Distinctive Roles of Sirtuins on Diabetes, Protective or Detrimental?

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.


INTRODUCTION
Sirtuins belong to class III histone deacylases, and in each deacylation cycle one molecule NAD + is consumed (1). SIRTs isoforms have been defined in mammals, such as SIRT1-7. Although they are equipped with a highly conserved structure of about 275 amino acids, just like the silent information regulator 2 in yeast (2), the C-and N-terminal extensions are distinctive, which are the predominant factor of sirtuins subcellular localization (3). SIRT1, SIRT6, and SIRT7 are principally found in the nucleus. SIRT2 is mainly located in the cytoplasm, and SIRT3-5 are located in the mitochondria (Figure 1). The catalytic core is made up of a small zinc-binding domain, a large Rossmann-fold domain, and a few flexible loops which bind these domains together. The large domain of most sirtuins resembles each other, characteristic of a β-sheet encircled by six α-helices, excluding SIRT2, which has seven α-helices (4). In the small domain, diversities are observed in the principal sequence. Firstly, the helix bundle is only absent in SIRT7 and SIRT6. Next, SIRT5 and SIRT4 have a loop and a short helix, yielding an insertion in the small domain. This feature might be essential for the mitochondrial localization (5). Lastly, 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. SIRT1-3 and SIRT6 exhibit remarkable demyristoylase activity (6,7). Except for functioning as an ADP-ribosyltransferase (8,9), SIRT4 also possesses a lipoamidase effect (10). By targeting carbamoyl phosphate synthetase (CPS1), SIRT5 can remove malonyl or succinyl groups in a manner very similar to deacetylation (11,12). SIRT6 deacetylates histone H3K9 & H3K56, and mono-ADP-ribosyltransferate long-chain acyl and acetyl groups (13). SIRT7 is distributed in all organs and tissues (14) and activates RNA polymerase I transcription.
Although several of its molecular substrate have been identified, including WSTF-ISWI chromatin remodeling complex (WICH), rDNA transcription factor UBF (the nucleolar upstream-binding factor) and RNA polI (15), SIRT7's catalytic activity remains elusive.
Diabetes is a global epidemic problem growing exponentially, posing a serious threat. Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic and endocrine disorder for human beings, characteristic of abnormal glucose level in blood. T2DM individuals are estimated to be 642 million by 2,040 globally (16). T2DM is predominately attributed to insulin resistance and pancreatic β-cell dysfunction (17,18). Insulin resistance, primarily in liver, muscle and adipose tissue as well, spoils glucose disposal, leading to β-cell insulin increase and hyperinsulinemia in a compensatory manner.
Blunted sirtuin activity has been reported to induce diabetes and metabolic syndrome, and aggravate high-fat diet (HFD) effects in mice. Exceptionally, SIRT4 prevents insulin secretion and stimulates T2DM. SIRT4 also negatively regulates fatty acid oxidation (FAO) in muscle and liver cells. A mutation in human SIRT1 caused a familial form of autoimmune diabetes (19)(20)(21). SIRT1 can interact with transcription factors and coactivators (RelA/p65, FOXO, and p53). T2DM group has lower SIRT1 mRNA levels compared with healthy group. There is a negative connection between fasting plasma glucose and SIRT1, as shown in the correlation analysis. 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). HFD triggers SIRT1 decrement in mice probably via proteolysis (19). SIRT1 expression is also reduced in obese humans (24,25), and meanwhile diabetes is alleviated in SIRT1overexpressed mice (26)(27)(28). SIRT6 is important for sustaining pancreatic β-cell function in mice. SIRT6 knockout leads to severe hypoglycemia in mice. SIRT6 deficiency results in liver steatosis and accelerates insulin resistance and obesity induced by diet. Overnutrition and aging decreased SIRT6 level as well as irregular lipid and glucose metabolism (29). SIRT7 deficiency in mice induces multi-systemic mitochondrial dysfunction. To fully understand the part SIRTs play in diabetes and to reveal regulatory mechanisms regarding SIRTs is the principal purpose in the current review.

SIRTs IN INSULIN RESISTANCE
Pancreatic β cells secret insulin after nutrient stimulation. In the fed state, glycolysis, glucose uptake, and glycogen formation will be promoted by insulin. The glucose homeostasis in adipose tissue and skeletal muscle can also be regulated by insulin (30). Insulin resistance will give rise to hyperuricemia, visceral adiposity, dyslipidemia, hypertension, and hyperglycemia. About 70% of glucose is disposed in muscle. Free fatty acids accumulation and inflammation in muscle triggeres abundant lipid deposition. Imbalanced muscle uptake promotes extra glucose to returns to the liver, which yields intense circulation of free fatty acids, finally leading to fat accumulation and insulin resistance.
Recently, SIRT2 has been implicated in sustaining insulin sensitivity and glucose homeostasis (48). In insulin-resistant livers and hepatocytes, SIRT2 expression was lowered, accompanied with mitochondrial dysfunction, extracellular signal-regulated kinase (ERK) activation, and amplified production of reactive oxygen species (ROS). On the contrary, insulin sensitivity and mitochondrial dysfunction was improved, and ROS generation was lessened in SIRT2-overexpressed insulin-resistant hepatocytes (49). In human peripheral blood mononuclear cells (PBMCs), insulin resistance and obesity negatively related with SIRT2 (50). As Protein Kinase B (Akt) substrates, FOXO transcription factors are deacetylated by SIRT2 (51)(52)(53)(54). However, the function of SIRT2 in insulin   signaling is still controversial. Under standard nutrient conditions, it has been suggested that Akt activation in insulinresponsive cells is mainly attributed to SIRT2, other than SIRT1 (55,56). However, SIRT2 overexpression strengthened insulin-induced Akt/GSK3β/p70S6 signaling in HeLa cells and 3T3-L1 preadipocytes (56). It's elusive whether the phenomenon was caused by alteration of Akt acetylation status. Further investigations are needed to explore whether Akt deacetylation mediated by SIRT2 disturbs both protein binding and downstream pathway. TUG (tether, containing a UBX domain, for GLUT4) plays a role in the exocytosis of glucose transporter type 4 (GLUT4) (57), and binds with SIRT2. SIRT2 regulated the acetylation of TUG in vitro and in vivo (58). Enhanced TUG acetylation was observed in the liver of SIRT2 knockout mice, alone with greater glucose uptake and more GLUT4 storage vesicles in response to insulin (58). Altogether, SIRT2 may exert distinctive and even opposing effect in response to insulin in different tissues.
However, SIRT4 has been reported to inhibit insulin secretion (9,59,60). SIRT4 overexpression promotes lipogenesis and dyslipidimeia, and meanwhile diminishes FAO. All these will lead to insulin resistance (21). SIRT4 mono-ADPribosylates insulin degrading enzyme and ATP/ADP translocases in β cells, leading to downregulation of insulin secretion induced by glucose (61). SIRT4 deletion declines ATP level and low ATP level will activate 5 ′ adenosine monophosphate-activated protein kinase (AMPK), PGC-1α and its target genes, both of which are involved in mitochondrial biogenesis and FAO. Dysregulation of AMPK signaling leads to autophagy deactivation, oxidative stress, and inflammation which are implicated in pathogenesis of insulin resistance (62).
SIRT6 plays an essential role pancreatic β-cell function and survival in mice (63). SIRT6 protected against insulin resistance and obesity induced by HFD (64). Akt phosphorylation at Ser 473 and Thr 308 were negatively regulate by SIRT6 through interfering with insulin receptors, insulin receptor substrate and various upstream molecules (65). In SIRT6 deficiency mice, increased Akt phosphorylation and activated insulin signaling is observed, yielding more glucose uptake and even hypoglycemia. Additionally, glucose induced more cell apoptosis and impaired insulin secretion severely in MIN6 β-cells in SIRT6 ablation mice. Contrariwise, SIRT6 overexpression rescued β-cell apoptosis and dysfunction (66,67).
Hence activating SIRT1, SIRT3, and SIRT6 would be a right option to struggle with T2DM due to the repression on PTP1B and UCP2 and final increment in insulin secretion. But SIRT4 functions in a negative way in diabetes development.
SIRT6 interferes with FOXO1, thus reducing gluconeogenic genes such as G6P and PEPCK (76). Hepatic gluconeogenesis was meaningfully upregulated in SIRT6 knockout mice, suggesting a compensatory reaction to hypoglycemia (77). General control non-repressed protein 5 (GCN5) acetylated PGC-1α and diminished the transcriptional activity of PGC-1α (72). SIRT6 could activate GCN5 (77). A hypoxia-inducible factor 1α (HIF-1α) inhibitor would rescue the hypoglycemia phenotype in SIRT6 deficiency mice. 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.

SIRTs IN CALORIE RESTRICTION AND EXERCISE
Calorie restriction (CR) has been reported to postpone the onset of diabetes. During the initial phase of CR, liver gluconeogenesis is activated by pancreatic α cells-secreted glucagon, during which the cyclic AMP response-elementbinding protein (CREB) and CREB-regulated transcription coactivator 2 (CRTC2) are involved. CR and exercise is beneficial for health and longevity, and genetic ablation of SIRT1, SIRT3, and SIRT6 would block the benefits provided by CR and exercise (79)(80)(81)(82)(83).

SIRTs IN MITOCHONDRIAL GLYCOLYSIS AND BIOGENESIS
ATP is generated in animal cells by two principal processes, glycolysis and mitochondrial oxidative phosphorylation. T2DM, obesity, and many other aging-related disorders are characteristic of amplified oxidative damage. ROS is generally produced in mitochondria, as superoxide (O − 2 ) is a byproduct during electron transport system metabolism. In response to excess glucose, SIRTs will orchestrate the ratio of respiration and glycolysis, consuming energy through proton leak (90). SIRT1 deacetylates PGC-1α, which is critical for mitochondrial function and gluconeogenesis. SIRT1 directly deacetylates and activates PGC-1α while SIRT3 enhances PGC-1α protein expression indirectly(91), through activating CREB and AMPK which accordingly increases downstream mitochondrial biogenesis targets (92)(93)(94). Significant mortality, defective thermogenesis, decreased hypoglycemia, and reduced FAO are obvious in SIRT3 knockout models (95). SIRT3 also deacetylates key genes in oxidative stress and mitochondrial antioxidant defense enzymes. The beneficial effects of SIRT3 on CR can chiefly be ascribed to inhibiting ROS (83). Actually, the alleviation in cellular oxidative stress that generates during CR is absent in SIRT3 knockout mice (82).

SIRTs IN THE METABOLIC HOMEOSTASIS OF SKELETAL MUSCLE
Skeletal muscle is a critical tissue to maintain energy homeostasis. Storage of lipid metabolites and fatty acids in muscle prevents glucose uptake, finally leading to T2DM (100, 101). Induction of fatty acid β-oxidation has emerged as a hopeful method to attenuate muscle insulin resistance in muscle.
SIRT2 negatively regulates insulin resistance and glucose uptake in C2C12 muscle cells. Akt/GSK3β signaling and glucose uptake which are driven by insulin was enlarged by inhibition of SIRT2 under insulin-resistance conditions (104). SIRT2 knockdown under insulin-resistant status enhanced insulin sensitivity in skeletal muscle cells. Nevertheless, blunt of SIRT3 and SIRT1 in C2C12 cells impairs insulin pathway and stimulates insulin resistance. Despite the fact that SIRTs possess a conserved catalytic domain, they exert a differential regulating effect on insulin resistance. SIRT3 Knockdown in muscle cells impairs insulin action and metabolic flexibility (105,106), and muscle ability to adjust to fuel oxidation (107). SIRT3 deletion amplified acetylation of pyruvate hydrogenase (PDH), yielding declining PDH activity, and subsequent less glucose oxidation. All these gave rise to a switch to FAO, even with glucose available (106,108).
SIRT4 negatively regulates mitochondrial biogenesis and FAO in muscles. SIRT4 regulates insulin secretion by modulating glutamate dehydrogenase. As expected, fat acid oxidative capability and mitochondrial metabolism enzymes in muscle and hepatocytes was upregulated in response to SIRT4 knockdown. In primary SIRT4 knockdown myotubes, phosphorylation of AMPK was activated, accompanied with intense cellular respiration and FAO. Moreover, protein and mRNA levels of SIRT1 were enhanced both in vitro and in vivo, largely attributed to the reduced SIRT4 levels (109).

SIRTs IN FATTY ACID OXIDATION
The development of T2DM and its complications is associated with lipid metabolism disorder. Inadequate FAO gives rise to the initiation of insulin resistance and lipid accumulation (110,111). SIRT1 fosters fat metabolism in liver cells, as demonstrated by the formation of fatty livers in mice with SIRT1 deletion in the liver (112,113). SIRT1 knockout mice hardly suppressed lipogenic genes or increased FAO genes in the background of fasting (112). In normal hepatocytes, SIRT1 interacts with the PPARα response element where it deacetylates PGC-1α and increases PPARα expression, thus stimulating FAO (113,114). Furthermore, once the fat anabolism-inducing factor PPARγ was deacetylated by SIRT1, the sterol regulatory element binding proteins (SREBPs) will be deactivated and become more susceptible to degradation (115), achieving more lipolysis. Deacetylation of PGC-1α and expression of β-oxidation genes was accordingly diminished due to SIRT2 function impairment (116).
SIRT3 plays an essential role in FAO in the mitochondria. Upon CR or fasting, SIRT3 is activated in mitochondria to stimulate FAO through inducing the deacetylation of long-chainspecific acyl coenzyme A dehydrogenase (LCAD) (95,117). SIRT3 stimulates ketogenesis and urea cycle as well (118,119). A chronic HFD reduced SIRT3 levels in mice, associated with LCAD function impairment and mitochondrial hyperacetylation (120).
SIRT4's effect is remarkably different from SIRT3 and SIRT1. Ablation of SIRT4 avoids steatosis during HFD (109). In addition, SIRT4 suppresses PPARα to prevent FAO, in the meantime SIRT4 inhibits malonyl CoA decarboxylase 1 (MCD1) to facilitate the synthesis of lipid (29). SIRT4 interferes with SIRT1-PPARα complex, therefore the activation effect of SIRT1 on PPARα and the inhibiting effect on FAO was abrogated.
Analogous to SIRT4, SIRT7 knockout in liver resulted in blunted triglyceride accumulation. Hepatic SIRT7 facilitated triglyceride storage/synthesis and fatty acid uptake by activating TR4/TAK1, a nuclear receptor participating in lipid metabolism. Moreover, the ubiquitin-proteasome pathway is also involved in the regulating effect of hepatic SIRT7 on lipid metabolism (121). SIRT7 also hinders TR4 degradation. TR4 involves in lipid balance by modulating monoacylglycerol O-acyltransferase 1, Cidec, cell death-inducing DFFA-like effector a (Cidea), and Cd36. SIRT7 has been reported to upsurge hepatic lipid accumulation owning to increasing Cd36 expression (121,122). Yoshizawa et al. (121) observed that HFD failed to stimulate glucose intolerance, obesity, or fatty liver in SIRT7 knockout mice. The conclusion is controversial to the result that SIRT7 knockout promoted fatty liver development (123,124). Compared with SIRT1, SIRT7 displays distinctive effect on maintaining liver lipid homeostasisa. Lipid storage is raised by SIRT7 by suppressing PPARα, like SIRT4 (125).

SIRTs IN THE METABOLIC HOMEOSTASIS OF ADIPOCYTE
Regarded as a storage compartment for fatty lipids, adipose tissue also serves as an important modulator for energy homeostasis, vascular remodeling endocrine functions, insulin sensitivity, and innate immune response (126). Adipokines, such as leptin and adiponectin, are systemically regulated by white adipose tissue (WAT). There is convincing evidence supporting that adiponectin derived from adipocyte plays an essential part in insulin resistance (127, 128). Moreover, adiponectin sustains glucose homeostasis and protects against diabetes and obesity.
Numerous SIRT1 benefits take place in WAT (129). SIRT1 inhibits lipogenesis and stimulates fat mobilization in adipocytes from WAT, via suppressing PPARγ. Eventually, peripheral utilization of the fat storages is raised (113). White fat can be switched to metabolically active brown fat due to SIRT1 deacetylation on PPARγ (130). Conversely, SIRT1 can be cleaved in WAT by caspase I and inflammasome which is activated by HFD (19).
SIRT1 knockdown reduced WAT mass in rats. The mRNA contents of PPARγ2 and PPARγ, both of which were adipogenic genes, are abridged in adipose, driving adipocyte differentiation and adipose loss. Adipocytes-specific SIRT1 knockdown led to lower plasma concentrations of adiponectin and leptin. In adipose of obese individuals, mRNA levels of SIRT1 were lower in than those of control group. In the opposite, obese patients have higher SIRT7 expressions in adipose. SIRT7 and SIRT1 promoters' methylation status are not closely associated with the upregulation or downregulation of their mRNA levels induced by obesity. In visceral adipose tissue (VAT) of obese patients, the content of miR-181a-3p and miR-34a-5p negatively associated with SIRT1 levels. In contrary, the expression of miR-125b-5p and miR-125a-5p negatively correlated with SIRT7 in VAT of slim subjects (131). Furthermore, MiR-93 impedes the metabolic target SIRT7 (132). SIRT7 has been identified as a chief driver of adipogenesis by inducing differentiation and maturation of early adipocyte precursors. PPARγ is adipogenic and its expression is reduced in the WAT of mice with SIRT7 deletion (132), designating that SIRT7 stimulates adipogenesis. SIRT7 can remove long-chain fatty acyl groups more efficiently than removing acetyl groups (133,134).
Inhibited SIRT2 expression and amplified HIF-1α expression are observed in VAT from obese individuals. HIF-1α hinders adipocyte-mediated fatty acid catabolism by blocking SIRT2-PGC-1α pathway, thereby favoring the progression of obesity (116). Diet-induced obesity was strengthened in SIRT6 knockout mice, principally attributed to hypertrophy of adipocyte other than differentiation of abnormal adipocyte (135).

SIRTs IN NEURONS UNDER DIABETIC CONDITIONS
In the anorexigenic proopiomelanocortin (POMC) neurons, SIRT1 is critical in preserving normal energy expenditure.
POMC neurons-specific SIRT1 knockout mice are vulnerable to diet-induced obesity (136). SIRT1 is also defensive against diabetes and obesity in the steroidogenic factor 1 neurons (137). Additionally, the peptide release of orexigenic agouti is suppressed by SIRT1 via interacting with FOXO1 (138,139). Nevertheless, SIRT1 ablation in neurons was related with insulin secretion in hypothalamic neurons (140).
SIRT2, PGC-1α, and P-AMPK declined dramatically in diabetic cortex. AMPK/SIRT/PGC-1α pathway, which mediates antioxidant abilities and mitochondrial biogenesis, is involved in cortex neurodegeneration progression under diabetic conditions (141). SIRT6 and SIRT2 expression were meaningfully reduced in the neural stem or embryo cells from pre-gestational maternal diabetes. Superoxide dismutase 1 (SOD1) mimetic and overexpression rescued the decrement of SIRT6 and SIRT2 in the diabetic embryopathy mouse model. Histone acetylation caused by Sirtuin decrement might participates in neural tube defects induced by diabetes.

SIRTs POLYMORPHISMS IN DIABETES
While abundant data point to the essential role of SIRTs activities, there are genetic polymorphisms of SIRT1 and SIRT2 concerning diabetes. rs10509291 and rs7896005 in SIRT1 genes are associated with T2DM development as well as reduced acute insulin response (142). In a report about Japanese patients with T2DM, four single nucleotide polymorphisms (SNPs) in SIRT1 that were positively correlated with diabetic nephropathy, and a haplotype containing the SNPs within SIRT1 locus had a stronger association (143). Moreover, SIRT1 mutation has been reported to link with autoimmune diabetes. Type 1 diabetes mellitus (T1DM) is an autoimmune disease characteristic of autoimmune-mediated β cell destruction. Lately, exome, and direct sequencing recognized a T-to-C exchange in exon 1 of SIRT1 in a patient diagnosed with T1DM, corresponding to a leucine-to-proline mutation at residue 107. It is speculated that the SIRT1 L107P mutation, located within the N-terminal protein-binding domain, could also disturb the oligomerization and activity (20). Furthermore, the prenatally famine-exposed kids, who have minor alleles of SIRT1 gene (GA and AA of rs1467568 and AG and GG of rs7895833), have a lower risk for T2DM in adult life (144). DNA sequence variants (DSVs), including g.38900237G > A, g.38900359C > T, g.38900561C > T, and g.38900912G > T, might upsurge SIRT2 gene promoter activity and SIRT2 levels, contributing to T2DM as a risk factor (50).
When it comes to another potent SIRT activator resveratrol, SIRTris Pharmaceuticals had launched an oral resveratrol formulation (SRT501), which has entered Phase III clinical trials for T2DM therapy (150). Effects of trans-resveratrol extract from Polygonum in patients with type 2 diabetes has completed Phase I clinical trials, with trial number NCT01677611 (151). In a dose-escalation Phase I trial, resveratrol clearance (5 g in a single dose) was rapid, and urine excretion reached 77% within 4 h, signifying that derivatives structure optimization with longer half-life is in great need (152). Moreover, derivatives SRT-2183, SRT-1720, and SRT-1460 are also discovered. But SRT-1720 was terminated owing to limited effect. SRT-2104 was more potent and the Phase II clinical trials has completed successfully (153). The pharmacokinetics and safety study of SRT2379 evaluated in healthy male volunteers has finished the Phase I clinical trials (154).

CONCLUSION
SIRTs play a noticeable role in modulating insulin resistance and glucose uptake in adipose tissue, liver, and muscle. SIRT1, SIRT2, SIRT3, and SIRT6 has been implicated to positively sustain insulin sensitivity and glucose homeostasis, rendering them attractive potential drug targets. While SIRT4 and SIRT7 negatively regulate insulin secretion and FAO.
Specifically, SIRT1 enhances fat catabolism in adipose tissue, skeletal muscle and liver by modifying the activity of PPARα, PPARγ, and PGC-1α. Apart from inducing fat catabolism, SIRT1 also promotes FAO, mitochondrial oxidative capacity and energy expenditure in fat tissue and skeletal muscle, not only through direct activation of PPARα, but also through secondary activation of AMPK and PPARα by SIRT1-mediated adiponectin synthesis. SIRT1 prevents lipogenesis and motivates free fatty acid release by inhibiting SREBP and PPARγ. SIRT1 exhibits conflicting effects on maintaining glucose homeostasis under fed and fasted conditions. In fed condition, SIRT1 reinforces pancreatic insulin secretion. In fasted status, SIRT1 promotes hepatic gluconeogenesis by deacetylating FOXO1 and PGC-1α. SIRT1 exerts insulin-sensitizing effect by inhibiting PTP1B and UCP2 expression and regulating adiponectin synthesis. SIRT2 increases insulin sensitivity in insulin-resistant hepatocytes, while decreases insulin sensitivity in skeletal muscle cells. Nevertheless, there is very limited literature on SIRT5 enzyme activity until the recent finding as it can remove succinyl or malonyl groups, and this action resembles deacetylation. SIRT5 is broadly expressed, but SIRT5-deficient mice are healthy, fertile, and without major clinical phenotype (155), inferring that SIRT5 is not indispensable for metabolic homeostasis at least under basal conditions. SIRT6 supports pancreatic β-cell function and sustains glucose homeostasis by acting as a HIF-1α corepressor. Conversely, SIRT4 and SIRT7 exhibited negative effect on diabetes therapy, such as aggravating lipogenesis, and inhibiting insulin secretion.
The majority of sirtuins isoforms are protective on diabetes and a minority appears to be detrimental, but the antagonism effect on the whole body remains elusive. Although several metabolic pathways and targets have been proposed to mediate SIRTs function on T2DM, some outstanding questions need to be resolved. Moreover, do these SIRTs act independently or synergistically on diabetes? How do they communicate for cooperative actions in cells? SIRTs are regulated by proteinprotein interactions and microRNAs at the level of translation and transcription (156), however, little is known about the epigenetic mechanisms modifying sirtuins. In some cases, sirtuins isoforms regulate certain essential enzymes in an opposite direction. For instance, PDH can be activated through deacetylation by SIRT3 (106), while both delipoamidating by SIRT4 or desuccinylating by SIRT5 inhibited PDH activity (157,158), and the question that which effect will win out is quite a puzzle. Furthermore, when SIRTs display both ADPribosyltransferase and deacetylase activity, the circumstances that decide the predominant activity need to be determined.
A plenty of clinical trials has been carried out, including resveratrol, metformin, and other SIRT activators. It is possible that in the foreseeable future one or more SIRT activators will be approved for diabetes therapy. As a well-known pharmaceutical preparation, the widespread usage of metformin facilitates the recruit of a large randomized controlled trial. Metformin has been regarded as the most promising candidate. But it's a little harder to explore the natural compounds in a large scale, such as curcumin, berberine, and genistein. It is attributed to the complexity in reducing batches variability of supplements and the difficulty in evaluating dietary intake in observational studies (159)(160)(161). Long-term, outcomes-based placebo-controlled rigorous clinical trials would be crucial to confirm the function of SIRT activators on diabetes.

AUTHOR CONTRIBUTIONS
JS and LF drafted the manuscript. All authors contributed in the discussion section, and approved it for publication.