Hydrogen Sulfide Donor NaHS Improves Metabolism and Reduces Muscle Atrophy in Type 2 Diabetes: Implication for Understanding Sarcopenic Pathophysiology

Sarcopenia, a loss of muscle mass and functionality, constitutes a major contributor to disability in diabetes. Hydrogen sulfide (H2S) dynamics and muscle mass regulatory signaling were studied in GK rats, a model for type 2 diabetes (T2D). GK rats exhibited a number of features that are consistent with sarcopenia and T2D including loss of muscle mass and strength, in addition to glucose intolerance, insulin resistance, and impaired β-cell responsiveness to glucose. Mechanistically, activation levels of Akt, a key modulator of protein balance, were decreased in T2D. Consequently, we confirmed reduced activity of mTOR signaling components and higher expression of atrophy-related markers typified by FoxO1/atrogin-1/MuRF1 and myostatin-Smad2/3 signaling during the course of diabetes. We observed in GK rat reduced antioxidant capacity (↓GSH/GSSG) and increased expression and activity of NADPH oxidase in connection with augmented rate of oxidation of lipids, proteins, and DNA. H2S bioavailability and the expression of key enzymes involved in its synthesis were suppressed as a function of diabetes. Interestingly, GK rats receiving NaHS displayed increased muscle Akt/mTOR signaling and decreased expression of myostatin and the FoxO1/MuRF1/atrogin-dependent pathway. Moreover, diabetes-induced heightened state of oxidative stress was also ameliorated in response to NaHS therapy. Overall, the current data support the notion that a relationship exists between sarcopenia, heightened state of oxidative stress, and H2S deficiency at least in the context of diabetes. Moreover, treatment with a potent H2S donor at an early stage of diabetes is likely to mitigate the development of sarcopenia/frailty and predictably reduces its devastating sequelae of amputation.

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Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes

Diabetes ◽

10.2337/diabetes.48.4.927 ◽

1999 ◽

Vol 48 (4) ◽

pp. 927-932 ◽

Cited By ~ 330

Author(s):

Y. Ihara ◽

S. Toyokuni ◽

K. Uchida ◽

H. Odaka ◽

T. Tanaka ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Gk Rats

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Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats

International Journal of Molecular Sciences ◽

10.3390/ijms222413671 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13671

Author(s):

Marcelo Queiroz ◽

Adriana Leandro ◽

Lara Azul ◽

Artur Figueirinha ◽

Raquel Seiça ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Endothelial Function ◽

Metabolic Parameters ◽

Perivascular Adipose Tissue ◽

Gk Rats ◽

Vascular Oxidative Stress ◽

Luteolin Treatment

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

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MALONDIALDEHYDE, ADIPONECTIN, NITRIC OXIDE, C-REACTIVE PROTEIN, TUMOR NECROSIS FACTOR-ALPHA AND INSULIN RESISTANCE RELATIONSHIPS AND INTER-RELATIONSHIPS IN TYPE 2 DIABETES EARLY STAGE IS METFORMIN ALONE ADEQUATE IN THIS STAGE

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2017v9i10.21149 ◽

2017 ◽

Vol 9 (10) ◽

pp. 176 ◽

Cited By ~ 4

Author(s):

Entsar A Saad ◽

Salem A. Habib ◽

Wael A. Refai ◽

Amira A. Elfayoumy

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Type 2 Diabetes ◽

Tumor Necrosis ◽

Early Stage ◽

Inflammation Markers ◽

C Reactive Protein ◽

Reactive Protein ◽

Necrosis Factor

Objective: Great interest is directed to inflammation and oxidative stress involvement in type 2 diabetes pathogenesis. Many researchers suggest they play roles but exactly how is still not clear enough. This encouraged us to investigate relations and potential inter-relationships between them and insulin resistance in type 2 diabetes in its early stage. Whether metformin drug alone, as frequently prescribed, is enough for type 2 diabetes management in this early stage was an objective.Methods: Blood sugar indices, adiponectin (ADIPOQ), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), nitric oxide (NO), C-reactive protein (CRP), liver and kidney function tests and lipid profile were monitored in non-diabetic volunteers, pre-diabetic and newly diagnosed type 2 diabetic patients before and after metformin drug utilization for 5 mo.Results: MDA, inflammation markers and alanine aminotransferase (ALT) were elevated, and blood sugar indices and lipid profile showed pathological alterations in diabetics compared to non-diabetics; changes were worse in type 2 cases. They were improved to different degrees by metformin treatment except for pancreatic β-cells function and ADIPOQ level showed no significant improvements and it couldn’t normalize ALT.Conclusion: Results reflected significant relations and inter-relationships between oxidative stress and inflammation markers in type 2 diabetes in its early stage and indicated that metformin may need to be combined with another drug.

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Influence of Oxidative Stress, Skeletal Muscle Mass and Obesity on Type 2 Diabetes Mellitus among Patients in Kumasi Metropolis

Trends in Medical Research ◽

10.3923/tmr.2014.107.115 ◽

2014 ◽

Vol 9 (2) ◽

pp. 107-115

Author(s):

Robert A. Ngala ◽

Albert Adu Asare

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Muscle Mass ◽

Skeletal Muscle Mass

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Effects of Atorvastatin and Insulin in Vascular Dysfunction Associated With Type 2 Diabetes

Physiological Research ◽

10.33549/physiolres.932554 ◽

2014 ◽

pp. 189-197 ◽

Cited By ~ 1

Author(s):

C. M. SENA ◽

P. MATAFOME ◽

T. LOURO ◽

E. NUNES ◽

R. M. SEIÇA

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Vascular Reactivity ◽

Vascular Dysfunction ◽

Lipid Peroxides ◽

Metabolic Parameters ◽

Carbonyl Stress ◽

Gk Rats

Atorvastatin and insulin have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that atorvastatin and insulin therapies alone or in combination could have beneficial effects on endothelium-dependent vascular reactivity, oxidative stress, inflammation and metabolic parameters in Goto-Kakizaki (GK) rats, a model of type 2 diabetes fed with atherogenic diet (GKAD). In parallel with the development of diabetes and lipid profile, the generation of oxidative stress was determined by measurement of lipid peroxides and oxidized proteins and the presence of inflammation was evaluated by assessing C-reactive protein (CRP). Additionally, endothelial dependent and independent vascular sensitivity to acetylcholine and sodium nitroprusside were evaluated. GKAD showed increased carbonyl stress, inflammation, fasting glycemia, dyslipidemia and endothelial dysfunction when compared to control GK rats. Noteworthy, supplementation with insulin deteriorated endothelial dysfunction while atorvastatin induced an improvement. Atorvastatin and insulin therapies in combination improved metabolic parameters, CRP levels and insulin resistance indexes and ameliorated endothelial dysfunction in GKAD rats while they were unable to reduce urinary 8-isoprostranes and plasma carbonyl compounds. The therapeutic association of atorvastatin and insulin provided a better metabolic control with a reduction in endothelial dysfunction in GKAD rats by a mechanism that involves an improvement in systemic inflammation.

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Comprehensive analysis of long non-coding RNAs and mRNAs in skeletal muscle of diabetic Goto-Kakizaki rats during the early stage of type 2 diabetes

PeerJ ◽

10.7717/peerj.8548 ◽

2020 ◽

Vol 8 ◽

pp. e8548

Author(s):

Wenlu Zhang ◽

Yunmeng Bai ◽

Zixi Chen ◽

Xingsong Li ◽

Shuying Fu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Wistar Rats ◽

Interaction Analysis ◽

Early Stage ◽

Differentially Expressed ◽

Acid Oxidation ◽

Gk Rats ◽

Non Coding Rnas

Skeletal muscle long non-coding RNAs (lncRNAs) were reported to be involved in the development of type 2 diabetes (T2D). However, little is known about the mechanism of skeletal muscle lncRNAs on hyperglycemia of diabetic Goto-Kakizaki (GK) rats at the age of 3 and 4 weeks. To elucidate this, we used RNA-sequencing to profile the skeletal muscle transcriptomes including lncRNAs and mRNAs, in diabetic GK and control Wistar rats at the age of 3 and 4 weeks. In total, there were 438 differentially expressed mRNAs (DEGs) and 401 differentially expressed lncRNAs (DELs) in skeletal muscle of 3-week-old GK rats compared with age-matched Wistar rats, and 1000 DEGs and 726 DELs between GK rats and Wistar rats at 4 weeks of age. The protein–protein interaction analysis of overlapping DEGs between 3 and 4 weeks, the correlation analysis of DELs and DEGs, as well as the prediction of target DEGs of DELs showed that these DEGs (Pdk4, Stc2, Il15, Fbxw7 and Ucp3) might play key roles in hyperglycemia, glucose intolerance, and increased fatty acid oxidation. Considering the corresponding co-expressed DELs with high correlation coefficients or targeted DELs of these DEGs, our study indicated that these dysregulated lncRNA-mRNA pairs (NONRATG017315.2-Pdk4, NONRATG003318.2-Stc2, NONRATG011882.2-Il15, NONRATG013497.2-Fbxw7, MSTRG.1662-Ucp3) might be related to above biological processes in GK rats at the age of 3 and 4 weeks. Our study could provide more comprehensive knowledge of mRNAs and lncRNAs in skeletal muscle of GK rats at 3 and 4 weeks of age. And our study may provide deeper understanding of the underlying mechanism in T2D of GK rats at the age of 3 and 4 weeks.

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Skeletal Muscle and Metabolic Health: How Do We Increase Muscle Mass and Function in People with Type 2 Diabetes?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa835 ◽

2020 ◽

Author(s):

Ebaa Al-Ozairi ◽

Dalal Alsaeed ◽

Dherar Alroudhan ◽

Nia Voase ◽

Amal Hasan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Resistance Exercise ◽

Muscle Mass ◽

Glycated Haemoglobin ◽

Current Data ◽

Primary Role ◽

Increased Risk ◽

And Function

Abstract Background Whilst skeletal muscles’ primary role is allowing movement, it has important metabolic roles, including in glycemic control. Indeed, evidence indicates that low muscle mass and function are associated with an increased risk of type 2 diabetes, highlighting its importance in the development of metabolic disease. Methods In this mini-review, we detail the evidence highlighting the importance of muscle in type 2 diabetes and the efficacy of resistance exercise in improving glycemic control alongside our approach to increase uptake of such exercise in people with type 2 diabetes. This summary is based in the authors’ knowledge of the filed supplemented by a Pubmed search using the terms “muscle,” “glycemic control,” “HbA1c,” “type 2 diabetes,” and “resistance exercise.” Results The main strategy to increases muscle mass is to perform resistance exercise and, although the quality of evidence is low, such exercise appears effective in reducing Glycated Haemoglobin (HbA1c) in people with type 2 diabetes. However, to increase participation we need to improve our understanding of barriers and facilitators to such exercise. Current data indicate that barriers are similar to those reported for aerobic exercise, with additional resistance exercise specific barriers of looking to muscular, increase risk of cardiovascular event, having access to specialized equipment and knowledge of how to use it. Conclusions The development of simple resistance exercises that can be performed anywhere, that use little or no equipment and are effective in reducing HbA1c will be, in our opinion, key to increasing the number of people with type 2 diabetes performing resistance exercise.

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