Mo-W8:6 Effect of rosuvastatin on hepatic and whole body insulin sensitivity in an animal model of insulin resistance and metabolic syndrome

Kefir supplementation in rats with induced metabolic syndrome was able to lower fasting glucose, fasting insulin levels, and reduce 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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Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00606.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. E920-E929 ◽

Cited By ~ 23

Author(s):

Esben S. Buhl ◽

Thomas Korgaard Jensen ◽

Niels Jessen ◽

Betina Elfving ◽

Christian S. Buhl ◽

...

Keyword(s):

Insulin Resistance ◽

Birth Weight ◽

Insulin Sensitivity ◽

Low Birth Weight ◽

Mrna Expression ◽

Hpa Axis ◽

Whole Body ◽

Oral Glucose ◽

Red Muscle ◽

Hpa Axis Activity

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4–5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phospho enolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser473phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW ( P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion ( P < 0.05 vs. Cx), whole body insulin resistance ( P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression ( P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser473phosphorylation. The ESC treatment normalized corticosterone secretion ( P < 0.05 vs. LBW), whole body insulin sensitivity ( P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression ( P < 0.05), and red muscle PKB Ser473phosphorylation ( P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

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Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00303.2014 ◽

2014 ◽

Vol 307 (7) ◽

pp. E571-E579 ◽

Cited By ~ 9

Author(s):

Andrew M. Cheng ◽

Norma Rizzo-DeLeon ◽

Carole L. Wilson ◽

Woo Je Lee ◽

Sanshiro Tateya ◽

...

Keyword(s):

Insulin Resistance ◽

Bone Marrow ◽

Insulin Sensitivity ◽

Vascular Tissue ◽

Vascular Inflammation ◽

Physiological Role ◽

Whole Body ◽

Aortic Tissue ◽

Protective Effects ◽

Downstream Mediator

Among the pleotropic effects of endothelial nitric oxide (NO) is protection against vascular inflammation during high-fat diet (HFD) feeding. The current work investigated the role of the enzyme vasodilatory-stimulated phosphoprotein (VASP) as a downstream mediator of the anti-inflammatory effect of NO signaling in vascular tissue. Relative to mice fed a low-fat diet (LFD), levels of VASP Ser239 phosphorylation, a marker of VASP activation, were dramatically reduced in aortic tissue of mice with obesity induced by consuming a HFD. As reported previously, the effect of the HFD was associated with increased aortic inflammation, as measured by increased NF-κB-dependent gene expression, and reduced vascular insulin sensitivity (including insulin-stimulated phosphorylation of eNOS and Akt). These effects of the HFD were recapitulated by VASP knockout, implying a physiological role for VASP to constrain inflammatory signaling and thereby maintain vascular insulin sensitivity. Conversely, overexpression of VASP in endothelial cells blocked inflammation and insulin resistance induced by palmitate. The finding that transplantation of bone marrow from VASP-deficient donors into normal recipients does not recapitulate the vascular effects of whole body VASP deficiency suggests that the protective effects of this enzyme are not mediated in immune or other bone marrow-derived cells. These studies implicate VASP as a downstream mediator of the NO/cGMP pathway that is both necessary and sufficient to protect against vascular inflammation and insulin resistance. As such, this work identifies VASP as a potential therapeutic target in the treatment of obesity-related vascular dysfunction.

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Abstract 610: Ineffective Suppression of Adipocyte Lipolysis in Metabolic Syndrome: An in vivo Test for Adipocyte Insulin Resistance

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.610 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jennifer L Ford ◽

Raymond C Boston ◽

Rachel E Walker ◽

Gregory C Shearer

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Insulin Sensitivity ◽

Lipid Droplet ◽

Minimal Model ◽

Initial Rate ◽

Intravenous Glucose Tolerance Test ◽

Intravenous Glucose ◽

In Vivo Test

Background: Insulin resistance is a major contributor to metabolic syndrome, disrupting both glucose and non-esterified fatty acid (NEFA) dynamics through ineffective glucose clearance and decreased suppression of lipid droplet lipolysis. The minimal model of glucose dynamics is used for glycemic insulin sensitivity however it does not measure adipocyte insulin sensitivity, the primary determinant of plasma NEFA. An in-vivo approach to measuring adipocyte insulin sensitivity using NEFA is employed, comparing healthy and metabolic syndrome subjects. Both the models are employed to estimate insulin sensitivity and validate the NEFA approach. Objective: To test the use of NEFA kinetics to measure adipocyte insulin sensitivity compared to the glucose minimal model. Approach and results: Metabolic syndrome (n=56) and optimally healthy (n=14) subjects underwent a frequently sampled intravenous glucose tolerance test, and plasma analyzed for insulin, glucose, and NEFA. Insulin sensitivity ( S I ) and glucose effectiveness ( S G ) were calculated from the glucose minimal model. S I was 1.7 (mU/L) -1 min -1 and 0.40 (mU/L) -1 /min -1 and S G was 0.027 min -1 and 0.017 min -1 for the healthy and metabolic syndrome groups, respectively, indicating substantial glycemic insulin resistance in the latter. A model using glucose as the driver for NEFA kinetics was then applied. We found the initial rate of NEFA utilization by tissues (NU) was less, but the threshold glucose (tG) and glucose concentration required for a unit change in lipolysis inhibition ( G i ) were greater in metabolic syndrome verses healthy (NU: 0.050[0.045, 0.057] vs. 0.068[0.054, 0.086] p=0.03; tG: 6.7[6.2, 7.2] vs. 5.0[4.3, 5.9] p=0.001; G i : 0.30[0.25, 0.35] vs. 0.17[0.07, 0.27] p=0.02). No differences were found in initial rate of NEFA production or glucose utilization. Conclusion: Our results indicate that suppression of lipid-droplet lipolysis requires greater stimulus in metabolic syndrome compared to insulin sensitive adipocytes. Further, the rate of NEFA removal is less in metabolic syndrome. These results reveal components of insulin sensitivity not demonstrated by the glucose model. The NEFA model provides a measurement of adipocyte insulin sensitivity not captured by glycemic indices.

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Improvement in Insulin Sensitivity and Dyslipidemia in Protease Inhibitor-Treated Adult Male Patients After Switch to Atazanavir/Ritonavir

Journal of Investigative Medicine ◽

10.2310/jim.0b013e3181641b26 ◽

2008 ◽

Vol 56 (2) ◽

pp. 539-544 ◽

Cited By ~ 24

Author(s):

Anthony J. Busti ◽

Roger Bedimo ◽

David M. Margolis ◽

Dana S. Hardin

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Antiretroviral Therapy ◽

Insulin Dose ◽

Whole Body ◽

Euglycemic Clamp ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Fat Redistribution ◽

Male Patients

BackgroundTreatment of human immunodeficiency virus (HIV) with protease inhibitors (PIs) is associated with insulin resistance, triglyceride-rich dyslipidemia, and fat redistribution. Atazanavir (ATV), a potent once-daily PI, has been recognized for its convenience to patients, and some studies describe improved lipid metabolism. However, its effects on insulin sensitivity have not been elucidated. We conducted this study to test the hypothesis that ATV improves insulin resistance and dyslipidemia.MethodsWe prospectively studied 9 HIV-infected men with dyslipidemia (median age, 53 years; baseline triglyceride level, >200 mg/dL) on stable PI-containing antiretroviral therapy who elected to change PI therapy to ritonavir-boosted ATV therapy, dose of 300/100 mg. We measured insulin resistance at baseline and after 12 weeks of therapy using a hyperinsulinemic euglycemic clamp (insulin dose, 200 mU/m2 minute). Fasting lipid profiles and body composition (whole-body dual energy x-ray absorptiometry) were also measured at baseline and after 12 weeks.ResultsAll 9 patients completed the study and maintained undetectable viral loads (<50 copies/mL) and stable CD4 counts. After 12 weeks, insulin sensitivity significantly improved (+28%; P = 0.008) in all patients. Triglyceride levels also improved.ConclusionsUsing the gold-standard euglycemic clamp, ritonavir-boosted ATV therapy improved PI-induced insulin resistance among dyslipidemic HIV-infected men on PI-based antiretroviral therapy. These findings were not attributable to a change in body weight and provide further evidence for ATV's unique metabolic profile among the PIs.

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The tumor suppressor TMEM127 regulates insulin sensitivity in a tissue-specific manner

Nature Communications ◽

10.1038/s41467-019-12661-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Subramanya Srikantan ◽

Yilun Deng ◽

Zi-Ming Cheng ◽

Anqi Luo ◽

Yuejuan Qin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tumor Suppressor ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Suppressor Gene ◽

Nutrient Sensing ◽

Whole Body ◽

Insulin Sensitizer

Abstract Understanding the molecular components of insulin signaling is relevant to effectively manage insulin resistance. We investigated the phenotype of the TMEM127 tumor suppressor gene deficiency in vivo. Whole-body Tmem127 knockout mice have decreased adiposity and maintain insulin sensitivity, low hepatic fat deposition and peripheral glucose clearance after a high-fat diet. Liver-specific and adipose-specific Tmem127 deletion partially overlap global Tmem127 loss: liver Tmem127 promotes hepatic gluconeogenesis and inhibits peripheral glucose uptake, while adipose Tmem127 downregulates adipogenesis and hepatic glucose production. mTORC2 is activated in TMEM127-deficient hepatocytes suggesting that it interacts with TMEM127 to control insulin sensitivity. Murine hepatic Tmem127 expression is increased in insulin-resistant states and is reversed by diet or the insulin sensitizer pioglitazone. Importantly, human liver TMEM127 expression correlates with steatohepatitis and insulin resistance. Our results suggest that besides tumor suppression activities, TMEM127 is a nutrient-sensing component of glucose/lipid homeostasis and may be a target in insulin resistance.

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Analysis of candidate genes in Polish families with obesity

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.083 ◽

2004 ◽

Vol 42 (5) ◽

Cited By ~ 6

Author(s):

Malgorzata Malczewska-Malec ◽

Iwona Wybranska ◽

Iwona Leszczynska-Golabek ◽

Lukasz Partyka ◽

Jadwiga Hartwich ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Body Mass ◽

Tolerance Test ◽

Whole Body ◽

Oral Glucose ◽

Sensitivity Index ◽

Model Assessment ◽

The Metabolic Syndrome

AbstractThis study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-γThe 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated.The single gene mutations such as CWe conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.

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Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00155.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. E799-E803 ◽

Cited By ~ 18

Author(s):

Gina B. Di Gregorio ◽

Rickard Westergren ◽

Sven Enerback ◽

Tong Lu ◽

Philip A. Kern

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Tolerance Test ◽

Intravenous Glucose Tolerance Test ◽

Whole Body ◽

Forkhead Transcription Factor ◽

Intravenous Glucose ◽

Insulin Resistant ◽

Diet Induced Obesity ◽

Tnf Α

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test ( r = −0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA ( P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-α, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.

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