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Case report| Volume 21, P42-45, April 2018

Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: The importance of ketonuria

Open AccessPublished:February 07, 2018DOI:https://doi.org/10.1016/j.msard.2018.02.007
Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: The importance of ketonuria
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      Highlights

      • •
        On starting DMF a patient with MS and Type 1 diabetes experienced severe gastro-intestinal side-effects, associated with ketonuria but satisfactory glucose control.
      • •
        The mechanism of ketonuria is not clear, but it may be overlooked as a cause of side-effects.
      • •
        Caution is advised in patients with MS and diabetes mellitus treated with DMF.

      Abstract

      Background

      Dimethyl fumarate (DMF) is approved for use in patients with relapsing-remitting multiple sclerosis (MS). Its mechanism of action is still not well understood, but besides the immunological pathways in MS, it may also affect the metabolism of normally functioning internal organs, tissues and cells.

      Case presentation

      We report on the case of 29-year-old woman with satisfactorily-controlled type 1 diabetes (T1D), who was diagnosed as having MS. After administration of DMF she experienced intense, adverse gastro-intestinal reactions together with ketonuria up to 160 mg/dL. The highest ketone concentrations in the urine were observed approximately 2 h after each DMF dose and always with co-existing adverse reactions. Dose reduction did not improve symptoms and treatment had to be stopped. Twelve hours after the last dose of DMF all laboratory results returned to normal ranges and all gastro-intestinal adverse reactions were resolved within the following 24 h.

      Conclusion

      This is a first report of ketonuria in a MS-patient with T1D treated with DMF. Patients with MS and co-existing metabolic diseases, which are not contraindicated for DMF treatment, represent a unique opportunity to address questions regarding the possible mechanisms of action of DMF on the cellular metabolism. The use of DMF in patients with metabolic diseases needs closer attention.

      Keywords

      1. Background

      Dimethyl fumarate is approved in the United States and in Europe for use in patients with relapsing-remitting multiple sclerosis (MS). It acts via the activation of the nuclear factor (erythroid-derived 2), related factor 2 (Nrf2) response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress (
      • Linker R.A.
      • Lee D.H.
      • Ryan S.
      • van Dam A.M.
      • Conrad R.
      • Bista P.
      • Zeng W.
      • Hronowsky X.
      • Buko A.
      • Chollate S.
      • Ellrichmann G.
      • Bruck W.
      • Dawson K.
      • Goelz S.
      • Wiese S.
      • Scannevin R.H.
      • Lukashev M.
      • Gold R.
      Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
      Brain. 2011; 134: 678-692
      ). Such a model of action, however unique among other drugs for MS, is unspecific for MS pathology, because it affects not only cells related to immunological processes in MS, but also numerous normally functioning body cells and tissues. One of the affected physiological pathways may be the oxidation of fatty acids, mainly carried out in the mitochondria of hepatocytes, which leads to production of so-called ketone bodies (e.g. hydroxybutyrate, acetoacetate and acetone).
      Although different adverse reactions (AR) had been reported after administration of DMF, such as flushing, gastrointestinal (GI) complications, pruritis, rash or erythema, the reason of their occurrence is still not clearly determined. After several cases of liver injury in patients treated with the DMF that were reported in the postmarketing setting, the prescribing information for the DMF has been updated recently to include a warning of potential liver injury. One of the initial symptoms of severe metabolic imbalance in patients taking DMF may be the presence of ketone bodies in the blood or in the urine. According to European labelling, ketonuria may be detected in up to 45% of patients taking DMF (

      EMEA, 2017. Tecfidera®, EPAR: Summary of product characteristics - Product Information. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf〉. (Accessed 8 June 2017).

      ,

      FDA, 2013. Tecfidera®, Application 204063Orig1s000, Medical Review. 〈https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000MedR.pdf〉. (Accessed 8 June 2017).

      ), however, the data from the clinical trials are not conclusive in the matter of the clinical importance of such findings (
      • Fox R.J.
      • Miller D.H.
      • Phillips J.T.
      • Hutchinson M.
      • Havrdova E.
      • Kita M.
      • Yang M.
      • Raghupathi K.
      • Novas M.
      • Sweetser M.T.
      • Viglietta V.
      • Dawson K.T.
      Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.
      N. Engl. J. Med. 2012; 367: 1087-1097
      ,
      • Gold R.
      • Kappos L.
      • Arnold D.L.
      • Bar-Or A.
      • Giovannoni G.
      • Selmaj K.
      • Tornatore C.
      • Sweetser M.T.
      • Yang M.
      • Sheikh S.I.
      • Dawson K.T.
      Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
      N. Engl. J. Med. 2012; 367: 1098-1107
      ), and there is still lack of any postmarketing, real-world observations.
      Routine laboratory testing during DMF treatment is usually carried out on a monthly-basis, rather than daily or hourly. Therefore, important metabolic fluctuations after each DMF dose may be overlooked in routine clinical practice. Patients with other co-existing metabolic diseases, which are not contraindicated for DMF treatment, represent a unique opportunity to address questions regarding possible mechanisms of action of DMF on the cellular metabolism. About 0.85% of MS patients suffer from type 1 diabetes mellitus (T1D) (
      • Langer-Gould A.
      • Albers K.B.
      • Van Den Eeden S.K.
      • Nelson L.M.
      Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study.
      Mult. Scler. 2010; 16: 855-861
      ). Both of these diseases belong to the autoimmunological spectrum and share several similarities in immunological and epidemiological features (
      • Tettey P.
      • Simpson Jr., S.
      • Taylor B.V.
      • van der Mei I.A.
      The co-occurrence of multiple sclerosis and type 1 diabetes: shared aetiologic features and clinical implication for MS aetiology.
      J. Neurol. Sci. 2015; 348: 126-131
      ). At present, there is no clear recommendation on how to treat a patient with MS and T1D (
      • Comi G.
      • Radaelli M.
      • Soelberg Sorensen P.
      Evolving concepts in the treatment of relapsing multiple sclerosis.
      Lancet. 2017; 389: 1347-1356
      ). Considering ketoacidosis as a possible life-threatening condition in patients with T1D, administration of DMF for the treatment of MS in such a specific population of patients requires closer attention regarding clinical relevance of post-DMF ketonuria.

      2. Case presentation

      A 29-year-old female patient, who has suffered from T1D for 20 years, was diagnosed with MS according to McDonald's 2010 criteria (1 relapse, many T2-hyperintense and T1-gadolinium enhancing lesions in the first brain MRI, EDSS 3.5). The patient was treated with multiple insulin doses (MDI) injected subcutaneously: Apidra SoloStar (Sanofi-Aventis, Germany) 8U three times a day as meal boluses and Lantus SoloStar (Sanofi-Aventis, Germany) 18U once daily in the evening (basal insulin). The dosing of insulin was additionally adjusted ad hoc according to the actual level of capillary blood glucose, determined on each measurement with electronic personal glucose meter performed directly before each meal (GlucoSense Pro, Genexo, Poland) and only when the level was over 200 mg/dL. Her glycated hemoglobin HbA1c was 8.3%. The patient regularly monitored the level of glucose and ketone bodies in her urine with a semi-quantitative visual strip test (Keto-Diastix, Bayer Diagnostics, Ireland), usually 4–6 times a day, and registered them in the self-control diary, along with the levels of glycaemia. The levels of glycaemia, glycosuria and ketonuria and major ARs registered on the selected days during treatment with DMF are presented in the Table 1
      Table 1The levels of glucose in the blood, ketone bodies and glucose in the urine and major adverse reactions registered on the selected days during DMF treatment in the self-control diary of a 29-years-old female patient with MS and type 1 diabetes mellitus.
      DMF doseDay of treatmentTime of a dayBreakfast+2 hoursLunch+2 hoursDinner
      Parameter9:00 a.m.11:00 a.m.2:00–4:00 p.m.4:00–6:00 p.m.7:30 p.m.10:00 p.m.
      120 mg BID (breakfast, dinner)3Glycaemia182178111136151
      Ketonuria805
      Glycosuria00
      ARsFlushing
      5Glycaemia23425425618060
      Ketonuria8080
      Glycosuria00
      ARsbloating
      7Glycaemia39731916169157
      Ketonuria160
      Glycosuria1000
      ARsvomiting
      240 mg BID (breakfast, dinner)10Glycaemia150110123161128
      Ketonuria160805
      Glycosuria000
      ARsNausea when fasting, abdominal pain till evening
      11Glycaemia295119126134183
      Ketonuria405
      Glycosuria00
      ARsBloating, belching
      12Glycaemia274151142136155
      Ketonuria40
      Glycosuria0
      ARsBloating, belching
      13Glycaemia1981161369873
      Ketonuria1605
      Glycosuria00
      ARsBloating, belching
      16Glycaemia209136141139164
      Ketonuria8080
      Glycosuria00
      ARsSevere abdominal pain, nausea, vomiting
      21Glycaemia10715817357148
      Ketonuria16015
      Glycosuria00
      ARsAbdominal pain, nausea
      26Glycaemia1198330213256164
      Ketonuria1608016080
      Glycosuria0000
      ARsSevere nauseavomiting
      27Glycaemia17433512452149156
      Ketonuria8016080515
      Glycosuria00000
      ARsNausea, abdominal pain all day
      28Glycaemia23117010759110162
      Ketonuria16016055
      Glycosuria10010000
      ARsNausea, loss of appetitemalaise
      29Glycaemia271103105180163
      Ketonuria80160155
      Glycosuria0000
      ARsloss of appetite, nausea, sleepiness all day
      30Glycaemia15921311484148152
      Ketonuria80160405
      Glycosuria0000
      ARsNausea, heartburn most of the day
      33Glycaemia118108137149303
      Ketonuria80155160160
      Glycosuria00000
      ARsNausea and vomiting
      34Glycaemia20117217010413386
      Ketonuria16016080158015
      Glycosuria000000
      ARsNausea, abdominal pain
      35Glycaemia16415717587147166
      Ketonuria808080404040
      Glycosuria000000
      ARsNausea all day, fatigue
      240 mg OD (dinner)36Glycaemia177168123128171
      Ketonuria155055
      Glycosuria00000
      ARs
      39Glycaemia231187176142163
      Ketonuria8080808040
      Glycosuria00000
      ARsNausea
      42Glycaemia18414818568166185
      Ketonuria8050550
      Glycosuria000000
      ARsNausea, abdominal pain
      43Glycaemia210196156148159
      Ketonuria408001550
      Glycosuria000000
      ARsHeadaches
      No drug44Glycaemia99179164111110
      Ketonuria54005
      Glycosuria0000
      ARs
      Note: All values are given in mg/dL. Glycaemia was assessed in the capillary blood with electronic personal glucose meter, ketone bodies and glucose levels in the urine were assessed with semi-quantitative visual strip test. DMF tablets were taken always with meals – breakfast and dinner, when twice daily (BID) and with dinner, when once daily (OD). ARs – adverse reactions, DMF – dimethyl fumarate.
      She started DMF with a titration dose (120 mg BID) within the first week, followed by a dose of 240 mg BID. She took the drug always with meals – breakfast and dinner, as indicated in the patient's information leaflet. She ate meals regularly: breakfast at 9:00 a.m., lunch between 2:00–4:00 p.m., dinner about 7:30 p.m., and administered insulin precisely right before each meal. At the beginning of the first week she experienced nausea, vomiting, abdominal pain and diarrhea (12 stools per day), which decreased within a few days. After dose escalation, the symptoms intensified again, especially in the second and third week, with nausea, malaise, permanent generalized weakness, loss of appetite, vomiting and abdominal pain. After 35 days the dose was decreased to 240 mg once daily in the evening, to minimize ARs appearing during the day. During DMF treatment, the level of urine ketones ranged from 5 mg/dL to 160 mg/dL, mostly without glycosuria, with the highest ketone concentrations around 2 h after each DMF dose and always with co-existing GI ARs. She drank approximately 2.5 L of water daily and her body weight was stable. Her insulin requirements remained stable at a level of 0.7 U/kg of body weight, just as they were before initiating DMF therapy.
      Because of persisting ARs and ketonuria, DMF was discontinued 41 days after the first dose administration. Twelve hours after the last dose of DMF all laboratory results returned to normal ranges and all GI adverse symptoms were resolved within the following 24 h. After 10 days of observation, interferon beta-1a intramusculary was started without any AR. During the following 8 months of observation there was no ketonuria detected at any day.
      As GI disorders are quite frequent upon DMF initiation and in most cases gradually resolve within time, no specific evaluation of the ARs was performed. Our patient was not febrile at any time and did not travel during the period of treatment with DMF. Arterial blood gasometry or stool studies were not performed and a full chemistry panel, along with complete blood count and urinalysis was performed just before the reduction of DMF dose to 120 mg once daily. All results of this test were within normal limits.

      3. Discussion

      The oral drug seemed to be the best option for our MS patient with T1D, because she had to administer numerous insulin injections each day. Moreover, diabetes mellitus is not contraindicated for DMF treatment. The explanation of ARs and ketonuria in relation to abnormal glucose metabolism in our patient was difficult, because there was no pattern or consistency between the observed parameters, where ketonuria was present for many hours each day, but only a few times with coexisting hyperglycemia and very rarely with glycosuria during 43 days of therapy. Since ketone bodies are often detected during prolonged fasting, alcohol abuse, hypoglycemia and hyperglycemia (> 300 mg/dL), we initially suspected fasting caused by nausea and abdominal pain. However, our patient was very cooperative and, despite ARs, ate, drank approximately 2.5 L of water per day and administered insulin regularly, thus we assumed this reason to be less likely. In the setting of vomiting, the patient may have still had inadequate carbohydrate intake despite regular food intake, leading to ketonuria, but vomiting was very sporadic, with nausea and abdominal pain as main ARs. The only significant association observed was co-incidence between ketonuria and DMF administration, therefore in our opinion, the main reason for ketonuria was DMF intake.
      Orally administered DMF undergoes rapid presystemic hydrolysis by esterases and is converted into its primary metabolite, monomethyl fumarate (MMF), which is also active. Dimethyl fumarate is not quantifiable in plasma, thus all pharmacokinetic analyses related to DMF were performed with plasma MMF concentrations. The Tmax of MMF is 2–2.5 h. In our patient, the highest level of urine ketones was observed up to 2 h post DMF intake. Moreover, the patient complained the most of nausea, malaise and abdominal pain about 1.5–3 h after DMT intake, therefore, we hypothesize that GI symptoms could be related to high level of ketones.
      Clinical symptoms of elevated level of ketones in the blood may be a specific smell of urine, nausea, vomiting, diarrhea, abdominal pain, polyuria or thirst and dry mouth. It should be especially alarming for a clinician in the case of a diabetic patient, because of possible life-threatening condition known as diabetic ketoacidosis (
      • Grabacka M.
      • Pierzchalska M.
      • Dean M.
      • Reiss K.
      Regulation of Ketone Body Metabolism and the Role of PPARalpha.
      Int. J. Mol. Sci. 2016; 17: 12
      ). In our patient external insulin was fully available and regularly used in MDI model, with individual doses adjusted according to every measurement of glycaemia, therefore ketoacidosis was much less likely. Additionally, no other clinical or laboratory symptoms of ketoacidosis were observed.
      The mechanism of ketonuria in patients with MS taking DMF is not clear and clinical data regarding its use in patients with diabetes mellitus is lacking. Results of experimental studies suggest, that Nrf2-pathway modulation may also interfere with diabetes mellitus. It has vasodilatory properties (
      • Lu T.
      • Sun X.
      • Li Y.
      • Chai Q.
      • Wang X.L.
      • Lee H.C.
      Role of Nrf2 signaling in the regulation of vascular BK channel Beta-1 subunit expression and BK channel function in high fat diet-induced diabetic mice.
      Diabetes. 2017;
      ) and may limit diabetes-associated vascular injury (
      • Sharma A.
      • Rizky L.
      • Stefanovic N.
      • Tate M.
      • Ritchie R.H.
      • Ward K.W.
      • de Haan J.B.
      The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction.
      Cardiovasc. Diabetol. 2017; 16: 33
      ). It may also prevent mitochondrial damage to inhibit the development or progression of diabetic retinopathy (
      • Kowluru R.A.
      • Mishra M.
      Epigenetic regulation of redox signaling in diabetic retinopathy: role of Nrf2.
      Free Radic. Biol. Med. 2017; 103: 155-164
      ) and may protect against acute oxidative stress-induced pancreatic ß-cell damage (
      • Fu J.
      • Zheng H.
      • Wang H.
      • Yang B.
      • Zhao R.
      • Lu C.
      • Liu Z.
      • Hou Y.
      • Xu Y.
      • Zhang Q.
      • Qu W.
      • Pi J.
      Protective role of nuclear factor E2-related Factor 2 against acute oxidative stress-induced pancreatic beta -cell damage.
      Oxid. Med. Cell Longev. 2015; 2015: 639191
      ). On the other hand, in the developing tubular cells it may induce nephrogenic diabetes insipidus (
      • Suzuki T.
      • Seki S.
      • Hiramoto K.
      • Naganuma E.
      • Kobayashi E.H.
      • Yamaoka A.
      • Baird L.
      • Takahashi N.
      • Sato H.
      • Yamamoto M.
      Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus.
      Nat. Commun. 2017; 8: 14577
      ) and interfere with the inhibition of renal Nrf2 (in rat renal proximal tubular cells) and angiotensinogen gene expression regulated by insulin (
      • Ghosh A.
      • Abdo S.
      • Zhao S.
      • Wu C.H.
      • Shi Y.
      • Lo C.S.
      • Chenier I.
      • Alquier T.
      • Filep J.G.
      • Ingelfinger J.R.
      • Zhang S.L.
      • Chan J.S.D.
      Insulin inhibits Nrf2 gene expression via heterogeneous nuclear ribonucleoprotein F/K in diabetic mice.
      Endocrinology. 2017; 158: 903-919
      ). As we did not observe any additional serious accompanying disorders or deviations from the normal state, and after discontinuation of DMF ketonuria was not observed, we suspect that Nrf2-pathway modulation could be the reason of ketonuria in our patient with MS and T1D.

      4. Conclusions

      The oral drug seemed to be the best option for our MS patient with T1D, because of necessity of numerous insulin injections. Unfortunately, the drug's not well understood mechanism of action resulted in metabolic dysregulation in this well-controlled diabetic patient. In our opinion, DMF should not be recommended in patients with MS and T1D until the effects of the drug on metabolic pathways is better understood. Further investigations are necessary regarding the causes of ketonuria in patients with MS treated with DMF. The question of how does DMF stimulate the ketogenesis is still open.

      Acknowledgements

      We would like to thank our patient, whose co-operation and meticulousness allowed us to draw attention to such an important problem.

      Consent

      Written informed consent was obtained from the patient for the publication of this case report.

      Conflicts of interest

      E Krzystanek received travel support and/or compensation for lectures and/or participation in advisory boards from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva, which have been exclusively used for the support of research activities.
      P Jarosz-Chobot does not report any conflicts of interests.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      References

        • Comi G.
        • Radaelli M.
        • Soelberg Sorensen P.
        Evolving concepts in the treatment of relapsing multiple sclerosis.
        Lancet. 2017; 389: 1347-1356
        View in Article

      2. EMEA, 2017. Tecfidera®, EPAR: Summary of product characteristics - Product Information. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf〉. (Accessed 8 June 2017).

        View in Article

      3. FDA, 2013. Tecfidera®, Application 204063Orig1s000, Medical Review. 〈https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000MedR.pdf〉. (Accessed 8 June 2017).

        View in Article
        • Fox R.J.
        • Miller D.H.
        • Phillips J.T.
        • Hutchinson M.
        • Havrdova E.
        • Kita M.
        • Yang M.
        • Raghupathi K.
        • Novas M.
        • Sweetser M.T.
        • Viglietta V.
        • Dawson K.T.
        Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.
        N. Engl. J. Med. 2012; 367: 1087-1097
        View in Article
        • Fu J.
        • Zheng H.
        • Wang H.
        • Yang B.
        • Zhao R.
        • Lu C.
        • Liu Z.
        • Hou Y.
        • Xu Y.
        • Zhang Q.
        • Qu W.
        • Pi J.
        Protective role of nuclear factor E2-related Factor 2 against acute oxidative stress-induced pancreatic beta -cell damage.
        Oxid. Med. Cell Longev. 2015; 2015: 639191
        View in Article
        • Ghosh A.
        • Abdo S.
        • Zhao S.
        • Wu C.H.
        • Shi Y.
        • Lo C.S.
        • Chenier I.
        • Alquier T.
        • Filep J.G.
        • Ingelfinger J.R.
        • Zhang S.L.
        • Chan J.S.D.
        Insulin inhibits Nrf2 gene expression via heterogeneous nuclear ribonucleoprotein F/K in diabetic mice.
        Endocrinology. 2017; 158: 903-919
        View in Article
        • Gold R.
        • Kappos L.
        • Arnold D.L.
        • Bar-Or A.
        • Giovannoni G.
        • Selmaj K.
        • Tornatore C.
        • Sweetser M.T.
        • Yang M.
        • Sheikh S.I.
        • Dawson K.T.
        Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
        N. Engl. J. Med. 2012; 367: 1098-1107
        View in Article
        • Grabacka M.
        • Pierzchalska M.
        • Dean M.
        • Reiss K.
        Regulation of Ketone Body Metabolism and the Role of PPARalpha.
        Int. J. Mol. Sci. 2016; 17: 12
        View in Article
        • Kowluru R.A.
        • Mishra M.
        Epigenetic regulation of redox signaling in diabetic retinopathy: role of Nrf2.
        Free Radic. Biol. Med. 2017; 103: 155-164
        View in Article
        • Langer-Gould A.
        • Albers K.B.
        • Van Den Eeden S.K.
        • Nelson L.M.
        Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study.
        Mult. Scler. 2010; 16: 855-861
        View in Article
        • Linker R.A.
        • Lee D.H.
        • Ryan S.
        • van Dam A.M.
        • Conrad R.
        • Bista P.
        • Zeng W.
        • Hronowsky X.
        • Buko A.
        • Chollate S.
        • Ellrichmann G.
        • Bruck W.
        • Dawson K.
        • Goelz S.
        • Wiese S.
        • Scannevin R.H.
        • Lukashev M.
        • Gold R.
        Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
        Brain. 2011; 134: 678-692
        View in Article
        • Lu T.
        • Sun X.
        • Li Y.
        • Chai Q.
        • Wang X.L.
        • Lee H.C.
        Role of Nrf2 signaling in the regulation of vascular BK channel Beta-1 subunit expression and BK channel function in high fat diet-induced diabetic mice.
        Diabetes. 2017;
        View in Article
        • Sharma A.
        • Rizky L.
        • Stefanovic N.
        • Tate M.
        • Ritchie R.H.
        • Ward K.W.
        • de Haan J.B.
        The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction.
        Cardiovasc. Diabetol. 2017; 16: 33
        View in Article
        • Suzuki T.
        • Seki S.
        • Hiramoto K.
        • Naganuma E.
        • Kobayashi E.H.
        • Yamaoka A.
        • Baird L.
        • Takahashi N.
        • Sato H.
        • Yamamoto M.
        Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus.
        Nat. Commun. 2017; 8: 14577
        View in Article
        • Tettey P.
        • Simpson Jr., S.
        • Taylor B.V.
        • van der Mei I.A.
        The co-occurrence of multiple sclerosis and type 1 diabetes: shared aetiologic features and clinical implication for MS aetiology.
        J. Neurol. Sci. 2015; 348: 126-131
        View in Article

      Article info

      Publication history

      Published online: February 07, 2018
      Accepted: February 5, 2018
      Received in revised form: January 20, 2018
      Received: August 22, 2017

      Identification

      DOI: https://doi.org/10.1016/j.msard.2018.02.007

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