Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912, USA.
J Pharmacol Exp Ther. 2010 Jan;332(1):173-80. doi: 10.1124/jpet.109.154633. Epub 2009 Sep 28.
Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel alpha7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-alpha. These changes were reversed by the alpha7-selective antagonist methyllycaconitine, confirming the involvement of alpha7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of alpha7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that alpha7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.
2 型糖尿病已成为普遍存在的公共卫生问题。该疾病的病因尚未完全确定，但似乎涉及外周和中枢神经系统通路的异常，以及突出的炎症成分。由于烟碱型乙酰胆碱受体（nAChRs）已知与抗炎途径相互作用，并与控制食欲和体重以及脂质和能量代谢有关，因此我们研究了它们在调节与疾病相关的生物学参数中的作用。在 2 型糖尿病模型中，纯合肥胖的瘦素抵抗 db/db 肥胖小鼠，我们测量了新型α7 nAChR 选择性激动剂[5-甲基-N-[2-（吡啶-3-基甲基）-1-氮杂双环[2.2.2]辛-3-基]噻吩-2-甲酰胺（TC-7020）]对体重、葡萄糖和脂质代谢以及促炎细胞因子的影响。TC-7020 的口服给药可减轻体重增加和食物摄入，降低升高的葡萄糖和糖化血红蛋白水平，并降低升高的血浆甘油三酯和促炎细胞因子肿瘤坏死因子-α水平。α7 选择性拮抗剂甲基六氢烟碱逆转了这些变化，证实了α7 nAChRs 的参与。体重增加的预防、食物摄入的减少和葡萄糖水平的正常化也被 Janus 激酶 2（JAK2）抑制剂α-氰基-（3,4-二羟基）-N-苄基肉桂酰胺（AG-490）阻断，表明这些作用涉及α7 nAChRs 与 JAK2-信号转导和转录激活因子 3 信号通路的连接。结果表明，α7 nAChRs 在调节与糖尿病相关的生物学参数中起着核心作用，并支持将这些受体作为治疗的新治疗策略的潜力。
