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Original Investigation |

Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis

Laura Negrotto, MD1; Mauricio F. Farez, MD, MPH1; Jorge Correale, MD1
[+] Author Affiliations
1Department of Neurology, Institute for Neurological Research Dr Raúl Carrea, Buenos Aires, Argentina
JAMA Neurol. 2016;73(5):520-528. doi:10.1001/jamaneurol.2015.4807.
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Importance  Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking.

Objectives  To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect.

Design, Setting, and Participants  A prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months).

Main Outcomes and Measures  Magnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function.

Results  Of 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] μg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] μg/mL, P < .001). Mean (SD) number of myelin basic protein peptide–specific cells secreting interferon γ and interleukin (IL)–17 were significantly reduced in patients receiving metformin compared with controls (interferon γ, 30.3 [11.5] vs 82.8 [18.8], P < .001; IL-17, 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide–specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and pioglitazone resulted in a significant increase in the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells compared with controls (metformin, 6.7 [1.5] vs 2.1 [1.0], P = .001; pioglitazone, 6.9 [0.8] vs 3.0 [0.8], P = .001).

Conclusions and Relevance  Treatment with metformin and pioglitazone has beneficial anti-inflammatory effects in patients with MS and MetS and should be further explored.

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Figure 1.
Disease Activity as Measured by Magnetic Resonance Imaging

A, Both metformin hydrochloride and pioglitazone hydrochloride were associated with a significant decrease in the number of new or enlarging T2 lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone. B, Both metformin and pioglitazone were associated with a significant decrease in the number of gadolinium diethylenetriamine penta-acetic acid (Gd)–enhancing lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone.

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Figure 2.
Immunologic Effects of Metformin in Patients With Multiple Sclerosis

A, Metformin hydrochloride treatment resulted in a robust increase of 5′ adenosine monophosphate–activated protein kinase (AMPK) expression. B, Increased AMPK expression was associated with a significant decrease in leptin levels. C, Increased AMPK expression was associated with a significant increase in adiponectin levels. D, Increased AMPK expression was associated with a decrease in the numbers of cells producing interferon (IFN) γ. E, Increased AMPK expression was associated with a decrease in the numbers of cells producing interleukin (IL)–17. F, Increased AMPK expression was associated with a robust increase in CD4+CD25+FoxP3+ regulatory T (Treg) cell percentages. Data are expressed as AMPK messenger RNA (mRNA) levels relative to glyceraldehyde 3-phosphate dehydrogenase, shown as mean (SE) of mRNA expression in peripheral blood mononuclear cells (PBMCs) from 20 patients treated with metformin and 18 control patients for whom samples were available (A). Results correspond to the number of cytokine-secreting cells specific for myelin basic protein83-102 per 105 PBMCs as determined by enzyme-linked immunospot assays, from patients treated with metformin and control patients (C and D). The number of antigen-specific cytokine-secreting cells was calculated by subtracting the number of spots obtained in zero antigen background control cultures from the number of spots obtained in cultures exposed to stimulating antigen. Each circle represents values from a single individual. Horizontal lines indicate mean group values. Pioglitazone was given as pioglitazone hydrochloride.

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Figure 3.
Immunologic Effects of Pioglitazone in Patients With Multiple Sclerosis

A, Pioglitazone hydrochloride treatment induced significant activation of peroxisome proliferator–activated receptor γ (PPARγ). B, Activation of PPARγ was associated with a significant decrease in leptin levels. C, Activation of PPARγ was associated with a significant increase in adiponectin levels. D, Activation of PPARγ was associated with a decrease in the numbers of cells producing interleukin (IL)–6. E, Activation of PPARγ was associated with a decrease in the numbers of cells producing tumor necrosis factor (TNF). F, Activation of PPARγ was associated with a robust increase in CD4+CD25+FoxP3+ regulatory T (Treg) cell percentages. Data are expressed as PPARγ messenger RNA (mRNA) levels relative to glyceraldehyde 3-phosphate dehydrogenase, shown as mean (SE) of mRNA expression in peripheral blood mononuclear cells (PBMCs) from 10 patients receiving pioglitazone and 14 control patients for whom samples were available (A). Results correspond to the number of cytokine-secreting cells specific for myelin basic protein83-102 per 105 PBMCs as determined by enzyme-linked immunospot assays, from patients treated with pioglitazone and control patients. The number of antigen-specific cytokine-secreting cells was calculated by subtracting the number of spots obtained in zero antigen background control cultures from the number of spots obtained in cultures exposed to stimulating antigen. Each circle represents values from a single individual. Horizontal lines indicate mean group values. Metformin was given as metformin hydrochloride.

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Figure 4.
Influence of Metformin and Pioglitazone on the Number and Function of Treg Cells

A, CD4+CD25+ regulatory T (Treg) cells and myelin basic protein83-102–specific T cells (CD4+CD25-effector T cells) were isolated from peripheral blood of patients receiving metformin hydrochloride, patients receiving pioglitazone hydrochloride, and controls, and co-cultured with CD4+CD25+ Treg cells at different ratios as indicated. Effector T cell proliferation was induced with the cognate peptide and measured using a standard 3H-thymidine incorporation assay. Results are expressed as percentage of inhibition of effector T cell proliferation, by Treg cells of either control patients or patients receiving metformin or pioglitazone, with proliferation in the absence of Treg cells considered as 100%. Data represent mean (SE) values of triplicate cultures from 4 independent experiments. B, Fifty thousand CD4+CD25+ Treg cells and CD4+CD25-effector T cells were stimulated with a combination of phorbol12-miristate 13-acetate, 100 ng/mL, and ionomycin, 1 μg/mL. Supernantants were collected 72 hours after stimulation and interleukin (IL)–10 and transforming growth factor-β measured by enzyme-linked immunosorbent assay. Data represent mean (SEM) values from 20 control patients, 20 patients treated with metformin, and 10 patients treated with pioglitazone. C, Sorted Treg cells from patients receiving metformin, patients receiving pioglitazone, and control patients caused suppression of proliferation in myelin basic protein peptide–reactive T cell lines induced by the cognate peptide. Cells were co-cultured at a 2:1 ratio. Inhibitory effects were abrogated by IL-10 depletion through RNA interference; negative controls consisted of cells transfected with control small interfering RNA (siRNA). Data represent mean (SEM) values from 10 patients per group.

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