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      Perspectives on Peripheral Neuropathy as a Consequence of Metformin-Induced Vitamin B12 Deficiency in T2DM

      review-article
      1 , * , 1 , 2
      International Journal of Endocrinology
      Hindawi

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          Abstract

          Peripheral neuropathy (PN) is a primary complication of type 2 diabetes mellitus (T2DM) and a direct manifestation of vitamin B12 deficiency. Examining the effects of metformin use on PN status became imperative following clinical studies that showed the vitamin B12-lowering effect of the medication. The complexity of the topic and the inconsistency of the results warrant consideration of topic-specific perspectives for better understanding of the available evidence and more appropriate design of future studies.

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          Most cited references39

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          Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

          Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Neurologic aspects of cobalamin deficiency.

            We reviewed 153 episodes of cobalamin deficiency involving the nervous system that occurred in 143 patients seen over a recent 17-year period at 2 New York City hospitals. Pernicious anemia was the most common underlying cause of the deficiency. Neurologic complaints, most commonly paresthesias or ataxia, were the first symptoms of Cbl deficiency in most episodes. The median duration of symptoms before diagnosis and treatment with vitamin B12 was 4 months, although long delays in diagnosis occurred in some patients. Diminished vibratory sensation and proprioception in the lower extremities were the most common objective findings. A wide variety of neurologic symptoms and signs were encountered, however, including ataxia, loss of cutaneous sensation, muscle weakness, diminished or hyperactive reflexes, spasticity, urinary or fecal incontinence, orthostatic hypotension, loss of vision, dementia, psychoses, and disturbances of mood. Multiple neurologic syndromes were often seen in a single patient. In 42 (27.4%) of the 153 episodes, the hematocrit was normal, and in 31 (23.0%), the mean corpuscular volume was normal. Neutropenia and thrombocytopenia were unusual even in anemic patients. In nonanemic patients in whom diagnosis was delayed, neurologic progression frequently occurred although the hematocrit remained normal. In 27 episodes, the serum cobalamin concentration was only moderately decreased (in the range of 100-200 pg/ml) and in 2 the serum level was normal. Neurologic impairment, as assessed by a quantitative severity score, was judged to be mild in 99 episodes, moderate in 39 and severe in 15. Severity of neurologic dysfunction before treatment was clearly related to the duration of symptoms prior to diagnosis. In addition, the hematocrit correlated significantly with severity, independent of the longer duration of symptoms in nonanemic patients. Four patients experienced transient neurologic exacerbations soon after beginning treatment with cyanocobalamin, with subsequent recovery. Followup evaluation was adequate to assess the neurologic response to vitamin B12 therapy in 121 episodes. All patients responded, and in 57 (47.1%), recovery was complete, with no remaining symptoms or findings on examination. The severity score was reduced by 50% or greater after treatment in 91% of the episodes. Residual long-term moderate or severe neurologic disability was noted following only 7 (6.3%) episodes. The extent of neurologic involvement after treatment was strongly related to that before therapy as well as to the duration of symptoms. The percent improvement over baseline neurologic status after treatment was inversely related to duration of symptoms and hematocrit. Some evidence of response was always seen during the first 3 months of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice.

              Metformin a well known antidiabetic drug has been recently investigated and proposed to promote neurogenesis and enhance the spatial memory formation. In the present study, we aim to investigate the neuroprotective effect of metformin with respect to Parkinson's disease (PD). MPTP (Sigma-Aldrich, St. Louis, MO, USA) (25mg/kg) along with Probenecid (250 mg/kg) was administrated for five consecutive days to induce Parkinsonism in mice. Metformin 500 mg/kg was administrated orally for 21 days. Motor co-ordination and locomotor activities were evaluated by rotarod and open-field tests. The oxidative stress levels were assessed by estimating the activity of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and lipid peroxidation (LPO) specifically in the midbrain. Dopaminergic degeneration was evaluated by analyzing the tyrosine hydroxylase (TH) by immunostaining and nissl staining of the substantia nigra (SN) region of the brain. In addition brain-derived neurotrophic factor (BDNF) was also estimated. Our findings demonstrated that long-term metformin treatment resulted in significant improvement of the locomotor and muscular activities in MPTP-treated mice than acute treatment. Metformin treatment significantly improved the antioxidant activity as compared to MPTP-treated group. TH-positive cells decreased up to 16% in MPTP-treated mice as compared to normal mice (P<0.001) and were found to be protected from degeneration in metformin-treated mice (47%, P<0.01). Interestingly, BDNF levels were found to be significantly elevated in metformin treatment group as compared to MPTP treatment mice (P<0.001). In conclusion, metformin possesses neuroprotective activity and provides preclinical support for therapeutic prospective of this compound in the treatment of PD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Endocrinol
                Int J Endocrinol
                IJE
                International Journal of Endocrinology
                Hindawi
                1687-8337
                1687-8345
                2017
                27 August 2017
                : 2017
                : 2452853
                Affiliations
                1Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
                2Department of Internal Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa
                Author notes
                *Marwan A. Ahmed: mrwnwd@ 123456yahoo.com

                Academic Editor: Ilias Migdalis

                Author information
                http://orcid.org/0000-0002-3909-7220
                Article
                10.1155/2017/2452853
                5591993
                28932240
                0e499397-19a4-40a1-be6d-d74bf7a86cea
                Copyright © 2017 Marwan A. Ahmed et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 May 2017
                : 31 July 2017
                Categories
                Review Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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