Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques

The incidence of alcohol use disorder (AUD) is higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapy (ART) has significantly reduced mortality, shifting the course of HIV infection to a chronic illness. However, this is associated with an increased incidence of comorbid conditions, including type 2 diabetes mellitus, insulin resistance, and cardiovascular complications. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, previous studies have demonstrated that chronic binge alcohol (CBA) administration decreases whole body insulin responsiveness, irrespective of ART administration. The objective of the current study was to determine the effects of CBA and ART on insulin-sensitive peripheral tissues before the development of overt clinical symptoms of SIV disease. Our results show that CBA reduced omental adipocyte cell size, increased collagen expression, and decreased the in vitro differentiation potential of adipose-derived stem cells. In contrast, it did not alter skeletal muscle or omental or hepatic expression of insulin signaling proteins. However, ART significantly decreased skeletal muscle expression of phosphatase and tensin homolog, total mechanistic target of rapamycin, and ribosomal protein S6. In addition, ART increased hepatic phosphorylation of AMP-activated protein kinase α and increased gene expression of key enzymes required for gluconeogenesis and fatty acid synthesis. These findings suggest that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that may underlie insulin resistance associated with alcohol, SIV, and ART. Whether this is translated in PLWH with AUD remains to be determined.

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Insulin resistance in PLHIV on HAART and HAART naïve PLHIV: A Cross-sectional Study

10.36106/ijar/3506686 ◽

2020 ◽

pp. 1-3

Author(s):

Prabir Kumar Ganguly ◽

Niladri Das

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Antiretroviral Therapy ◽

Cross Sectional Study ◽

Metabolic Effects ◽

People Living With Hiv ◽

Model Assessment ◽

Sectional Study ◽

Cross Sectional ◽

Group I

ABSTRACT HAART (Highly active antiretroviral therapy) has transformed a fatal disease to a chronic, manageable disease. But long term toxicities are emerging after prolonged exposure to antiretroviral therapy(ART). Adverse metabolic effects like dyslipidemia, increased blood pressure, and insulin resistance(IR) have been attributed to HAART. Therefore, the use of HAART raises concerns regarding metabolic disorders and cardiovascular risk in HIV(Human immunodeficiency virus) infected patients. Objective: To determine the prevalence of insulin resistance in a cohort of HIV infected patients on HAART as compared to HAART naïve PLHIV(People living with HIV) Methods: A cross sectional study includes 53 subjects, out of which 26 were PLHIV on ART –Group I, 27 were ART naïve PLHIV-Group II was conducted. Insulin resistance was determined by homeostasis model assessment (HOMA-IR) mathematical model. Statistical analysis was performed to assess the association between demographic, clinical characteristics, laboratory results and insulin resistance. Results: 69.5 % PLHIV on HAART showed IR, as compared to 37 % of ART naïve PLHIV (p= 0.01). MetS(Metabolic Syndrome) was found in 53.8% among PLHIV on ART , compared to 11.1% among ART naïve PLHIV(p= 0.001) .In the multivariate analysis, presence of metabolic syndrome was found to be directly associated with insulin resistance.

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

Endocrinology ◽

10.1210/en.2011-1955 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2142-2151 ◽

Cited By ~ 34

Author(s):

Miles J. De Blasio ◽

Kathryn L. Gatford ◽

M. Lyn Harland ◽

Jeffrey S. Robinson ◽

Julie A. Owens

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Glucose Transporter ◽

Postnatal Growth ◽

Whole Body ◽

Poor Growth ◽

Hepatic Expression ◽

Metabolic Genes

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.

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Skeletal Muscle Insulin Resistance in Endocrine Disease

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/527850 ◽

2010 ◽

Vol 2010 ◽

pp. 1-13 ◽

Cited By ~ 50

Author(s):

Melpomeni Peppa ◽

Chrysi Koliaki ◽

Panagiotis Nikolopoulos ◽

Sotirios A. Raptis

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Receptor ◽

Polycystic Ovary ◽

Glycogen Synthesis ◽

Whole Body ◽

Endocrine Disorders ◽

Peripheral Tissues ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Resistance

We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

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Metabolomic Profile of Skeletal Muscle and Its Change Under a Mixed-Mode Exercise Intervention in Progressively Dysglycemic Subjects

Frontiers in Endocrinology ◽

10.3389/fendo.2021.778442 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lukasz Szczerbinski ◽

Aleksandra Golonko ◽

Mark Taylor ◽

Urszula Puchta ◽

Paulina Konopka ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Mixed Mode ◽

Skeletal Muscles ◽

Molecular Mechanisms ◽

Exercise Intervention ◽

Metabolic Effects ◽

Whole Body ◽

Lipid Species ◽

Male Patients

Skeletal muscles play an essential role in whole-body glucose homeostasis. They are a key organ system engaged in the development of insulin resistance, and also a crucial tissue mediating the beneficial metabolic effects of physical activity. However, molecular mechanisms underlying both these processes in skeletal muscle remain unclear. The aim of our study was to compare metabolomic profiles in skeletal muscle of patients at different stages of dysglycemia, from normoglycemia through prediabetes to T2D, and its changes under a mixed-mode (strength and endurance) exercise intervention. We performed targeted metabolomics comprising several major metabolite classes, including amino acids, biogenic amines and lipid subgroups in skeletal muscles of male patients. Dysglycemic groups differed significantly at baseline in lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, glutamine, ornithine, and carnosine. Following the exercise intervention, we detected significant changes in lipids and metabolites related to lipid metabolism, including in ceramides and acylcarnitines. With their larger and more significant change over the intervention and among dysglycemic groups, these findings suggest that lipid species may play a predominant role in both the pathogenesis of type 2 diabetes and its protection by exercise. Simultaneously, we demonstrated that amino acid metabolism, especially glutamate dysregulation, is correlated to the development of insulin resistance and parallels disturbances in lipid metabolites.

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Exercise, heat shock proteins and insulin resistance

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0529 ◽

2017 ◽

Vol 373 (1738) ◽

pp. 20160529 ◽

Cited By ~ 19

Author(s):

Ashley E. Archer ◽

Alex T. Von Schulze ◽

Paige C. Geiger

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Heat Shock ◽

Heat Shock Proteins ◽

Metabolic Effects ◽

Diabetic Patients ◽

Alcoholic Fatty Liver ◽

Insulin Resistant ◽

Exercise Induced ◽

Shock Proteins

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

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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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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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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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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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