Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis
Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis
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DOI：
10.1001/jamaneurol.2015.4807
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发表时间：
2016-05-01
期刊：
影响因子：
29
通讯作者：
Correale, Jorge
中科院分区：
文献类型：
--
作者：
Negrotto, Laura;Farez, Mauricio F.;Correale, Jorge
代谢综合征（MetS）被认为会影响多种自身免疫性疾病，包括多发性硬化症（MS）。用于MetS的治疗，如盐酸二甲双胍和盐酸吡格列酮的抗炎作用已得到证实，尽管缺乏支持在MS中使用这些治疗的临床证据。或吡格列酮与MS和MetS患者中通过脑磁共振成像测量的疾病活动减少相关，并评估其潜在机制抗炎作用设计、背景和参与者一项前瞻性队列研究于2012年3月1日至2014年12月30日在一家私人MS转诊中心在50名患有MS的肥胖患者中进行，这些患者也发生了MetS。20例患者接受盐酸二甲双胍，850 - 1500 mg/d，10例患者接受盐酸吡格列酮，15 - 30 mg/d; 20例未接受治疗的患者作为对照。各组在性别、年龄、体重指数、扩展残疾状态量表评分、疾病持续时间、年复发率和治疗状态方面具有可比性。患者随访平均（SD）为26.7（2.7）个月（范围，24-33个月）。主要结果和措施磁共振成像的大脑进行了6个月的时间间隔，并登记新的或扩大T2病变或钆增强病变的存在。测定血清瘦素和脂联素水平。外周血单个核细胞的细胞因子的生产进行了测定，作为调节T细胞的数量和function.Results的50例患者，6个月的治疗后，20例MS患者谁与二甲双胍和10谁接受吡格列酮治疗显示了显着减少的数量，新的或扩大的T2病变（二甲双胍，研究入组时2.5至第24个月时0.5;吡格列酮，研究入组时2.3至第24个月时0.6），以及钆增强病变（二甲双胍，研究入组时1.8至第24个月时0.1;吡格列酮，研究入组时2.2至第24个月时0.3）。与对照组相比，两种治疗均导致平均（SD）瘦素水平下降（二甲双胍，5.5 [2.4] vs 10.5 [3.4] ng/mL，P < .001;吡格列酮，4.1 [0.8] vs 11.0 [2.6] ng/mL，P <0.001）和平均（SD）脂联素血清水平升高（二甲双胍，15.4 [5.5] vs 4.5 [2.4] μ g/mL，P < .001;吡格列酮，12.6 [3.6] vs 4.8 [0.6] μ g/mL，P < .001）。分泌干扰素的髓鞘碱性蛋白肽特异性细胞的平均（SD）数量。和白细胞介素（IL）-17在接受二甲双胍的患者中与对照组相比显著降低（干扰素，30.3[11.5] vs 82.8 [18.8]，P < .001; IL-17，212.4 [85.5] vs 553.8 [125.9]，P < .001）。与对照组相比，接受吡格列酮治疗的患者显示分泌IL-6和肿瘤坏死因子的髓鞘碱性蛋白肽特异性细胞的平均（SD）数量显著减少（IL-6，361.6 [80.5] vs 1130.7 [149.21]，P <0.001;肿瘤坏死因子，189.9 [53.4] vs 341.0 [106.0]，P <0.001）。与对照组相比，二甲双胍和吡格列酮均导致CD 4 + CD 25 + FoxP 3+调节性T细胞的数量和调节功能显著增加二甲双胍，6.7 [1.5] vs 2.1 [1.0]，P = .001;吡格列酮，6.9 [0.8] vs 3.0 [0.8]，结论和相关性二甲双胍和吡格列酮治疗具有有益的抗抑郁作用。MS和MetS患者的炎症效应，应进一步探讨。
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] mu g/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] mu g/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon. and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon., 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.