Sirtuins as Possible Drug Targets in Type 2 Diabetes
Sirtuins as Possible Drug Targets in Type 2 Diabetes
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DOI：
10.2174/1389450111314060002
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发表时间：
2013-06-01
影响因子：
3.2
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Kitada, Munehiro;Kume, Shinji;Koya, Daisuke
2型糖尿病（T2 DM）发病率的上升是工业化国家的主要公共卫生问题，并且世界范围内迫切需要新的治疗策略来预防T2 DM。众所周知，热量限制（CR）可以延缓从酵母到啮齿动物的生物体的衰老过程，并延缓许多与年龄有关的疾病的发作，包括糖尿病。因此，代谢模拟CR的分子可能代表T2 DM的新治疗靶点。Sirtuin 1（SIRT 1）是Sir 2的哺乳动物同源物，最初被鉴定为NAD（+）依赖的组蛋白脱乙酰酶，其活性与CR下的寿命密切相关。越来越多的证据表明，SIRT 1通过其对许多已知底物的脱乙酰酶活性来调节葡萄糖-脂质代谢，并且通过其直接或间接参与胰岛素敏感器官（包括脂肪组织、肝脏和骨骼肌）中的胰岛素信号传导在代谢途径中具有许多作用。此外，SIRT 1调节胰岛素分泌、脂联素产生、炎症、代谢、昼夜节律和氧化应激，这些共同促进胰岛素抵抗的发展。此外，SIRT 1和几种SIRT 1激活剂的过表达对糖尿病动物模型和人类的葡萄糖稳态和胰岛素敏感性具有有益作用。因此，SIRT 1可能代表了预防胰岛素抵抗和T2 DM相关疾病的新的治疗靶点。此外，SIRT 3和SIRT 6在葡萄糖和脂质代谢中起着至关重要的作用。本文综述了SIRT 1、SIRT 3和SIRT 6在代谢中的生物学功能，并讨论了它们作为T2 DM治疗靶点的潜在作用。
The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem in industrialized countries, and new therapeutic strategies to prevent T2DM are urgently needed worldwide. It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related diseases, including diabetes. Molecules that mimic CR metabolically may therefore represent new therapeutic targets for T2DM. Sirtuin1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a NAD(+)-dependent histone deacetylase, and its activity is closely associated with longevity under CR. Growing evidence suggests that SIRT1 regulates glucose-lipid metabolism through its deacetylase activity for many known substrates and has many roles in the metabolic pathway through its direct or indirect involvement in insulin signaling in insulin-sensitive organs, including adipose tissue, liver and skeletal muscle. In addition, SIRT1 regulates insulin secretion, and adiponectin production, inflammation, gluconeogenesis, circadian rhythms and oxidative stress, which together contribute to the development of insulin resistance. Moreover, the overexpression of SIRT1 and several SIRT1 activators have beneficial effects on glucose homeostasis and insulin sensitivity in diabetic animal models and humans. Therefore, SIRT1 may represent a new therapeutic target for the prevention of diseases related to insulin resistance and T2DM. In addition, SIRT3 and SIRT6 play crucial roles in glucose and lipid metabolism. In this review, we summarize the current understanding of the biological functions of SIRT1, SIRT3 and SIRT6 in metabolism and discuss their potential role as therapeutic targets in T2DM.