Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART

The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV ( n = 12), HAART but no PI ( n = 10), and HIV-seronegative controls ( n = 10). Stable isotope tracers [1-13C]palmitate and [1,1,2,3,3-2H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50% V̇o2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV + RTV 5.1 ± 1.2 vs. HIV + no PI 5.9 ± 2.8 vs. Control 7.4 ± 2.2 μmol·kg fat-free mass (FFM)−1·min−1; palmitate oxidation: HIV + RTV 1.6 ± 0.8 vs. HIV + no PI 1.6 ± 0.8 vs. Control 2.5 ± 1.7 μmol·kg FFM·min, P < 0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.

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Comparing the Fasting and Random-Fed Metabolome Response to an Oral Glucose Tolerance Test in Children and Adolescents: Implications of Sex, Obesity, and Insulin Resistance

Nutrients ◽

10.3390/nu13103365 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3365

Author(s):

Jennifer L. LaBarre ◽

Emily Hirschfeld ◽

Tanu Soni ◽

Maureen Kachman ◽

Janis Wigginton ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Acid Oxidation ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Nutrient Metabolism

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8–17 years, BMI percentile 5–85%) and overweight and obese (OVOB, n = 228, aged 8–17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.

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Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000948 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000948 ◽

Cited By ~ 3

Author(s):

Martha Guevara-Cruz ◽

Einar T Godinez-Salas ◽

Monica Sanchez-Tapia ◽

Gonzalo Torres-Villalobos ◽

Edgar Pichardo-Ontiveros ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Gut Microbiota ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Oral Glucose ◽

Model Assessment ◽

Metabolic Endotoxemia

ObjectiveObesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.Research design and methods45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.ResultsIn the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.ConclusionsChange in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.

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Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Endocrinology ◽

10.1210/en.2005-0938 ◽

2005 ◽

Vol 146 (12) ◽

pp. 5341-5349 ◽

Cited By ~ 343

Author(s):

Jonathan Buchanan ◽

Pradip K. Mazumder ◽

Ping Hu ◽

Gopa Chakrabarti ◽

Matthew W. Roberts ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Mouse Models ◽

Acid Oxidation ◽

Contractile Dysfunction ◽

Oxidation Rates ◽

Myocardial Substrate ◽

Old Mice

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased β-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-α regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-α regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

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One-hour glucose level of the oral glucose tolerance test: the new valuable indicator of insulin resistance in patients with adrenal incidentalomas

Endocrine Abstracts ◽

10.1530/endoabs.63.p435 ◽

2019 ◽

Author(s):

Antoan Stefan Sojat ◽

Ljiljana Marina ◽

Miomira Ivovic ◽

Milina Tancic Gajic ◽

Zorana Arizanovic ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Glucose Level ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Adrenal Incidentalomas ◽

Oral Glucose Tolerance

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The waist-height ratio is a potential anthropometric index of insulin resistance: Observations based on oral glucose tolerance test in lean, normo-glycaemic, Asian Indian males from Southern India

Clinical Epidemiology and Global Health ◽

10.1016/j.cegh.2021.100762 ◽

2021 ◽

pp. 100762

Author(s):

Shajith Anoop ◽

Felix Jebasingh.K ◽

Dona Maria Philip ◽

Mathews Edatharayil Kurian ◽

Venkataraghava Mohan ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Asian Indian ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Height Ratio ◽

Anthropometric Index ◽

Waist Height Ratio

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Metabolomics analysis reveals altered metabolites in lean compared with obese adolescents and additional metabolic shifts associated with hyperinsulinaemia and insulin resistance in obese adolescents: a cross-sectional study

Metabolomics ◽

10.1007/s11306-020-01759-y ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Elisabeth Müllner ◽

Hanna E. Röhnisch ◽

Claudia von Brömssen ◽

Ali A. Moazzami

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Glucose Tolerance ◽

Insulin Response ◽

Oral Glucose ◽

Response Level ◽

Metabolic Alterations ◽

Obese Adolescents ◽

Branched Chain ◽

Metabolomics Analysis

Abstract Introduction Hyperinsulinaemia and insulin resistance (IR) are strongly associated with obesity and are forerunners of type 2 diabetes. Little is known about metabolic alterations separately associated with obesity, hyperinsulinaemia/IR and impaired glucose tolerance (IGT) in adolescents. Objectives To identify metabolic alterations associated with obesity, hyperinsulinaemia/IR and hyperinsulinaemia/IR combined with IGT in obese adolescents. Methods 81 adolescents were stratified into four groups based on body mass index (lean vs. obese), insulin responses (normal insulin (NI) vs. high insulin (HI)) and glucose responses (normal glucose tolerance (NGT) vs. IGT) after an oral glucose tolerance test (OGTT). The groups comprised: (1) healthy lean with NI and NGT, (2) obese with NI and NGT, (3) obese with HI and NGT, and (4) obese with HI and IGT. Targeted nuclear magnetic resonance-based metabolomics analysis was performed on fasting and seven post-OGTT plasma samples, followed by univariate and multivariate statistical analyses. Results Two groups of metabolites were identified: (1) Metabolites associated with insulin response level: adolescents with HI (groups 3–4) had higher concentrations of branched-chain amino acids and tyrosine, and lower concentrations of serine, glycine, myo-inositol and dimethylsulfone, than adolescents with NI (groups 1–2). (2) Metabolites associated with obesity status: obese adolescents (groups 2–4) had higher concentrations of acetylcarnitine, alanine, pyruvate and glutamate, and lower concentrations of acetate, than lean adolescents (group 1). Conclusions Obesity is associated with shifts in fat and energy metabolism. Hyperinsulinaemia/IR in obese adolescents is also associated with increased branched-chain and aromatic amino acids.

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QOL-43. ENDOCRINE AND METABOLIC CHANGES IN CHILDREN TREATED FOR MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.700 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii439-iii439

Author(s):

Alexey Kalinin ◽

Natalia Strebkova ◽

Olga Zheludkova

Keyword(s):

Insulin Resistance ◽

Body Composition ◽

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Impaired Glucose Tolerance ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Hormone Deficiency ◽

Oral Glucose ◽

Oral Glucose Tolerance

Abstract We examined 63 patients (40 males/23 females) after complex treatment of medulloblastoma. Patients had a median age (range) of 11.3 (5.5 ÷ 17.9) years. The median time after the end of treatment was 3.7 (1.5 ÷ 11.6) years. Endocrine disorders were detected with the following frequency: growth hormone deficiency - 98.41% (62 of 63 patients), thyroid hormone deficiency – 69.8% (44/63), adrenal hormone deficiency - 17.4% (11/63). Three cases (4.7%) of premature sexual development were also detected. Lipids levels, beta-cell function and insulin resistance (IR) during 2-h oral glucose tolerance test were evaluated. A mono frequent bioelectrical impedanciometer was used to measure body composition. Overweight (SDS BMI> 1) was observed only in 16 patients (3 girls and 13 boys), obesity (SDS BMI> 2) in 1 boy. Dyslipidemia was found in 34 patients (54%). All patients underwent oral glucose tolerance test. Insulin resistance (ISI Matsuda <2.5 and/or HOMA-IR> 3.2) was detected in 7 patients (11/1%), impaired glucose tolerance (120 min glucose ≥7.8 mmol / l) was observed in 2 patients with IR and in 2 patients without IR. At the same time, IR and impaired glucose tolerance were encountered in only 5 children with overweight and no one with obesity. All patients with impaired glucose tolerance had normal values of fasting glucose (4.3 ÷ 5.04 mmol / l) and HbA1c (4.8 ÷ 5.8%). A bioelectrical impedanciometer was used to measure body composition in 49 cases, the percentage of adipose tissue was increased in 14 patients (28%) with normal BMI.

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Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

Acta Endocrinologica ◽

10.1530/eje.1.02046 ◽

2005 ◽

Vol 153 (6) ◽

pp. 963-969 ◽

Cited By ~ 53

Author(s):

Dorte X Gram ◽

Anker J Hansen ◽

Michael Wilken ◽

Torben Elm ◽

Ove Svendsen ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Sensory Nerve ◽

Zucker Rats ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Nerve Activity ◽

Calcitonin Gene ◽

Obese Rats ◽

Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

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Effects of Micronutrient Supplementation on Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced Obesity

Cells ◽

10.3390/cells10071751 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1751

Author(s):

Saroj Khatiwada ◽

Virginie Lecomte ◽

Michael F. Fenech ◽

Margaret J. Morris ◽

Christopher A. Maloney

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Glucose Tolerance ◽

Antioxidant Capacity ◽

Fasting Glucose ◽

Oral Glucose ◽

Model Assessment ◽

Micronutrient Supplementation ◽

Sprague Dawley ◽

Triglyceride Accumulation

Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.

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