Consolim-Colombo Fernanda M, Sangaleti Carine T, Costa Fernando O, Morais Tercio L, Lopes Heno F, Motta Josiane M, Irigoyen Maria C, Bortoloto Luiz A, Rochitte Carlos Eduardo, Harris Yael Tobi, Satapathy Sanjaya K, Olofsson Peder S, Akerman Meredith, Chavan Sangeeta S, MacKay Meggan, Barnaby Douglas P, Lesser Martin L, Roth Jesse, Tracey Kevin J, Pavlov Valentin A
University of Sao Paulo, Hypertension Unit, Sao Paulo, Brazil.
Nove de Julho University (UNINOVE), PPG, Sao Paulo, Brazil.
JCI Insight. 2017 Jul 20;2(14). doi: 10.1172/jci.insight.93340.
Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS.
In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV).
Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV.
Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy.
ClinicalTrials.gov, number NCT02283242.
Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.
代谢综合征（MetS）是一种由肥胖引发的全球性疾病，会增加患2型糖尿病和心血管疾病的风险。尽管炎症被认为与MetS的发病机制有关，但其病理生理机制仍知之甚少。本研究旨在评估加兰他敏（一种具有抗炎特性的中枢性乙酰胆碱酯酶抑制剂）对与胰岛素抵抗和心血管风险相关的炎症标志物以及MetS患者的其他代谢和心血管指标的影响。
在这项随机、双盲、安慰剂对照试验中，MetS患者（每组30人）每天口服8毫克加兰他敏，持续4周，随后每天口服16毫克，持续8周，或服用安慰剂。主要结局是通过与MetS相关的细胞因子和脂肪因子的血浆水平评估炎症。次要终点包括体重、脂肪组织储存、血浆葡萄糖、胰岛素、胰岛素抵抗稳态模型评估（HOMA-IR）、胆固醇（总胆固醇、高密度脂蛋白、低密度脂蛋白）、甘油三酯、血压、心率和心率变异性（HRV）。
与安慰剂相比，加兰他敏使促炎分子肿瘤坏死因子（TNF）的血浆水平降低（-2.57 pg/ml [95%可信区间 -4.96至-0.19]；P = 0.035），瘦素水平降低（-12.02 ng/ml [95%可信区间 -17.71至-6.33]；P < 0.0001），抗炎分子脂联素水平升高（2.71 μg/ml [95%可信区间 1.93至3.49]；P < 0.0001）和白细胞介素-10水平升高（1.32 pg/ml，[95%可信区间 0.29至2.38]；P = 0.002）。加兰他敏还显著降低了血浆胰岛素和HOMA-IR值，并改变了HRV。
低剂量加兰他敏可减轻MetS患者的炎症和胰岛素抵抗。这些发现支持对加兰他敏在MetS治疗中的进一步研究。
ClinicalTrials.gov，编号NCT02283242。
巴西圣保罗州研究资助基金会（FAPESP）和国家科学技术发展委员会（CNPq）以及美国国立卫生研究院（NIH）。
