scholarly journals CORRECTING GLUTATHIONE DEFICIENCY AND MITOCHONDRIAL DYSFUNCTION IN OLDER HUMANS: A RANDOMIZED CLINICAL TRIAL

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S416-S416
Author(s):  
Rajagopal V Sekhar ◽  
Premranjan Kumar ◽  
Jean W Hsu ◽  
James Suliburk ◽  
George E Taffet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Physical Function ◽  
Gait Speed ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Double Blind ◽  
Mitochondrial Fatty Acid ◽  
Glutathione Deficiency

Abstract Aging is associated with impaired mitochondrial fatty-acid oxidation (MFO) due to unknown mechanisms, and interventions are lacking. We hypothesized that impaired MFO in aging occurs due to Glutathione-deficiency and tested this in a randomized, placebo-controlled double-blind clinical-trial in 24 older-humans (71.1y) and 12 young-controls (25.5y) using calorimetry, muscle-biopsy and tracer-protocols. Older-humans received either GlyNAC (Glycine 1.33mmol/kg/d and N-acetylcysteine 0.83mmol/kg/d as Glutathione precursors) or isonitrogenous-placebo for 16-weeks; young-controls received GlyNAC for 2-weeks. Compared to young-controls, older humans had significantly lower Glutathione, impaired MFO, lower gait-speed and physical-function, and higher oxidative-stress, inflammation and insulin-resistance. GlyNAC supplementation in older-humans significantly improved and restored MFO; increased gait-speed (19%,) and physical-function; and decreased oxidative-stress (TBARS 80%), inflammation (IL-6 83%; TNF-alpha 58%), and insulin-resistance (HOMA-IR 68%), but young-controls were unaffected. These data provide proof-of-concept that GlyNAC supplementation could improve the health of older-humans by correcting Glutathione-deficiency and mitochondrial-defects to improve gait-speed, oxidative-stress, inflammation and insulin-resistance.

scholarly journals CORRECTING GLUTATHIONE DEFICIENCY IN AGING: IMPACT ON MITOCHONDRIA, STRENGTH, INFLAMMATION AND METABOLIC DEFECTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S415-S416
Author(s):  
Rajagopal Sekhar ◽  
George E Taffet ◽  
Roger Fielding
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Diastolic Heart Failure ◽  
Nutritional Intervention ◽  
Primary Objective ◽  
Double Blind ◽  
Glutathione Deficiency ◽  
The Impact

Abstract Aging is associated with deficiency of Glutathione, the most abundant, intracellular, antioxidant protein, but underlying mechanisms are unknown and interventions limited. This symposium is primarily focused on the results of placebo-controlled, double-blind randomized clinical-trial (RCT) on the impact of correcting Glutathione deficiency in older humans on mitochondrial impairment, oxidative stress, strength, inflammation, and insulin resistance. Dr. Jahoor’s presentation will serve as an introduction by discussing mechanisms underlying Glutathione deficiency and validation of a novel nutritional intervention based on supplementing glycine and N-acetylcysteine (GlyNAC) to correct Glutathione deficiency in older-humans. Dr. Sekhar will present the results of a pilot 16-week pilot randomized, placebo-controlled, double-blind clinical trial in older humans investigating the effect of supplementing GlyNAC (vs. placebo) to improve Glutathione levels and oxidative-stress in 24 older-humans and 12 young-humans on impaired mitochondrial fuel-oxidation (MFO) and other defects. The trial met its primary objective that that GlyNAC supplementation (and not placebo) significantly improved Glutathione deficiency and corrected impaired MFO (and defects in its molecular regulation), and also significantly improved gait-speed (increased 19% increase to match young-humans), muscle-strength, exercise-capacity, and lowered oxidative-stress (80%) inflammation (IL-6 83%, TNF-alpha 58%), and insulin-resistance (68%). Dr. Taffet will discuss age-induced diastolic heart failure, and the effect of supplementing GlyNAC (vs. NAC alone) in aged 24-month old mice with diastolic heart-failure, impaired myocardial MFO and cardiac-inflammation. Collectively this symposium on Glutathione and Aging will highlight the discovery that supplementing GlyNAC to correct Glutathione deficiency in older-humans has significant health benefits, and could be a novel nutritional-intervention in aging.

scholarly journals The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance

1987 ◽  
Vol 243 (2) ◽  
pp. 549-553 ◽  
Author(s):  
I D Caterson ◽  
L D Astbury ◽  
P F Williams ◽  
M A Vanner ◽  
G J Cooney ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pyruvate Dehydrogenase ◽  
Serum Insulin ◽  
Pyruvate Dehydrogenase Complex ◽  
Active Form ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Gold Thioglucose ◽  
Mitochondrial Fatty Acid

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.

scholarly journals Nutraceutical Improves Glycemic Control, Insulin Sensitivity, and Oxidative Stress in Hyperglycemic Subjects: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

2020 ◽  
Vol 15 (4) ◽  
pp. 1934578X2091868
Author(s):  
Akkarach Bumrungpert ◽  
Patcharanee Pavadhgul ◽  
Rewadee Chongsuwat ◽  
Surat Komindr
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Glycemic Control ◽  
Lipid Profiles ◽  
Oxidative Stress Markers ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Stress Markers ◽  
And Oxidative Stress

The aim of this research was to investigate the effects of nutraceuticals including bitter melon, fenugreek, cinnamon, alpha-lipoic acid, zinc, biotin, chromium, and cholecalciferol on glycemic control, insulin sensitivity, lipid profiles, oxidative stress, and inflammatory markers in hyperglycemia. The study design was a randomized, double-blind, placebo-controlled trial. Subjects with hyperglycemia were randomly divided into 2 groups. The treatment group ( n = 52) was given a nutraceutical and the control group ( n = 50) was provided with a placebo for 12 weeks. Fasting blood glucose (FBG), hemoglobin A1c (HbA1C), homeostatic model assessment of insulin resistance (HOMA-IR), lipid profiles, biomarkers of oxidative stress, and inflammation were assessed before and after the intervention at 6 weeks and 12 weeks. Nutraceutical supplementation demonstrated a statistically significant decrease in FBG (13.4% and 18.9%), HbA1C (6.5% and 11.3%), and HOMA-IR (28.9% and 35.2%) compared with the placebo. Moreover, low-density lipoprotein-cholesterol (LDL-C) level was significantly reduced in the nutraceutical group (7.1% and 9.3%). Furthermore, the nutraceutical significantly decreased oxidative stress markers, oxidized LDL-C (14.8% and 18.9%) and malondialdehyde (16.6% and 26.2%) compared with the placebo. In conclusion, this nutraceutical can improve glycemic control, insulin resistance, lipid profiles, and oxidative stress markers in hyperglycemic subjects. Therefore, it has the potential to decrease cardiovascular disease risk factors. Clinical trial registration: TCTR20180907001, www.clinicaltrials.in.th.

scholarly journals Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione

Aging Cell ◽  
2013 ◽  
Vol 12 (3) ◽  
pp. 415-425 ◽  
Author(s):  
Dan Nguyen ◽  
Susan L. Samson ◽  
Vasumathi T. Reddy ◽  
Erica V. Gonzalez ◽  
Rajagopal V. Sekhar
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Protective Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid

scholarly journals Randomized double blind clinical trial evaluating the Ellagic acid effects on insulin resistance, oxidative stress and sex hormones levels in women with polycystic ovarian syndrome

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Mahnaz Kazemi ◽  
Fatemeh Lalooha ◽  
Mohammadreza Rashidi Nooshabadi ◽  
Fariba Dashti ◽  
Maria Kavianpour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Sex Hormones ◽  
Polycystic Ovarian Syndrome ◽  
Density Lipoprotein ◽  
Double Blind ◽  
Tnf Α ◽  
The Mean ◽  
Ovarian Syndrome

Abstract Objective The design of this study was due to the report of the antioxidant properties of Ellagic acid (EA) for its evaluation on the Insulin resistance (IR), oxidative stress and sex hormones levels in women with polycystic ovarian syndrome (PCOS). Methods In this randomized, double-blind, placebo-controlled clinical trial, 60 patients were recruited. Patients were randomly allocated consumed a capsule containing 200 mg of EA per day (n = 30) or placebo (n = 30) for 8 weeks. The fasting blood sugar (FBS), insulin, IR, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), total antioxidant capacity (TAC), Malondialdehyde (MDA), C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), sex hormones and anti-mullerian hormone (AMH) were measured at the beginning and end of the study. Result At the end of the study, the mean of FBS, insulin, IR, TC, TG, LDL, MDA, CRP, TNF-α, total testosterone, prolactin and AMH were significantly decreased in the intervention group compared to the placebo group (P < 0.05). Also, there was a significant increase in the mean of TAC after supplementation with EA (P < 0.05). At the end of the study, no significant changes were observed in the mean of anthropometric factors, physical activity and food intake (P > 0.05). Conclusion EA supplementation can be helpful as a diet supplement in women with PCOS through improvement in insulin resistance. This supplement may be used to reduce metabolic disorders in women. Trial registration This study was retrospectively (07–07-2019) registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20141025019669N12).

Abstract 33: Impaired Mitochondrial Metabolism Contributes To Endothelial Dysfunction And Hypertension Independently From Oxidative Stress

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Anna Dikalova ◽  
Liliya Tkachuk ◽  
Svetlana Vafina ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Mitochondrial Metabolism ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Metabolic Conditions

Metabolic disorders contribute to pathogenesis of endothelial dysfunction, and mitochondrial deacetylase Sirt3 is critical in regulation of metabolic and antioxidant functions, but the role of Sirt3 has been largely ignored. We have recently shown that Sirt3 level is reduced in human hypertension. We propose Sirt3 as a novel target to improve the treatment of endothelial dysfunction and hypertension. Oxidative stress promotes metabolic dysregulation while metabolic conditions increase production of reactive oxygen species. In this work we have discerned the pathological role of impaired mitochondrial metabolism and oxidative stress using our new SOD2K68R deacetylation mimic mouse model. SOD2K68R mice are protected from oxidative stress because mutation of lysine 68 to arginine prevents SOD2 inactivation by acetylation. To define the specific role of impaired mitochondrial metabolism in endothelial dysfunction and hypertension, we have crossed SOD2K68R with Sirt3 -/- mice. Resultant SOD2K68R-Sirt3 -/- mice are protected from mitochondrial oxidative stress but have impaired Sirt3-mediated mitochondrial metabolism. We have tested the hypothesis that impaired Sirt3-mediated mitochondrial metabolism in SOD2K68R-Sirt3 -/- mice promotes vascular dysfunction and hypertension. SOD2K68R-Sirt3 -/- mice are protected from AngII-induced superoxide measured by mitoSOX and DHE. Meanwhile, systolic blood pressure in AngII-infused SOD2K68R-Sirt3 -/- mice was substantially higher than in SOD2K68R mice but lower than in Sirt3 -/- mice. To define the role of mitochondrial metabolism in vascular homeostasis we analyzed metabolic, inflammatory, and cellular pathways. LCAD hyperacetylation and increased HIF1α in SOD2K68R-Sirt3 -/- mice indicates impaired mitochondrial fatty acid oxidation and increased glycolysis which were further exacerbated by AngII-infusion and NFkB/ICAM increase promoting vascular inflammation. The loss of VeCAD in SOD2K68R-Sirt3 -/- Sham mice was further aggravated in AngII-infusion supporting alteration of endothelial phenotype in SOD2K68R-Sirt3 -/- mice. These data indicate that impaired mitochondrial metabolism contributes to endothelial dysfunction and hypertension independently from oxidative stress.

scholarly journals Randomized Double Blind Clinical Trial Evaluating the Ellagic Acid Effects on Insulin Resistance, Oxidative Stress and Sex Hormones Levels in Women With Polycystic Ovarian Syndrome

2021 ◽  
Author(s):  
Mahnaz Kazemi ◽  
Fatemeh Lalooha ◽  
Mohammadreza Rashidi Nooshabadi ◽  
Fariba Dashti ◽  
Maria Kavianpour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Sex Hormones ◽  
Polycystic Ovarian Syndrome ◽  
Density Lipoprotein ◽  
Double Blind ◽  
Tnf Α ◽  
The Mean ◽  
Ovarian Syndrome

Abstract Objective: The design of this study was due to the report of the antioxidant properties of Ellagic acid (EA) for its evaluation on the Insulin resistance (IR), oxidative stress and sex hormones levels in women with polycystic ovarian syndrome (PCOS). Methods: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients were recruited. Patients were randomly allocated consumed a capsule containing 200 mg of EA per day (n = 30) or placebo (n = 30) for 8 weeks. The fasting blood sugar (FBS), insulin, IR, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), total antioxidant capacity (TAC), Malondialdehyde (MDA), C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), sex hormones and anti-mullerian hormone (AMH) were measured at the beginning and end of the study. Result: At the end of the study, the mean of FBS, insulin, IR, TC, TG, LDL, MDA, CRP, TNF-α, total testosterone, prolactin and AMH were significantly decreased in the intervention group compared to the placebo group (P<0.05). Also, there was a significant increase in the mean of TAC after supplementation with EA (P<0.05). At the end of the study, no significant changes were observed in the mean of anthropometric factors, physical activity and food intake (P>0.05). Conclusion: EA supplementation can be helpful as a diet supplement in women with PCOS through improvement in insulin resistance. This supplement may be used to reduce disorders in women, including infertility.Trial Registration: This study was retrospectively (07-07-2019) registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20141025019669N12).

scholarly journals GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 154
Author(s):  
Rajagopal V. Sekhar
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Plasma Ffa ◽  
Underlying Mechanisms

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research.

Sign in / Sign up

Export Citation Format

Share Document