Abstract
Dysregulation of metabolic pathways leads to type 2 diabetes, characteristic of high glucose concentration caused by insulin resistance. The histone deacetylases sirtuins exhibit remarkable enzymatic activities. Accumulating evidence indicates that sirtuins can be pharmacologically activated to ameliorate diabetes. Here, we evaluated different roles of sirtuins (SIRT1-SIRT7) in diabetes progression and described their involvement in metabolic pathways of skeletal muscle, adipose tissue and liver. The nuclear sirtuins, SIRT1, SIRT6, and SIRT7, regulate the activity of key transcription factors and cofactors in almost all tissues with the cellular responses to energy demands. The mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, regulate the activity of mitochondrial enzymes in response to fasting and calorie restriction. Moreover, genetic polymorphisms of SIRT1 and SIRT2 have been reported to associate with diabetes development. It's worth noting that SIRT1, SIRT2, SIRT3, and SIRT6 are positive regulators of insulin resistance in most cases. In the opposite, SIRT4 and SIRT7 inhibit insulin secretion and fatty acid oxidation. Identification of SIRT1 activators for diabetes has gained wide attention, such as metformin, resveratrol, and resveratrol derivatives. Randomized, prospective, and large-scale clinical trials are warrant to uncover the responsibilities of SIRTs modulators on diabetes progress.
Highlights
Sirtuins belong to class III histone deacylases, and in each deacylation cycle one molecule NAD+ is consumed [1]
Enhanced TUG acetylation was observed in the liver of SIRT2 knockout mice, alone with greater glucose uptake and more glucose transporter type 4 (GLUT4) storage vesicles in response to insulin [58]
Mice with SIRT6 knockout in brains exhibited lower levels of insulin-like growth factor 1 (IGF-1) and growth hormone than control mice, similar to the effect achieved in whole-body SIRT6 knockout mice [78], suggesting that the central nervous system is critical in glucose metabolism
Summary
Sirtuins belong to class III histone deacylases, and in each deacylation cycle one molecule NAD+ is consumed [1]. SIRT5 and SIRT4 have a loop and a short helix, yielding an insertion in the small domain. SIRT1 has a 5-residue loop in this domain, neighboring to the zinc-binding cysteine. Those dissimilarities in the catalytic core might closely relate with their key properties. The expression of SIRT1 in monocytes and granulocytes of T2DM might associate with glucose/lipid metabolism status [22]. In both of the kidney and liver of diabetic rats, SIRT1 and SIRT2 gene expressions reduced considerably than blank control group [23]. To fully understand the part SIRTs play in diabetes and to reveal regulatory mechanisms regarding SIRTs is the principal purpose in the current review
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