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Glutathione and other diseases

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Glutathione and diabetes

Diabetes has become one of the most prominent chronic diseases in many of the world’s populations. Whilst type 1 is genetic in origin, type 2 is primarily a lifestyle disease. Diabetes and the associated hyperglycaemia (high blood glucose) is related to an increase in the production of free radicals by a process called glycation. In essence, it is a process whereby the elevated blood glucose binds to proteins, in turn creating free radicals. The free radicals produced by glycation can be up to 50 times higher than normal and are implicated in ageing and tissue damage.[1]

Additionally, both type 1 and 2 diabetes are associated with low glutathione. [1-9] The resulting oxidative stress and depletion of the cellular antioxidant defense system contributes to the progress of coronary artery disease. This plays a major role in the development of diabetes and its ongoing complications.

Glutathione in its role as a free radical scavenger has been shown to drastically reduce the occurrence and duration of oxidative stress. Enhancing cellular glutathione is therefore of paramount importance in managing diabetes and reducing negative medical outcomes.

Glutathione and infertility

Globally, infertility is a major health problem and can cause significant financial and psychological stress. In many cases, the cause of infertility cannot be established, but oxidative stress is believed to be a major contributor due to its influence on the reproductive lifespan of both men and women.

Treatments that focus on enhancing the cellular antioxidant defense mechanism therefore play an important role in combating infertility and complications during pregnancy. Glutathione has shown to be the most effective antioxidant in the body due to its ability to not only boost the antioxidant defense, but also recycle other key antioxidant such as Vitamin C. [10-13]

Glutathione and cardiovascular diseases

Cardiovascular disease (CDV) is the number 1 cause of death globally, taking an estimated 18 million lives each year. Whilst an increased risk of CDV is often genetic in origin, the effect of negative lifestyle choices such as excessive alcohol consumption, smoking and poor diet play a well documented role in the development of CVD.

Complications in the cardiovascular system arise from elevated levels of free radicals which cause tissue damage and interrupt cellular signalling mechanisms [14]. Apart from lifestyle choices, there is a wide range of medical conditions that, by their nature, produce excessive free radicals, including diabetes, hypertension, stroke, and obesity. Whilst small bouts of increased levels of free radicals is normal, indeed required for signalling purposes and immune responses, it is the oxidative stress caused by sustained and excessive free radical production that leads to deleterious health outcomes [15].

Means to prevent this sustained damage caused by oxidative stress have been studies extensively and are of major therapeutic interest [16]. Whilst there is an abundance of pharmacological means to control chronic diseases such as diabetes or hypertension, reducing excessive production of free radicals from all possible sources presents a major challenge.

As the principal intracellular antioxidant, Glutathione has been extensively researched. This interest stems from numerous studies into chronic diseases in which elevated levels of free radicals cause sustained oxidative stress. Glutathione acts directly by scavenging free radicals and several studies have reported that patients with heart disease have lower levels of glutathione. Furthermore, a reduction of glutathione levels was also reported in subjects with asymptomatic CVD, which suggest that measuring and supplementing glutathione levels may help detect and treat such cases early. [14-22]

Glutathione and kidney disease

Oxidative stress is considered a main player in kidney disease and associated mortality rates. This sustained production of free radicals is in part caused by the frequent and regular dialysis required to treat patients. Glutathione demand in these patients is therefore much higher in order to cope with the increased oxidative stress.

Low levels of glutathione are a hallmark in kidney disease and this is thought to be caused by diminished levels of an enzyme called GCL which is the first step in the production of cellular glutathione. This enzyme is responsible for the production of gamma-glutamylcysteine, the direct precursor to glutathione. Since cysteine is removed from the blood in dialysis patients, supplementing with cysteine has a positive effect on glutathione levels, however it only addresses a small part of the problem. The diminished levels of GCL are of much greater concern. To address this problematic enzyme in dialysis patients, supplementation with gamma-glutamylcysteine has been shown to bypass GCL altogether by providing cells with the first building block of glutathione.  Not only does gamma-glutamylcysteine readily enter cells, once inside it is quickly and easily converted to glutathione.[23]  [24, 25]

References

1.            Whillier, S., P.W. Kuchel, and J.E. Raftos, Oxidative Stress in Type II Diabetes Mellitus and the Role of the Endogenous Antioxidant Glutathione, in Role of the Adipocyte in Development of Type 2 Diabetes, C. Croniger, Editor. 2011.

2.            Robertson, R.P., et al., Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes, 2003. 52(3): p. 581-7.

3.            Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.

4.            Sekhar, R.V., et al., Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine. Diabetes Care, 2011. 34(1): p. 162-167.

5.            Sheikh-Ali, M., J.M. Chehade, and A.D. Mooradian, The Antioxidant Paradox in Diabetes Mellitus. American Journal of Therapeutics, 2011. 18(3): p. 266-278 10.1097/MJT.0b013e3181b7badf.

6.            van der Crabben, S.N., et al., Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans. Metabolism, 2011. 60(1): p. 99-106.

7.            Furfaro, A.L., et al., Impaired synthesis contributes to diabetes-induced decrease in liver glutathione. International Journal of Molecular Medicine, 2012. 29(5): p. 899-905.

8.            Pastore, A., et al., All glutathione forms are depleted in blood of obese and type 1 diabetic children. Pediatric Diabetes, 2012. 13(3): p. 272-277.

9.            Darmaun, D., et al., Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation. Pediatr Diabetes, 2008. 9(6): p. 577-82.

10.          Agarwal, A. and L.H. Sekhon, The role of antioxidant therapy in the treatment of male infertility. Human Fertility, 2010. 13(4): p. 217-225.

11.          Adeoye, O., et al., Review on the role of glutathione on oxidative stress and infertility. JBRA Assist Reprod, 2018. 22(1): p. 61-66.

12.          Ross, C., et al., A systematic review of the effect of oral antioxidants on male infertility. Reproductive biomedicine online, 2010. 20(6): p. 711-723.

13.          Lanzafame, F.M., et al., Oxidative stress and medical antioxidant treatment in male infertility. Reproductive biomedicine online, 2009. 19(5): p. 638-659.

14.          Bajic, V.P., et al., Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease. Oxid Med Cell Longev, 2019. 2019: p. 5028181.

15.          Goszcz, K., et al., Antioxidants in Cardiovascular Therapy: Panacea or False Hope? Front Cardiovasc Med, 2015. 2: p. 29.

16.          Li, H.G., S. Horke, and U. Forstermann, Oxidative stress in vascular disease and its pharmacological prevention. Trends in Pharmacological Sciences, 2013. 34(6): p. 313-319.

17.          van der Pol, A., et al., Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail, 2019. 21(4): p. 425-435.

18.          Mistry, R.K. and A.C. Brewer, Redox-Dependent Regulation of Sulfur Metabolism in Biomolecules: Implications for Cardiovascular Health. Antioxid Redox Signal, 2019. 30(7): p. 972-991.

19.          Kanaan, G.N. and M.E. Harper, Cellular redox dysfunction in the development of cardiovascular diseases. Biochim Biophys Acta Gen Subj, 2017. 1861(11 Pt A): p. 2822-2829.

20.          Go, Y.-M. and D.P. Jones, Cysteine/cystine redox signaling in cardiovascular disease. Free Radical Biology and Medicine, 2011. 50(4): p. 495-509.

21.          Houston, M.C., Nutraceuticals, Vitamins, Antioxidants, and Minerals in the Prevention and Treatment of Hypertension. Progress in cardiovascular diseases, 2005. 47(6): p. 396-449.

22.          Mills, B.J., et al., Blood glutathione and cysteine changes in cardiovascular disease. Journal of Laboratory & Clinical Medicine, 2000. 135(5): p. 396-401.

23.          Alhamdani, M.S., Impairment of glutathione biosynthetic pathway in uraemia and dialysis. Nephrol Dial Transplant, 2005. 20(1): p. 124-8.

24.          Santangelo, F., et al., Restoring glutathione as a therapeutic strategy in chronic kidney disease. Nephrology Dialysis Transplantation, 2004. 19(8): p. 1951-5.

25.          Ashworth, A. and S.T. Webb, Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery? Interact CardioVasc Thorac Surg, 2010. 11(3): p. 303-308.

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