CC BY
14
UDC 616.8:616.379-008.64 DOI: 10.22141/2224-0721.15.7.2019.186062
K. Singh, T. Yuzvenko <E, D. Kogut )
Ukrainian Research and Practical Centre for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine, Kyiv, Ukraine
Transketolase activators as a novel therapy: their significance in the pathogenesis and treatment of diabetic microvascular complications
For citation: Miznarodnij endokrinologicnij zurnal. 2019;15(7):576-579. doi: 10.22141/2224-0721.15.7.2019.186062
Abstract. The review article presents an analysis of the literature on the effect of thiamine and its derivatives on the metabolism in cells and its role in the pathogenesis of complications of diabetes mellitus. The features of the conversion of an inactive form that enters the human body with food and drugs into the active form of thiamine are considered. The metabolic pathways of thiamine and its derivatives are also clarified. The article describes the features of allithiamine and the practical importance of its metabolism in cells for the treatment of complications of diabetes mellitus, in particular, diabetic polyneuropathy. The data in this article will help clinicians understand the relevance and necessity of using drugs containing thiamine in their practice.
Keywords: diabetes mellitus; microvascular complications; transketolase; diabetic polyneuropathy; thiamine; allithiamines; review
—1 ' ,—1 ® Огляд л^ератури
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International Journal of Endocrinology
Introduction
Approximately 425 million people in the world have diabetes mellitus (DM), out of which around 1.3 million cases of DM were registered in Ukraine. The global prevalence of DM in individuals over the age of 18 years has risen from 4.7 % in 1980 to 8.5 % in 2014 [1]. According to the WHO, diabetes was the seventh leading cause of death in 2016.
DM is characterized by hyperglycemia-induced tissue damage as established in the Diabetes Control and Complications Trial and the U.K. Prospective Diabetes Study. Generally, the damaging effects of hyperglycemia are differentiated into microvascu-lar complications (diabetic retinopathy, neuropathy and nephropathy) and macrovascular complications (coronary artery disease, peripheral artery disease and
stroke). The effects of hyperglycemia are not seen in all cells of the body, but are distinct only in certain types of cells: neurons and Schwann cells in peripheral nerves, capillary endothelial cells, mesangial cells in the renal glomerulus due to their inability to effectively maintain a constant level of glucose, in contrast most cells are able to reduce the transport of glucose when exposed to hyperglycemia [2, 3].
Diabetic sensory polyneuropathy (DSPN) is amongst the most common long-term complications of diabetes [7]. It has been estimated that 50 % of diabetic patients will have neuropathy within 25 years of their disease history [8]. The increased risk of non-traumatic foot amputations and lower extremity disease in diabetic patients has been attributed to DSPN [9, 10]. An early diagnosis helps identify patients at risk before the onset of disabling
© 2019. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
Для кореспонденци: Юзвенко Т.Ю., доктор медичних наук, заступник директора, УкраТнський науково-практичний центр ендокринноТ xipyprif, трансплантаци ендокринних оргашв i тканин МОЗ УкраТни, Кловський y3Bi3, 13а, м. КиТв, 01021, УкраТна; e-mail: tatyuzvenko@gmail.com
For correspondence: T. Yuzvenko, MD, PhD, Deputy Director, Ukrainian Research and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine, Klovsky Descent, 13a, Kyiv, 01021, Ukraine; e-mail: tatyuzvenko@gmail.com Full list of author information is available at the end of the article.
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complications. Despite its common occurrence, DSPN shows considerable variability in prevalence. This can be attributed to the differences in definitions of neuropathy and the tests used for the evaluation [11].
Information on existing mechanisms
The exact mechanism of damage to the peripheral nerves due to hyperglycemia is not understood fully but is likely to be related to sorbitol accumulation, advanced glycation end products (AGE) and oxidative stress [5]. Peripheral neuropathy may manifest in various forms: sensory, focal, multifocal, autonomic. Although neurological signs and symptoms are recommended diagnostic tools [12], subjectivity, lack of reproducibility and proficiency of the examiner leads to inaccuracies [13]. Moreover, asymptomatic neuropathy is common, present in up to 50 % of cases, and clinical features do not always correlate with the severity of pathological changes [14]. Other forms of neuropathy may replicate the picture in diabetic sensory neuropathy and mononeuropa-thy [5]. Chronic inflammatory polyneuropathy, vitamin B12 deficiency, hypothyroidism, and uremia should be considered while evaluating diabetic polyneuropathy in patients [15].
Diabetic autonomous neuropathy is also one of the important factors leading to morbidity and mortality in diabetic patients. Neuropathic changes may manifest as gastroparesis, constipation, erectile dysfunction, bladder dysfunction, resting tachycardia, silent ischemia, and even cardiac arrest [15].
The pathobiology of diabetic complications as a unifying mechanism has been explained in the Banting lecture in 2004. Hyperglycemia-induced mitochondrial superoxide production activates the four damaging pathways by inhibiting GAPDH that leads to microvascular diabetic complications.
The polyol pathway activation resulted from the increased glucose flux causes sorbitol accumulation in cells. Increased sorbitol is considered as the underlying mechanism in the development of diabetic microvascu-lar complications [4, 5].
Advanced glycation end products pathway leads to the increase of the major intracellular AGE precursor me-thylglyoxal [4]. These substances have been linked with the formation of microaneurysms and pericyte loss [5].
Protein kinase C pathway is activated due to the inhibition of GAPDH activity that leads to the increase in glyceraldehyde-3-phosphate which is a precursor to dia-cylglycerol [4].
Hexosamine pathway realizes by the conversion of fructose-6-phosphate by the enzyme GFAT to UDP-N-acetylglucosamine [4], which results in increased expression of TGF p1 and plasminogen activator inhibi-tor-1 [6].
Prophylaxis and treatment
According to the generally approved guidelines and practices, the primary goal of the therapy in DM patients is to control symptoms and prevent worsening of micro-vascular diabetic complications. Although some studies
suggest that tight glycemic control and avoidance of gly-cemic excursions may improve symptoms in diabetic peripheral neuropathy [5].
One of the novel approaches for the prevention and treatment of diabetic complications based upon the unifying mechanism for the pathogenesis of diabetic complications is using the transketolase activators [4]. Fruc-tose-6-phosphate and glyceraldehyde-3-phosphate are also final products of transketolase reaction in the pentose phosphate shunt [16]. As glycolytic intermediates can flow to the pentose phosphate pathway depending on the concentration of substrate presented to transke-tolase and as in the case of diabetic patients with hyper-glycemia, activation of transketolase diverts the flux of glycolytic intermediates away from the damaging pathways [5]. The enzyme transketolase requires a co-factor thiamine for activation.
Thiamine diphosphate, also known as thiamine pyrophosphate or cocarboxylase is a water-soluble vitamin. Thiamine diphosphate is the coenzyme for five key metabolic enzymes: mitochondrial pyruvate dehydrogenase complexes, oxoglutarate dehydrogenase complexes, branched-chain 2-oxo acid dehydrogenase complexes, 2-hydroxyacyl-CoA lyase 1 as well as the cytosolic trans-ketolase.
Allithiamine (benfotiamine) is a member of the class of lipophilic thiamine derivatives. The unique properties of the allithiamines result from the opening of the thiazole ring of thiamine upon reaction with sulphur compounds. Upon dephosphorylation of benfotiamine in the intestinal tract [17, 18] a lipophilic molecule is produced, which readily diffuses across cell membranes and is absorbed much better than water-soluble thiamine salts. This property allows for greater absorption both in the intestines and in target tissues as compared with thiamine itself. Following penetrating into the cell, the molecule undergoes catalytic reduction by intracellular sulfhydryl compounds and/or enzymatic debenzoylation [17], closing the thiazole ring and releasing the active thiamine into the cell and circulation [17].
In one study, thiamine activated transketolase by 25 % in arterial endothelial cells, benfotiamine activated transketolase by 250 % [5].
The properties of benfotiamine and its role in cell metabolism have been described in various fundamental research papers, to name a few: Hammes H.P. et al. described that benfotiamine prevents the increase in UDP-N-acetylglucosamine, and normalizes protein kinase C activity and prevents nuclear factor kappa B activation in retina of diabetic patients [20]. Berrone E., Beltramo E. et al. demonstrated that benfotiamine corrects imbalances in the polyol pathway by decreasing aldose reductase activity, sorbitol concentrations and intracellular glucose, thereby protecting endothelial cells from glucose-induced damage [21]; benfotiamine corrects glucose-induced endothelial cell damage by normalizing cell replication rates and decreasing apop-tosis [21].
The significance of benfotiamine in clinical practice has also been demonstrated in many clinical trials with
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variable trial designs, patient groups and history of diabetes, e.g. the BEDIP study and BENDIP study.
Conclusions
As allithiamines activate transketolase more significantly, further investigation is needed to verify the effect of allithiamines in comparison to thiamine diphosphate in terms of their affinity to THTR-1 receptor and THTR-2 receptor, which are encoded by the reduced folate carrier family.
In the Ukrainian Research and Practical Centre for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues, we have also been studying the role of benfotiamine. A fundamental study regarding the efficacy of benfotiamine in treating patients with diabetic polyneuropathy in its various stages of manifestation and its effect on the expression of genes of the reduced folate carrier is being carried out.
The detailed description of the study is out of the scope of this article and will be presented in consequent articles.
Conflicts of interests. Authors declare the absence of any conflicts of interests and their own financial interest that might be construed to influence the results or interpretation of their manuscript.
References
1. Emerging Risk Factors Collaboration, N, Gao P, Se-shasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative metaanalysis of 102 prospective studies. Emerging Risk Factors Collaboration. Lancet. 2010 Jun 26;375(9733):2215-22. doi: 10.1016/S0140-6736(10)60484-9.
2. Kaiser N, Sasson S, Feener EP, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42(1):80-89. doi: 10.2337/diab.42.1.80.
3. Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P. Overexpression of glucose transporters in rat me-sangial cells cultured in a normal glucose milieu mimics the diabeticphenotype. J Clin Invest. 1995 0ct;96(4):1802-14. doi: 10.1172/JCI118226.
4. Brownlee M. The pathobiology of diabetic complications, a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. doi: 10.2337/diabetes.54.6.1615.
5. Fowler MJ. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 2008;26(2):77-82. doi: 10.2337/diaclin.26.2.77.
6. Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator in-hibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A. 2000 Oct 24;97(22): 12222-6. doi: 10.1073/ pnas.97.22.12222.
7. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinop-athy, and nephropathy in a population-based cohort: the Roch-
_iEI
ester Diabetic Neuropathy Study. Neurology. 1993;43(4):817-24. doi: 10.1212/wnl.43.4.817.
8. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285-93. doi: 10.2337/dc10-1303.
9. Vamos EP, Bottle A, Edmonds ME, Valabhji J, Majeed A, Millett C. Trends in lower extremity amputations in people with and without diabetes in England. 1996-2005. Diabetes Res Clin Pract. 2010;87(2):275-82. doi: 10.1016/j.diabres.2009.11.016.
10. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005 Jan 12;293(2):217-28. doi: 10.1001/jama.293.2.217.
11. Llewelyn JG, Tomlinson DR, Thomas PK. Diabetic Neuropathies. In: Dyck PJ, Thomas, PK, editors. Peripheral Neuropathy. 4th Edition. Philadelphia: Elsevier; 2005. 19511992 pp.
12. Dyck PJ. Severity and staging of diabetic polyneuropathy. In: Gries FA, Cameron NE, Low PA, Ziegler D, editors. Textbook of Diabetic Neuropathy. Stuttgart, Thieme; 2003. 170175 рр.
13. Dyck PJ, Overland CJ, Low PA, et al. Signs and symptoms versus nerve conduction studies to diagnose diabetic sen-sorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve. 2011;42(2):157-64. doi: 10.1002/mus.21661.
14. Boulton AJM, Malik RA, Arezzo JC, Sosensko JM. Diabetic Somatic neuropathies. Diabetes Care. 2004;27(6):1458— 78. doi: 10.2337/diacare.27.6.1458.
15. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956-962. doi: 10.2337/diaca-re.28.4.956.
16. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003(3);9:294-299. doi:10.1038/nm834.
17. Rote Liste, 2008. Fachinfo-Service, Fach informations verzeichnis Deutschland (einschlieslich EU-Zulassungen), Verlag Rote Liste Service GmbH, Frankfurt/Main.
18. Volvert ML, Seyen S, Piette M, et al. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 2008 Jun 12;8:10. doi: 10.1186/1471-2210-8-10.
19. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther. 1996 Feb;34(2):47-50. doi: 10.1186/1471-2210-8-10.
20. Hammes HP, Du X, Edelstein D, et al. Benfothaimine blocks three major pathways of hyperglycemic damage and prevents experimental diabetes. Nat Med. 2003 Mar;9(3):294-9. doi: 10.1038/nm834.
21. Beltramo E, Berrone E, Buttiglieri S, Porta M. Thiami-ne and benfothiamine prevent increased apoptosis in endotheli-al cells and pericytes cultured in high glucose. Diabetes Metab Res Rev. 2004 Jul-Aug;20(4):330-6. doi:10.1002/dmrr.470.
Received 11.08.2019 Revised 29.08.2019 Accepted 15.09.2019 ■
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Information about authors
K. Singh, endocrinologist, Department of Prophylaxis and Treatment of Diabetes, Ukrainian Research and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine, Kyiv, Ukraine
T. Yuzvenko, MD, PhD, Deputy Director, Ukrainian Research and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine, Kyiv, Ukraine; ORCID iD: https://orcid.org/0000-0003-4229-2075
Kogut D., endocrinologist, Department of Prophylaxis and Treatment of Diabetes, Ukrainian Research and Practical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine, Kyiv, Ukraine; ORCID iD: https://orcid.org/0000-0003-1135-2215
Снгх К., Юзвенко Т., Когут Д.
Укранський науково-практичний центр ендокринноïxipypriï, трансплантацИ ендокринних opraHiB та тканин МОЗ Украни, м. Ки)'в, Украна
Активатори транскетолази як новий niAxiA до лкування: ïx значення в патогенезi та лкуванн дiабетичниx мкросудинних ускладнень
Резюме. В оглядовш статп наведено аналiз лггературних даних про вплив TiaMiHy i його похщних на метаболiзм у клиинах i його роль у патогенезi ускладнень цукрового дiабетy. Розглянуто особливосп перетворення неактивноï форми, яка потрапляе в оргашзм людини з продуктами харчування та препаратами, в активну форму таам^. Та-кож розглянуп особливосп метаболiчних шляхив тiамiнy i його похщних. Описанi особливостi алiтiамiнy i приклад-
не значення його метаболiзмy в клiтинах для лiкyвання ускладнень цукрового дiабетy, зокрема дiабетичноï поль нейропати. Данi, наведенi в цш статтi, допоможуть клшь цистам зрозушти важливiсть та необхiднiсть використан-ня в своïй практицi препаратiв, що мiстять тiамiн. Ключовi слова: цукровий дiабет; мiкросyдиннi усклад-нення; транскетолаза; дiабетична полiнейропатiя; тiамiн; алiтiамiн; огляд
Сингх К., Юзвенко Т., Когут Д.
Украинский научно-практический центр эндокринной хирургии, трансплантации эндокринных органов и тканей МЗ Украины, г. Киев, Украина
Активаторы транскетолазы как новый подход к лечению: их значение в патогенезе и лечении диабетических микрососудистых осложнений
Резюме. В обзорной статье приведен анализ литературных данных о влиянии тиамина и его производных на метаболизм в клетках и его роли в патогенезе осложнений сахарного диабета. Рассмотрены особенности преобразования неактивной формы, которая попадает в организм человека с продуктами питания и препаратами, в активную форму тиамина. Также рассмотрены особенности метаболических путей тиамина и его производных. Описаны особенности аллитиамина и прикладное значе-
ние его метаболизма в клетках для лечения осложнений сахарного диабета, в частности диабетической полиней-ропатии. Данные, приведенные в этой статье, помогут клиницистам понять значимость и необходимость использования в своей практике препаратов, содержащих тиамин.
Ключевые слова: сахарный диабет; микрососудистые осложнения; транскетолаза; диабетическая полинейропа-тия; тиамин; аллитиамин; обзор
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