scholarly journals Supplementing Glycine and N-acetylcysteine (GlyNAC) in Aging HIV Patients Improves Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Endothelial Dysfunction, Insulin Resistance, Genotoxicity, Strength, and Cognition: Results of an Open-Label Clinical Trial

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 390
Author(s):  
Premranjan Kumar ◽  
Chun Liu ◽  
James W. Suliburk ◽  
Charles G. Minard ◽  
Raja Muthupillai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Cognitive Decline ◽  
Muscle Protein ◽  
Glucose Production ◽  
Premature Aging ◽  
Open Label ◽  
Breakdown Rates ◽  
Genomic Damage

Background: Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC). Methods: We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition. Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC. Conclusions: This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, and warrants additional investigation.

scholarly journals Reversing cognitive-decline in older adults in an open-label clinical trial: novel mechanisms and the role of GlyNAC

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 857-857
Author(s):  
Chun Liu ◽  
Rajagopal Sekhar ◽  
Premranjan Kumar ◽  
Charles Minard ◽  
Shaji Chacko
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Older Adults ◽  
Cognitive Decline ◽  
Cognitive Testing ◽  
Open Label ◽  
Healthy Older Adults ◽  
Symbol Substitution ◽  
Trail Making ◽  
Endogenous Antioxidant

Abstract Age-associated cognitive-decline is an important risk factor for Alzheimer’s disease, but interventions are lacking. We conducted an open-label trial to test our hypotheses on whether: (1) compared to 8 healthy young adults (25y), 8 ‘healthy’ older adults (74y) have cognitive decline, decreased glucose availability for the brain due to mitochondrial dysfunction, elevated insulin-resistance, oxidative-stress and elevated inflammation; (2) supplementing glycine and N-acetylcysteine (GlyNAC) for 24-weeks corrects deficiency of the endogenous-antioxidant Glutathione and improves these defects, and thereby cognition; (3) stopping GlyNAC supplementation for 12-weeks results in a decline in accrued benefits. Outcome measures included cognitive testing (Montreal cognitive assessment; trail-making tests; verbal-fluency tests; digital-symbol substitution-test), mitochondrial fuel-oxidation, RBC-Glutathione concentrations, plasma oxidative-stress, insulin-resistance and inflammation, and tracer-studies to measure glucose metabolism. Results validated our hypotheses and showed that GlyNAC-supplementation corrected these defects and improved cognition. This trial suggests that supplementing GlyNAC may be important for improving/preventing age-associated cognitive-decline in older adults.

scholarly journals Reversing Cognitive Decline in Aging: Reversible Mechanistic Defects and a Novel Nutritional Intervention

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 857-857
Author(s):  
Rajagopal Sekhar ◽  
George Taffet
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Older Adults ◽  
Cognitive Decline ◽  
Mitochondrial Dysfunction ◽  
Nutritional Intervention ◽  
Open Label ◽  
Aged Mice ◽  
Naturally Occurring ◽  
Glutathione Deficiency

Abstract Aging is the biggest risk factor for cognitive-decline and Alzheimer’s disease (AD), but underlying mechanisms are not well-understood and interventions are lacking. Cognitive-decline in AD has been associated with deficiency of glutathione, (the most abundant, intracellular, antioxidant protein), elevated oxidative-stress, insulin-resistance and increased inflammation. We identified and reported that glutathione-deficiency and oxidative-stress in older-adults occur due to decreased availability of precursor amino-acids glycine and cysteine, and can be corrected with GlyNAC (a combination of glycine and the cysteine precursor N-acetylcysteine). We hypothesized that cognitive decline in older-adults is linked to glutathione-deficiency, mitochondrial-dysfunction, oxidative-stress, insulin-resistance, and inflammation. The first abstract discusses the rationale and findings of an open-label clinical trial: compared to young-humans, older-adults had cognitive-decline, glutathione-deficiency, mitochondrial-dysfunction, abnormal glucose-metabolism and insulin-resistance, oxidative-stress, endothelial-dysfunction and inflammation. These defects were improved/reversed by supplementing GlyNAC for 24-weeks, but benefits receded on stopping GlyNAC for 12-weeks. The second abstract presents a study in 8 young (20-weeks old) and 16 aged (90-weeks old) wild-type male C57BL/6J mice where we found that aged-mice had naturally-occurring cognitive-impairment, and brain defects in glutathione-deficiency, oxidative-stress, glucose-transport, mitochondrial glucose-oxidation, insulin-resistance, endoplasmic-reticulum stress, autophagy, mitophagy, inflammation, senescence, genomic and telomere damage. Aged-mice received either GlyNAC or isonitrogenous-placebo supplementation for 8-weeks, and only GlyNAC-fed mice improved cognition and brain defects. Collectively these data highlights the discovery of novel and reversible mechanistic defects in older-adults and aged-mice with naturally-occurring cognitive-decline, and identifies that supplementing GlyNAC can improve brain-health and cognition. These findings could have important implications for reversing cognitive-decline in older-adults, and AD.

scholarly journals Comparative effects of sex hormone deprivation on the brain of insulin-resistant rats

2019 ◽  
Vol 241 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Jirapas Sripetchwandee ◽  
Hiranya Pintana ◽  
Piangkwan Sa-nguanmoo ◽  
Chiraphat Boonnag ◽  
Wasana Pratchayasakul ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cognitive Decline ◽  
Mitochondrial Dysfunction ◽  
Dendritic Spine ◽  
High Fat Diet ◽  
High Fat ◽  
Long Term Depression ◽  
Impaired Insulin

Obese-insulin resistance following chronic high-fat diet consumption led to cognitive decline through several mechanisms. Moreover, sex hormone deprivation, including estrogen and testosterone, could be a causative factor in inducing cognitive decline. However, comparative studies on the effects of hormone deprivation on the brain are still lacking. Adult Wistar rats from both genders were operated upon (sham operations or orchiectomies/ovariectomies) and given a normal diet or high-fat diet for 4, 8 and 12 weeks. Blood was collected to determine the metabolic parameters. At the end of the experiments, rats were decapitated and their brains were collected to determine brain mitochondrial function, brain oxidative stress, hippocampal plasticity, insulin-induced long-term depression, dendritic spine density and cognition. We found that male and female rats fed a high-fat diet developed obese-insulin resistance by week 8 and brain defects via elevated brain oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity, reduced dendritic spine density and cognitive decline by week 12. In normal diet-fed rats, estrogen deprivation, not testosterone deprivation, induced obese-insulin resistance, oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression, hippocampal dysplasticity and reduced dendritic spine density. In high-fat–diet-fed rats, estrogen deprivation, not testosterone deprivation, accelerated and aggravated obese-insulin resistance and brain defects at week 8. In conclusion, estrogen deprivation aggravates brain dysfunction more than testosterone deprivation through increased oxidative stress, brain mitochondrial dysfunction, impaired insulin-induced long-term depression and dendritic spine reduction. These findings may explain clinical reports which show more severe cognitive decline in aging females than males with obese-insulin resistance.

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 Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

2015 ◽  
Vol 225 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Sandra Pereira ◽  
Anu Shah ◽  
I George Fantus ◽  
Jamie W Joseph ◽  
Adria Giacca
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Protein ◽  
Protein Carbonyl ◽  
Hepatic Insulin Resistance ◽  
Skeletal Muscle Protein ◽  
Protein Carbonyl Content ◽  
Peripheral Insulin Resistance ◽  
Plasma Ffa

Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidantN-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic–euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.

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).

N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress

2003 ◽  
Vol 285 (4) ◽  
pp. E744-E753 ◽  
Author(s):  
C. Andrew Haber ◽  
Tony K. T. Lam ◽  
Zhiwen Yu ◽  
Neehar Gupta ◽  
Tracy Goh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
High Glucose ◽  
Muscle Protein ◽  
Fold Increase ◽  
Protein Carbonyl ◽  
Protein Carbonyl Content ◽  
High Concentrations

Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 ± 1.7 vs. HG 32.4 ± 1.9 mg · kg–1 · min–1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 ± 3.5 mg · kg–1 · min–1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.

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