Mitochondria as a Target for Future Diabetes Treatments
Keywords:Reactive Oxygen Species, Mitochondrial DNA, Diabetes Mellitus, , Electron Transport, Oxidative Phosphorylation
Diabetes mellitus is rapidly becoming the world’s most dangerous serial killer. Type 1 diabetes (T1D) is a currently incurable autoimmune disease marked by progressive, and eventually exhaustive, destruction of the insulin-producing pancreatic beta cells. Type 2 diabetes (T2D) describes the combination of insulin resistance in peripheral tissue, insufficient insulin secretion from the pancreatic beta cells, and excessive glucagon secretion from the pancreatic alpha cells. T1D as well as severe cases of T2D are treated with insulin replacement, which can merely be considered as life support for the acute phases of the disease. Islet replacement of insulin-producing pancreatic beta cells represents a potential treatment method for both insulin-depleted diabetes (T1D) and insulin-resistant diabetes (T2D) and may shift diabetes management from life saving measures to a cure. One of the key challenges in islet transplants is the generation of reactive oxygen species (ROS) and the associated oxidative stress, which restricts graft longevity. A major leak of ROS takes place during oxidative phosphorylation at mitochondrial electron transport chain (ETC). Additionally, hyperglycemia-induced superoxide (O2•-) production has been linked to the development and progression of diabetic complications, both macrovascular and microvascular. Decreasing ROS in diabetic patients may prevent the incidence of long term diabetes complications. This review provides an overview of the role of mitochondria in diabetes, introducing them as a possible target for future treatment of diabetes.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004 Jan;27 Suppl 1:S5-S10.
Centers for Disease Control and Prevention. National Diabetes Statistics Re¬port 2014: Estimates of diabetes and its burden in the United States. Atlanta, GA: U.S. Department of Health and Human Services. Report number: 1, 2014.
Kadowaki T. Insights into insulin resistance and type 2 diabetes from knoc¬kout mouse models. J Clin Invest. 2000 Aug;106(4):459-65.
Bailey CJ, Blonde L, Del Prato S, Leiter LA, Nesto R; Global Partnership for Effecti¬ve Diabetes Management. What are the practical implications for treating diabetes in light of recent evidence? Updated recommendations from the Global Partner¬ship for Effective Diabetes Management. Diab Vasc Dis Res. 2009 Oct;6(4):283-7.
Bastaki S. Diabetes mellitus and its treatment. Int J Diabetes & Metabo¬lism. 2005;13(3):111-34.
Jakhmola V, Tangri P. Diabetes Mellitus a silent killer: Role of DPP4 inhibi¬tors in treatment. JPSBR. 2012 Mar-Apr; 2(2):49-53.
Dardano A, Bianchi C, Del Prato S, Miccoli R. Insulin degludec/insulin as¬part combination for the treatment of type 1 and type 2 diabetes. Vasc Health Risk Manag. 2014 Aug;10(1):465-75.
Chhabra P, Brayman KL. Current status of immunomodulatory and cellu¬lar therapies in preclinical and clinical islet transplantation. J Transplant. 2011;2011:637692.
Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabe¬tes Care. 2012 Jul;35(7):1436-45.
Ramkumar KM, Sekar TV, Bhakkiyalakshmi E, Foygel K, Rajaguru P, Berger F, et al. The impact of oxidative stress on islet transplantation and monitoring the graft survival by non-invasive imaging. Curr Med Chem. 2013;20(9):1127-46.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Loannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009 Jul 21;6(7):e1000100.
Papa S, Martino PL, Capitanio G, Gaballo A, De Rasmo D. The oxidative phosphoryla¬tion system in mammalian mitochondria. In: Scatena R, Bottoni P, Giardina B, editors. Advances in mitochondrial Medicine. 1st ed. Dordrecht: Springer; 2012. p. 3-38.
Mitchell P, Moyle J. Chemiosmotic hypothesis of oxidative phosphoryla¬tion. Nature. 1967 Jan 14;213(5072):137-9.
Alberts B, Johnson A, Lewis J, Raff M, Roberts K. Energy conversion: Mitochondria and chloroplasts. In: Alberts B, Johnson A, Lewis J, Raff M, Roberts K, et al, editors. Molecular biology of the cell. 5th ed. New York: Garland Science; 2007. p. 813-78.
Morales-Indiano C, Lauzurica R, Pastor MC, Bayés B, Sancho A, Troya M, et al. Greater posttransplant inflammation and oxidation are associated with worsening kidney function in patients with pretransplant diabetes mellitus. Transplant Proc. 2009 Jul-Aug; 41(6):2126-8.
Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J. 2000 Jan 15;345 Pt 2:161–79.
Nafar M, Sahraei Z, Salamzadeh J, Samavat S, Vaziri ND. Oxidative stress in kidney transplantation: causes, consequences, and potential treatment. Iran J Kidney Dis. 2011 Nov;5(6):357-72.
Carter BW, Schucany WG. Brown adipose tissue in a newborn. Proc (Bayl Univ Med Cent). 2008 Jul; 21(3):328-30.
Cali T, Ottolini D, Brini M. Mitochondrial Ca2+ as a key regulator of mitochondrial activities. In: Scatena R, Bottoni P, Giardina B, editors. Advances in mitochondrial medicine. 1st ed. Dordrecht: Springer. 2012. p. 53-73.
Brownlee M. The pathobiology of diabetic complications: a unifying me¬chanism. Diabetes. 2005 Jun;54(6):1615-25.
Chung SS, Ho EC, Lam KS, Chung SK. Contribution of polyol pathway to dia¬betes-induced oxidative stress. J Am Soc Nephrol. 2003 Aug;14(Suppl 3):S233-6.
Knowles JR. Enzyme-catalyzed phosphoryl transfer reactions. Annu Rev Biochem. 1980 Jul; 49(1):877-919.
Shen GX. Mitochondrial dysfunction, oxidative stress and diabetic cardiovas¬cular disorders. Cardiovasc Hematol Disord Drug Targets. 2012 Dec;12(2):106-12.
Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003 Oct 15;552(Pt 2):335-44.
Xu H, Czerwinski P, Hortmann M, Sohn HY, Förstermann U, Li H. Protein kinase C alpha promotes angiogenic activity of human endothelial cells via induction of vascular endothelial growth factor. Cardiovasc Res. 2008 May 1;78(2):349-55.
Hammes HP, Martin S, Federlin K, Geisen K, Brownlee M. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11555-8.
Berg JM, Tymoczko JL, Stryer L. Glycolysis and gluconeogenesis. In: Ahr K, Baker A, Tymoczko N, Goldman D, Moscatelli B, et al, editors. Biochemistry. 6th ed. New York: W. H. Freeman. 2006. p. 433-74.
Thallas-Bonke V, Cooper ME. Tandem inhibition of PKC in Diαβetic nephro¬pathy: it takes two to tango? Diabetes. 2013 Apr;62(4):1010-1.
Yan SF, D'Agati V, Schmidt AM, Ramasamy R. Receptor for advanced glycation endproducts (RAGE): a formidable force in the pathogenesis of the cardiovas-cular complications of diabetes & aging. Curr Mol Med. 2007 Dec;7(8): 699-710.
Holub BJ. Metabolism and function of myo-inositol and inositol phospho¬lipids. Annu Rev Nutr. 1986 Jul;6(1):563-97.
Maitra A. Endocrine system. In: Kumar V, Abbas AK, Aster JC, editors. Rob¬bins basic pathology. 9th ed. Philadelphia: Elsevier Saunders. 2013. p. 715-64.
Salway JG, Whitehead L, Finnegan JA, Karunanayaka A, Barnett D, Payne RB. Effect of myo-inositol on peripheral-nerve function in diabetes. Lancet. 1978 Dec 16;2(8103):1282-4.
Newsholme P, Haber EP, Hirabara SM, Rebelato EL, Procopio J, Morgan D, et al. Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mi¬tochondrial ROS production and activity. J Physiol. 2007 Aug 15;583(Pt 1):9-24.
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-acti¬vated signaling pathways mediators of insulin resistance and beta-cell dys¬function? Diabetes. 2003 Jan;52(1):1-8.
Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010 Apr 30;106(8):1319-31.
Squadrito GL, Pryor WA. Oxidative chemistry of nitric oxide: the roles of superoxi¬de, peroxynitrite, and carbon dioxide. Free Radic Biol Med. 1998 Sep;25(4-5):392-403.
Brownlee M. Biochemistry and molecular cell biology of diabetic compli¬cations. Nature. 2001 Dec 13;414(6865):813-20.
El-Khoury R, Kemppainen KK, Dufour E, Szibor M, Jacobs HT, Rustin P. Engineering the alternative oxidase gene to better understand and counteract mitochondrial defects: state of the art and perspectives. Br J Pharmacol. 2014 Apr;171(8):2243-9.
Bouaita A, Augustin S, Lechauve C, Cwerman-Thibault H, Benit P, Simonu¬tti M, et al. Downregulation of apoptosis-inducing factor in Harlequin mice induces progressive and severe optic atrophy which is durably prevented by AAV2-AIF1 gene therapy. Brain. 2012 Jan;135(Pt 1):35-52.
How to Cite
Authors who publish with this journal agree to the following terms:
- The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
- Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
- The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
- Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site; with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
- The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
- Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
- The Author represents and warrants that:
- the Work is the Author’s original work;
- the Author has not transferred, and will not transfer, exclusive rights in the Work to any third party;
- the Work is not pending review or under consideration by another publisher;
- the Work has not previously been published;
- the Work contains no misrepresentation or infringement of the Work or property of other authors or third parties; and
- the Work contains no libel, invasion of privacy, or other unlawful matter.
- The Author agrees to indemnify and hold Publisher harmless from the Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.
Enforcement of copyright
The IJMS takes the protection of copyright very seriously.
If the IJMS discovers that you have used its copyright materials in contravention of the license above, the IJMS may bring legal proceedings against you seeking reparation and an injunction to stop you using those materials. You could also be ordered to pay legal costs.
If you become aware of any use of the IJMS' copyright materials that contravenes or may contravene the license above, please report this by email to email@example.com
If you become aware of any material on the website that you believe infringes your or any other person's copyright, please report this by email to firstname.lastname@example.org