, body composition with a dual-energy X-ray absorptiometry scan, and insulin sensitivity with the composite Matsuda Index. Outcome Measures We studied the association between fat distribution, ectopic lipid deposition, and insulin sensitivity in pre- and postmenopausal women. Results Postmenopausal women had an increased lipid deposition in the liver [0.68% (0.44 to 0.99) vs 0.49% (0.38 to 0.64), P = 0.01] and skeletal muscle [3% (2 to 4) vs 2% (1 to 3), P = 0.001] and had a 28% lower Matsuda insulin sensitivity index during an oral glucose tolerance test (6.31 ± 3.48 vs 8.78 ± 4.67, P = 0.05) compared with premenopausal women. Total fat mass and leg fat mass were stronger predictors of ectopic lipid deposition, and visceral fat mass was a stronger predictor of both ectopic lipid deposition and insulin resistance in postmenopausal women compared with premenopausal women. Conclusions For a given subcutaneous and visceral fat depot size, postmenopausal women show increased ectopic lipid deposition and insulin resistance compared with premenopausal women. It is suggested that lipid deposition in liver and skeletal muscle may represent important mechanistic links between the changes in fat depots and the increased incidence of insulin resistance seen after menopause.

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Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study

Acta Endocrinologica ◽

10.1530/eje.1.02065 ◽

2006 ◽

Vol 154 (1) ◽

pp. 131-139 ◽

Cited By ~ 18

Author(s):

Lenora M Camarate S M Leão ◽

Mônica Peres C Duarte ◽

Dalva Margareth B Silva ◽

Paulo Roberto V Bahia ◽

Cláudia Medina Coeli ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Postmenopausal Women ◽

Fat Mass ◽

Visceral Fat ◽

Increased Risk

Background: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. Objective: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. Design: Thirty-seven postmenopausal women aged 42–62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. Methods: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. Results: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. Conclusion: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.

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Abstract P048: A Model Of Chronic Insufficient Sleep Increases Markers Of Insulin Resistance In Postmenopausal But Not Premenopausal Women

Circulation ◽

10.1161/circ.143.suppl_1.p048 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Faris M Zuraikat ◽

Samantha Scaccia ◽

Ayanna Campbell ◽

Bin Cheng ◽

Marie-Pierre St-Onge

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Adverse Effects ◽

Postmenopausal Women ◽

Menopausal Status ◽

Premenopausal Women ◽

Full Sample ◽

Insulin Levels ◽

Short Sleep ◽

Sleep Condition

Introduction: Insufficient sleep is widely prevalent among US adults and is a risk factor for type 2 diabetes (T2D). Experimental studies show adverse effects of acute, severe short sleep on insulin sensitivity, but it is unclear whether these reflect risks associated with milder short sleep routinely observed in the general population. To date, no study has evaluated the impact of prolonged mild sleep curtailment on markers of insulin resistance in women or whether these effects differ by menopausal status, known to impact insulin sensitivity. Hypothesis: Glucose and insulin levels, as well as a measure of insulin resistance (HOMA-IR), will increase during 6 wk of sleep restriction (SR) relative to adequate sleep (AS). Adverse effects of prolonged short sleep will be exacerbated in postmenopausal women. Methods: Thirty-four women (age: 38±14 y; BMI: 25.6±3.6 kg/m2; n=10 postmenopausal) with adequate habitual total sleep time (TST) (453±33 min) took part in a randomized crossover study with two 6-wk phases: AS and SR. In AS, participants were asked to maintain stable nightly bed and wake times determined from 2 wk of screening with wrist actigraphy and sleep logs. In SR, bedtime was delayed to reduce TST by approximately 1.5 h/night. Sleep was measured continuously using actigraphy and verified weekly for compliance. At wk 0, 3, 4, and 6 fasting blood samples were collected. Outcomes included glucose and insulin levels as well as HOMA-IR scores, calculated from those values. Linear-mixed models tested interactions of sleep condition with week on outcome measures in the full sample and by menopausal status. Results: Sleep condition impacted the change in TST from baseline (P<0.0001), which was reduced in SR and unchanged in AS (-79±6 vs -4±6min). In the full sample, there was no sleep condition by week interactions for glucose (P=0.67), insulin (P=0.14), or HOMA-IR (P=0.16). Similar results were observed in premenopausal women (all P>0.50). However, in postmenopausal women, there was a significant effect of sleep condition on change in insulin (P=0.046) and HOMA-IR (P=0.039) over the 6 wk. In SR, insulin (slope: 0.26±0.28 μU/mL) and HOMA-IR (slope: 0.07±0.08) increased, while AS resulted in reductions in these outcomes (insulin slope: -0.56±0.29 μU/mL; HOMA-IR slope: -0.16±0.08). Conclusions: We provide the first evidence that chronic short sleep, even if mild, adversely affects insulin sensitivity in postmenopausal women. In contrast, maintenance of AS may improve glycemic regulation. Interestingly, prolonged short sleep did not impact markers of insulin resistance in premenopausal women; further investigation into these life-stage related differences, including underlying mechanisms, is warranted. Results suggest that, in postmenopausal women, a group at heightened risk of poor sleep and T2D, achieving adequate sleep may be an effective strategy to improve cardiometabolic health.

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Green tea polyphenols ameliorate metabolic abnormalities and insulin resistance by enhancing insulin signalling in skeletal muscle of Zucker fatty rats

Clinical Science ◽

10.1042/cs20200107 ◽

2020 ◽

Vol 134 (10) ◽

pp. 1167-1180

Author(s):

Jing Cheng ◽

Yi Tan ◽

Jiong Zhou ◽

Linda Xiao ◽

Michael Johnson ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Body Weight ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Green Tea ◽

Visceral Fat ◽

Insulin Signalling ◽

Tea Polyphenols ◽

Green Tea Polyphenols

Abstract In the present study, we evaluated the metabolic effects of green tea polyphenols (GTPs) in high-fat diet (HFD) fed Zucker fatty (ZF) rats, in particular the effects of GTP on skeletal muscle insulin sensitivity. Body weight, visceral fat, glucose tolerance, lipid profiles and whole-body insulin sensitivity were measured in HFD-fed ZF rats after 8-week-treatment with GTP (200 mg/kg of body weight) or saline (5 ml/kg of body weight). Zucker lean rats were studied as controls. Ex vivo insulin-mediated muscle glucose uptake was assessed. Immunoblotting was used to evaluate the expression of key insulin signalling proteins in skeletal muscle. GTP treatment attenuated weight gain (P<0.05) and visceral fat accumulation (27.6%, P<0.05), and significantly reduced fasting serum glucose (P<0.05) and insulin (P<0.01) levels. Homoeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was lower (P<0.01) in GTP-treated animals compared with ZF controls. Moreover, insulin-stimulated glucose uptake by isolated soleus muscle was increased (P<0.05) in GTP-ZF rats compared with ZF-controls. GTP treatment attenuated the accumulation of ectopic lipids (triacyl- and diacyl-glycerols), enhanced the expression and translocation of glucose transporter-4, and decreased pSer612IRS-1 and increased pSer473Akt2 expression in skeletal muscle. These molecular changes were also associated with significantly decreased activation of the inhibitory (muscle-specific) protein kinase (PKC) isoform, PKC-θ. Taken together, the present study has shown that regular ingestion of GTP exerts a number of favourable metabolic and molecular effects in an established animal model of obesity and insulin resistance. The benefits of GTP are mediated in part by inhibiting PKC-θ and improving muscle insulin sensitivity.

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The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results

Frontiers in Nutrition ◽

10.3389/fnut.2021.694568 ◽

2021 ◽

Vol 8 ◽

Author(s):

Anouk Gijbels ◽

Inez Trouwborst ◽

Kelly M. Jardon ◽

Gabby B. Hul ◽

Els Siebelink ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Dietary Intervention ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Primary Study ◽

Sensitivity Index ◽

Tissue Specific

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism.Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes.Methods: In total, 240 overweight/obese (BMI 25 – 40 kg/m2) men and women (age 40 – 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either “No MIR/LIR,” “MIR,” “LIR,” or “combined MIR/LIR.” Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet.Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.

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Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content andMValue

Journal of Diabetes Research ◽

10.1155/2016/3684831 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Beverly S. Hong ◽

Ying Li ◽

Shuiqing Lai ◽

Juan Liu ◽

Hongyu Guan ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Lipid Content ◽

Linear Regression Analysis ◽

Fat Deposition ◽

Sensitivity Index ◽

Ectopic Fat ◽

Insulin Sensitivity Index ◽

Fat Depots

Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status.Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT), 17 with impaired glucose tolerance (IGT), and 13 with type 2 diabetes mellitus (T2DM). All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (Mvalue) and magnetic resonance imaging to measure the hepatocellular lipid content (HCL), skeletal muscle fat content including intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of tibialis anterior (ta), and soleus muscle (sol).Results. TheMvalue of NGT group was higher than those of IGT and T2DM groups (P=0.001). Participants with T2DM had the highest HCL and IMCL (ta) compared with those in NGT and IGT groups (P=0.001). TheMvalue had an inverse relationship with HCL (r=-0.789,P=0.001), IMCL (sol) (r=-0.427,P=0.002), and IMCL (ta) (r=-0.419,P=0.002). Stepwise linear regression analysis showed that HCL (standardizedβ=-0.416;P=0.001) had an independent relationship withMvalue.Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.

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Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa026 ◽

2020 ◽

Vol 4 (4) ◽

Author(s):

Riku Klén ◽

Miikka-Juhani Honka ◽

Jarna C Hannukainen ◽

Ville Huovinen ◽

Marco Bucci ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Cross Sectional Study ◽

Whole Body ◽

Sensitivity Index ◽

Model Assessment ◽

Serum Samples ◽

Euglycemic Hyperinsulinemic Clamp ◽

Cross Sectional

Abstract Purpose Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures. Material and Methods The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [18F]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment—insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI). Results WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (ρ = 0.83 vs −0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR’s or revised QUICKI’s (ρ = 0.67 vs −0.58 and 0.59; both nonsignificant) in the test dataset. Conclusion Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals.

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Abstract P250: Insulin Resistance During Pregnancy is Inversely Associated With Gynoid Fat Distribution Postpartum

Circulation ◽

10.1161/circ.137.suppl_1.p250 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Katherine H Ingram ◽

Roxanna Lopez

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Insulin Sensitivity ◽

Gestational Weight Gain ◽

Body Fat ◽

Visceral Fat ◽

Post Partum ◽

Lower Body ◽

Negatively Associated ◽

Gestational Weight

An association between abdominal adiposity and insulin resistance is well-established. Recent research indicates that subcutaneous fat accumulation in the lower body may be associated with higher levels of insulin sensitivity. Hypothesis: This pilot study tested the hypothesis that the distribution of body fat in the lower body after pregnancy is negatively associated with gestational insulin resistance. Methods: In 32 nulliparous pregnant women (age 27±4.5, BMI 29.5±7.9, 69% non-hispanic white), the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was computed from fasting glucose and insulin at 24-28 weeks gestation. Body composition was assessed at mid-gestation (18-20 weeks) and at four weeks post-partum. Total body fat was estimated via bioelectrical impedance (InBody 720) and skinfold thicknesses were measured at seven sites. Dual-energy xray absorptiometry (DXA) measures of regional fat (gynoid, visceral, and leg) were obtained post-partum only. Gestational weight gain was monitored by medical records. Partial correlation analyses were controlled for age and race and then analyses were repeated controlling for baseline (mid-gestation) body fat percent. HOMA-IR was log-transformed for normality. Results: HOMA-IR was associated with post-partum body fat ( r =0.45, p < .05) and adiposity in the trunk region ( r =0.58, 0.57 and 0.52 for DXA visceral fat, suprailiac skinfold, and abdominal skinfold, respectively, p < .01), but not with gestational weight gain ( r =.07, p = ns), DXA gynoid region ( r = 0.26, p = ns), or any other leg measure. When analyses were further controlled for baseline body fat, post-partum measures of lower-body adiposity were strongly and negatively correlated with HOMA-IR ( r = -0.66, -0.48, and -0.48 for thigh skinfold, DXA gynoid, and DXA leg, respectively, p < .05 for all). Neither DXA visceral fat ( r = .23; p = ns) nor any other post-partum fat measures were associated with HOMA-IR when controlling for baseline body fat. Conclusions: Gestational insulin resistance was negatively associated with post-partum thigh fat accumulation, independent of overall body fat. These data indicate that insulin sensitivity may be associated with the ability to store fat in the lower body and should warrant further study of subcutaneous leg fat as a metabolically “healthy” storage depot.

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Abstract P297: Reduced Fat Mass and Improved Insulin Sensitivity in Overweight Black Women after Completion of 6-month Worksite Weight Loss Program

Circulation ◽

10.1161/circ.127.suppl_12.ap297 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Benjamin M Leon ◽

Bernard V Miller ◽

Gloria Zalos ◽

Kong Y Chen ◽

Anne E Sumner ◽

...

Keyword(s):

Weight Loss ◽

Black Women ◽

Insulin Sensitivity ◽

Fat Mass ◽

Caloric Intake ◽

Mass Gain ◽

The United States ◽

Sensitivity Index ◽

Web Based ◽

Total Fat

Background: As the epidemic of obesity in the United States steadily worsens, black women are disproportionately affected. Diminished insulin sensitivity has been linked with obesity and heightened risk of subsequent type 2 diabetes (T2D) and cardiovascular disease (CVD). Hypothesis: We propose that a decrease in fat mass achievable by weight loss intervention at the worksite improves insulin sensitivity in overweight black women. Methods: Fifty-four overweight black women [age 45±10 years (mean±SD), BMI range 25.9 to 54.7 kg/m 2 ] completed a 6-month program that included web-based nutrition information and/or dietitian counseling and access to exercise rooms near their work areas. All participants were advised to reduce daily caloric intake by 500 kcal and instructed to increase daily activity by 5,000 steps, measured by pedometer, above baseline readings. The following measurements were performed: weight, total fat mass by dual-energy X-ray absorptiometry, and insulin sensitivity index (S I ) calculated from the minimal model. Repeat of all measurements was performed at 6 months. Results: Baseline S I (median 3.0 liter/mU -1 •min -1 , range 0.74 to 7.58 liter/mU -1 •min -1 , with lower values signifying insulin resistance) was negatively associated with fat mass (r= -0.584, P<0.001) independent of age. Significant reductions in weight (92.6±18.1 to 91.1±18.9 kg, P<0.01) and fat mass (40.8±12.4 to 39.4±12.6 kg, P<0.01) were determined for subjects completing the program. Reduction in fat mass following completion of the program was associated with an increase in S I (r= -0.293, P=0.032). When analyzed by tertiles of fat mass change (Figure), compared to the tertile with net fat mass gain (far left bar), the two tertiles with net fat mass loss had significantly improved insulin sensitivity (higher S I ). Conclusions: Even modest fat mass reduction in overweight non-diabetic black women with a combination of diet and exercise can improve insulin sensitivity, which has the potential to reduce or delay the onset of T2D and CVD.

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Adiponectin improves insulin sensitivity via activation of autophagic flux

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0096 ◽

2017 ◽

Vol 59 (4) ◽

pp. 339-350 ◽

Cited By ~ 18

Author(s):

Penny Ahlstrom ◽

Esther Rai ◽

Suharto Chakma ◽

Hee Ho Cho ◽

Palanivel Rengasamy ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Er Stress ◽

Western Blotting ◽

Muscle Cells ◽

Dominant Negative ◽

Skeletal Muscle Cells ◽

Dominant Negative Mutant ◽

Autophagic Flux

Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2α and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. In summary, adiponectin-induced autophagy in skeletal muscle cells alleviated HIHG-induced ER stress and insulin resistance.

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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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