Sirtuins as Possible Drug Targets in Type 2 Diabetes
Munehiro Kitada, Shinji Kume, Keizo Kanasaki, Ai Takeda-Watanabe and Daisuke Koya
Affiliation: Division of Diabetology & Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa Prefecture 920-0293, Japan.
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.
Keywords: Sirtuins, SIRT1, SIRT3, SIRT6, type 2 diabetes, insulin resistance.
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