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Home , Methylcobalamin, Vitamin K

The potential protective role of K in diabetic neuropathy

DILIP MEHTA

Viridis Biopharma 6/10 Jogani Industrial Complex ew cases of diabetes are symptomatic pain relief (3-5). V. N. Purav Marg, Chunabhatti increasing worldwide at a rapid Mumbai 400022, India The etiopathology of peripheral pace, with the total number of neuropathy is poorly understood and many [email protected] people with diabetes was projected factors, including dietary deficiencies, may www.viridisbiopharma.com Nto rise from 171 million in 2000 to 366 million contribute to the clinical manifestation of the in 2030 – an increase of nearly 200 million in condition. Deficiency of (also only three decades. There are more cases of known as cobalamin), which results in a lack diabetes in women and urban populations, of a related compound, , is with diabetes in developing countries projected manifested by megaloblastic anemia, and to double in the coming years (1). has been associated with significant Based on reports from the Centers for neurological pathology, especially peripheral Disease Control and Prevention, type 2 neuropathy (6-8). Vitamin B12 is also diabetes dult onset diabetes affects associated with the onset of diabetic approximately 9.3% of the general neuropathy. In patients with diabetic population in the United States in contrast to neuropathy, vitamin B12 deficiency may be 25.9% among those 65 years or older (2). aggravated by the use of antidiabetic agents Diabetes mellitus accounts for 90% of the such as metformin (9-11). Even short-term cases of diabetes patients (3,4). treatment with metformin causes a decrease The prevalence of type 2 diabetes in serum cobalamin, folic acid and an increases with age, higher then 25 body increase in homocysteine, which leads to mass index and the presence of the disease in patients with in family history. The onset of symptoms is Dilip Mehta diabetes. Therefore, diabetic patients are gradual, often masked by chronic tiredness often advised to consume vitamin B12 and and stress of daily life (3,4). folic acid supplements as a prophylactic and have their levels monitored regularly. One of the most common and debilitating However, review of the epidemiological manifestations of diabetes is diabetic data to find the prevalence of vitamin B12 neuropathy or an inflammatory condition deficiency in early type 2 diabetic patients affecting the function and structure of the and the relationship with severity of peripheral nerves. This condition may peripheral neuropathy, found no evidence precede by years the formal diagnosis of that the use of oral vitamin B12 supplements diabetes. At least 50% of patients with is associated with improvement in the clinical diabetes have some form of neuropathy (5). symptoms of diabetic neuropathy. Currently, Early signs of peripheral neuropathy there is no effective treatment of diabetic manifest through what is colloquially neuropathy and persistence of the neurological described as “pins and needles” pain, symptoms, despite routine treatment, is a well paresthesia, loss of sensation in the feet and identified unmet medical need. loss of deep tendon reflexes at the ankles. The risk of developing peripheral neuropathy A recent clinical observation by two increases with the duration of diabetes and researchers, Dr. Dilip Mehta from Viridis Inc. deteriorating glycemic control. Some patients and Dr. Vaydia Ashok from Medical Research with neuropathy may experience extremely Center-Kasturba Health Society, Mumbai, is painful symptoms, whereas others may have that relieves idiopathic muscle objectively marked neurological deficit cramps as well as symptoms of diabetic without significant painful neurological neuropathy; this illuminating observation led symptoms. Current clinical management to a pioneering human study evaluating the guidelines for diabetic peripheral neuropathy effects of vitamin K2 (menaquinone-7 or are limited to adequate glucose control and K2-7) in peripheral neuropathy caused by

20 MARCH/APRIL 2017 VITAMINS vitamin B12 deficiency and/or type 2 THE ROLE OF myelin and repair of peripheral nerves diabetes. An open-labeled clinical study after demyelinating injury. Furthermore, was conducted in 30 patients clinically The etiology of diabetic neuropathy has research conducted in recent years linked presenting with peripheral neuropathy and been debated and one of the emerging alterations in sphingolipid to suffering from either megaloblastic anemia possibilities is neuropathy as an the aging process and neurodegenerative due to vitamin B12 deficiency and/or type 2 inflammatory autoimmune condition that disorders such as Alzheimer’s disease and diabetes. The Ethics Committee Approval for damages the myelin sheet of peripheral Parkinson’s disease. the study was obtained from the Ethics nerves and the potential role of vitamin K Committee of T.N.M.C.&B.Y.L. Nair Ch. in alleviating this condition. Chronic Hospital, and the trial was registered with inflammatory demyelinating REFERENCES Registry of India (CTRI). polyneuropathy (CIDP) is a relapsing– Out of 30 patients enrolled for the remitting, immune system-mediated 1) Wild S., Roglic G., Green A., Sicree R., King study 23, 13 male and 10 female, patients disorder of the peripheral nervous system. H. “Global prevalence of diabetes: estimates were suffering from megaloblastic anemia There is an increasing body of literature for the year 2000 and projections for 2030” and 7, 3 male and 4 female, patients had Diabetes Care 2004, 27 (5), 1047-53. suggesting that the prevalence of CIDP 2) type 2 diabetes mellitus. The patients tends to be higher in diabetic patients, National Diabetes Statistics Report: Estimates were divided in two groups based upon of Diabetes and Its Burden in the United States especially in those of older age. Some (trans: Services U.S.D.o.H.a.H.); Centers for the validated visual analog scale score for investigators report CIDP to be more Disease Control and Prevention, Atlanta, GA, the degree of severity of symptoms of frequent in patients with diabetes, while 2014. peripheral neuropathy, i.e. tingling and others report equal occurrence of CIDP in 3) AACE Task Force for Developing a Diabetes numbness along with weakness, fatigue type 1 diabetes and type 2 diabetes (13,14). Comprehensive Care Plan Endocr. Pract. 2011, and cramps. The group A (Severe, 25 The preliminary report on clinical 17 (Suppl 2), 1-53. subjects) had a VAS score of 8-9 and efficacy of vitamin K2-7 in diabetic 4) Chin R.L., Rubin M. “Diabetic Neuropathy” in , 2nd Edn., group B (Moderate, 5 subjects) with a neuropathy may be particularly interesting Principles of Diabetes Mellitus score of 6-8. Vitamin K2-7 capsules (100 Poretsky L. Ed.; Springer, New York, 2010, in view of reported role of this vitamin in pp.357-70. mg/capsule, twice a day) was given orally myelin synthesis and myelin repair in 5) Russell J.W., Zilliox L.A. “Diabetic for 8 weeks. Patients kept a regular record central and peripheral nervous systems neuropathies” of the intensity of the symptoms during Continuum: Lifelong Learning (15). Myelin belongs to a group of in Neurology 2014, 20, 1226-40. the baseline and throughout the study. complex called sphingolipids, 6) Head K.A. “Peripheral neuropathy: At the baseline group A had VAS score present in all mammalian cells where they pathogenic mechanisms and alternative of 8-9, and group B had VAS score of 6-8. are major components of cell membranes. therapies” Altern. Med. Rev. 2006, 11, 294-329. By fourth week, the score in group A had They are present in particularly high 7) Andrès E., Loukili N.H., Noel E. et al. reduced to 5-6 with the reduction in the concentrations in cells of the central and “Vitamin B12 (cobalamin) deficiency in intensity of the symptoms of tingling and elderly patients” CMAJ 2004, 171, 251-9. peripheral nervous systems with the major 8) Liu K.W, Dai L.K, Jean W. “Metformin-related numbness. Patients reported feeling sphingolipids consisting of ceramide, vitamin B12 deficiency” Age Ageing. 2006, improvements with the supplementation. sphingomyelin, cerebroside, , and 35, 200-1. Further, they reported that the weakness ganglioside. Certain sphingolipids in the 9) Ting R.Z., Szeto C.C., Chan M.H., Ma K.K., and fatigue had also reduced. Patients central and peripheral nervous systems are Chow K.M. “Risk factors of vitamin B(12) who had also complained of cramps were highly correlated with the levels of deficiency in patients receiving metformin” feeling better, reporting significant vitamin K. Arch. Intern. Med. 2006, 166, 1975-9. reduction of occurrence and intensity of In the nervous system, vitamin K 10) Dunnigan S.K., Ebadi H., Breiner. A., cramps. The VAS score in group B had operates through the and Katzberg. H.D., Lovblom. L.E., Perkins B.A., Bril V. “Comparison of diabetes patients with reduced to 3-4. The pattern in reduction of activation of Gla residues on GAS6 the symptoms in group B was similar to “demyelinating” diabetic sensorimotor (growth arrest-specific gene 6 protein) polyneuropathy to those diagnosed with CIDP” group A. By the end of eight weeks, the which is structurally related to another Brain and Behavior 2013, 3 (6), 656-63. VAS score in both groups was reduced to vitamin K-dependent protein (VKDP), 11) Dunnigan S.K., Ebadi H., Breiner A., 1-2, especially the intensity of tingling and anticoagulation factor . GAS6 and Katzberg H.D., Barnett C., Perkins B.A., Bril numbness sensation was reduced related S protein bind and activate the V. “The characteristics of chronic inflammatory concurrent with the length of vitamin K2-7 receptor tyrosine kinases of the Tyro3, Axl, demyelinating polyneuropathy in patients with supplementation. Interestingly, at the and Mer (TAM) family involved in cellular and without diabetes – An observational onset of the study, 10 out of 23 patients signaling which stimulates the generation study” PloS One 2014, 9 (2), e89344. in the vitamin B12 deficiency group had of central nervous system repair cells 12) Kulkarni V.K., Upase D.P., Dound Y.A., Jadhav S.S, Bhave A.A., Mehta D.S, Vaidya residual neuropathic symptoms in spite of (oligodendrocytes) and increased myelin adequate blood levels of vitamin B12; the A.D.B. “The effect of vitamin K2-7 in production including repair after myelin peripheral neuropathy due to Vitamin B12 symptom score reduced following vitamin injury (demyelinating injury). and/or diabetes mellitus: A K2-7 therapy. Vitamin K2-7 was well may also act in the central nervous system Preliminary Stud”. tolerated by all patients, with no subjective The Indian Practitioner independently of its role in the 2013, 66 (10), 625-9. and objective adverse events reported carboxylation reaction. In this independent 13) Sharma K.R., Cross J., Ayyar D.R., Martinez- during the period of therapy. of the VKDP mechanism, vitamin K is Arizala A., Bradley W.G. “Diabetic This preliminary study has shown for critical for healthy myelin by activating demyelinating polyneuropathy responsive to the first-time that vitamin K2-7 at a dose 3-ketodihydrosphingosine (3- intravenous immunoglobulin therapy” Archives of 100 mg twice a day for 8 weeks was KDS) involved in sphingolipid synthesis. of Neurology 2002, 59 (5), 751-7. well tolerated and safe with a significant 14) Sharma K.R., Cross J., Farronay O., Ayyar D.R., Shebert R.T., Bradley W.G. “Demyelinating therapeutic activity. This initial study In conclusion, the discussed pioneering neuropathy in diabetes mellitus” Archives of encourages a larger sample size, placebo- clinical study in managing peripheral Neurology 2002, 59 (5), 758-65. controlled randomized double-blind trial of neuropathy with vitamin K2-7 is supported 15) Ferland G. “Vitamin K and the Nervous System: vitamin K2-7 in the management of by literature data demonstrating that An Overview of its Actions” Adv. Nutr. 2012, diabetic neuropathy (12). vitamin K may stimulate regeneration of 3, 204-12.

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