Protein Modifications as Manifestations of Hyperglycemic Glucotoxicity in Diabetes and Its Complications

Abstract

Diabetes and its complications are hyperglycemic toxicity diseases. Many metabolic pathways in this array of diseases become aberrant, which is accompanied with a variety of posttranslational protein modifications that in turn reflect diabetic glucotoxicity. In this review, we summarize some of the most widely studied protein modifications in diabetes and its complications. These modifications include glycation, carbonylation, nitration, cysteine S-nitrosylation, acetylation, sumoylation, ADP-ribosylation, O-GlcNAcylation, and succination. All these posttranslational modifications can be significantly attributed to oxidative stress and/or carbon stress induced by diabetic redox imbalance that is driven by activation of pathways, such as the polyol pathway and the ADP-ribosylation pathway. Exploring the nature of these modifications should facilitate our understanding of the pathological mechanisms of diabetes and its associated complications.

Keywords

diabetes hyperglycemia redox imbalance glucotoxicity posttranslational modifications oxidative stress carbon stress

Introduction

Glucose is a fundamental molecule for life, and its combustion is exploited in all ways to sustain life. While glucose is essential for cellular survival, too much of it is detrimental.^1–3 This is the case in diabetes that either originates from or manifests the dysregulation of glucose metabolism.⁴ In type 1 diabetes, pancreatic µ-cells are destroyed by autoimmune response, and hence no insulin would be available for stimulating glucose metabolism, leading to diabetic hyperglycemia.^4–6 In type 2 diabetes, insulin resistance usually precedes µ-cell dysfunction via a failure of compensation mechanism.^7–9 Initially, insulin resistance would aggravate more insulin secretion by increasing µ-cell mass.^1,8,10–12 However, such an increase has a limit and will eventually fail to meet the needs for more insulin secretion.^9,13,14 Under this circumstance, µ-cells die, insulin levels decrease, and frank type 2 diabetes mellitus develops and progresses.^15–18 Regardless of the types of diabetes, it is the persistent level of hyperglycemia that causes all the metabolic problems manifested by diabetic complications, such as blindness, peripheral neuropathy, and chronic kidney disease.^6,19,20 Indeed, all the metabolic problems can be attributed to hyperglycemic glucotoxicity.^1,2,21–25

Therefore, how glucotoxicity is attained in diabetes? Protein modifications induced directly or indirectly by hyper-glycemia manifest glucotoxicity. In this review, we attempt to summarize a variety of protein modifications in diabetes. We believe that many of these protein modification processes could serve as therapeutic targets or have therapeutic values. We focus on diabetic protein modifications, including glycation, carbonylation, nitration, nitrosylation, acetylation, ADP-ribosylation, and succination. But before expanding on these modifications, we would like to briefly overview the dysregulated glucose metabolic pathways in diabetes.

Glucose Metabolism and Redox Imbalance in Diabetes

When blood glucose level is persistently high, the body will attempt to mobilize all the possible pathways involved in glucose clearance. One such significant pathway is the polyol pathway.^26–29 This pathway is usually dormant in nondia-betic state but can be activated to metabolize up to 30% of the glucose pool in diabetes.³⁰ The pathway involves two reactions, catalyzed by aldose reductase and sorbitol dehydroge-nase, respectively. As shown in Figure 1A, the pathway makes excess NADH by consuming NADPH, hence breaking the redox balance between NADH and NAD⁺. As the aldose reductase reaction is rate limiting, inhibition of aldose reductase has been shown to prevent the occurrence of diabetes and diabetic complications.^31–34 Additionally, glucose is converted into fructose, a sugar molecule whose metabolism bypasses glucokinase and phosphorfructokinase-1 in the glycolytic pathway and thus is less regulated,^35–37 thereby inducing metabolic stress.³⁵ Excess NADH can overload the mitochondrial electron transport chain and drive overproduction of reactive oxygen species (ROS), which can attack proteins and induce protein modifications.^35,38 Additionally, consumption of NADPH by the polyol pathway can impair the function of glutathione reductase that uses NADPH to regenerate the reduced form of glutathione (GSH) from the oxidized form of glutathione (GSSG),³⁹ thus further aggravating cellular redox imbalance.⁴⁰

Figure 1.

Major enzymatic pathways activated by diabetic hyperglycemia that can impair cellular redox imbalance between NADH and NAD⁺. The polyol pathway (A) produces NADH, while the ADP-ribosylation pathway (B) can potentially deplete NAD⁺, accentuating the redox imbalance status between NADH and NAD⁺.

Also in diabetes, chronic production of ROS can cause DNA damage.^41–44 This damage will activate poly-ADP-ribose polymerase that is evolved to repair the damaged DNA molecules.^45–47 As poly-ADP-ribose polymerase uses NAD+ as its substrate (Fig. 1B) and is often overactivated,⁴⁸ its activation usually can deplete NAD+ and leads to the further accentuation of redox imbalance, thereby, causing cell death.^49–52 It should be pointed out that while activation of both the polyol pathway and the ADP-ribosylation pathway by diabetic hyperglycemia initially appears to be defensive and adaptive, the eventual consequences are lethal. Therefore, diabetes and its complications could be considered as a failure of compensation diseases.^53–55

Moreover, diabetic hyperglycemia can also activate other metabolic or signaling pathways. These are summarized in Figure 2, which, in addition to the polyol pathway^27,56 and the ADP-ribosylation pathway mentioned earlier, also include the glycation pathway,^57,58 the hexosamine pathway,^59,60 and the PKC activation pathway.^61,62 All these aberrant pathways have been shown to eventually elevate cellular ROS levels,^63,64 hence further aggravating cellular redox imbalance and oxidative stress.³⁸ This redox imbalance is probably the driving force for diabetic ROS production and oxidative stress, which are involved in a variety of protein posttranslational modifications.⁶³

Figure 2.

Pathways that are activated or upregulated by diabetic hyperglycemia. In addition to the two pathways shown in Figure 1, diabetic hyperglycemia can also cause activation of the protein kinase C pathway, accumulation of advanced glycation end-products, and upregulation of the hexosamine pathway that fuels the substrate for protein GlcNAcylation. All these pathways have been suggested to be involved in reactive oxygen species production and oxidative stress in the pathogenesis of diabetes and its complications.^64,192,193

Protein Modifications in Diabetes

Protein modifications are strategies routinely used by cells to expand their function^65–67 but can also reflect the status quo of struggled cellular functions under stressed conditions.^68–71 Figure 3 summarizes the types of posttranslational protein modifications in diabetes that are covered in this review. The modifications can be classified into two categories: irreversible and reversible. Irreversible protein modifications include carbonylation, nitration, and glycation, and reversible protein modifications include nitrosylation, acetylation, sumoylation, O-GlcNAcylation, ADP-ribosylation, and succination.

Figure 3.

Protein modifications in diabetes reviewed in this article. These modifications include carbonylation, nitration, succination, ADP-ribosylation, O-GlcNAcylation, glycation (AGEs), sumoylation, acetylation, and nitrosylation. All these protein modifications can manifest glucotoxicity in diabetes.

Advanced Glycation end Products

Glucose, in its reduced form, can directly react with proteins.^72,73 The reaction usually takes place between the glucose's aldehyde group and the side chain of lysine residues as well as the N-terminal amino groups for given proteins.^72,73 The initial species is a Schiff base that can rearrange to form an Amadori intermediate. This intermediate can further rearrange to form varying forms of advanced glycation end products (AGEs).^72,73

Glucose can also undergo autoxidation to form ketoal-dehyde and hydrogen peroxide in the presence of transition metals.^58,74,75 The resulting ketoaldehyde can further react with the amino groups in proteins. This is followed by the formation of ketoimine via Schiff's base. The ketoimine is then involved in the formation of protein-linked AGEs.^58,75,76 It should be noted that fructose can also induce protein glycation.⁷⁷

Protein can also be modified by methylglyoxal (MGO), a reactive product in the glycolytic pathway.^78–81 MGO is a carbonyl-containing compound and mainly reacts with lysine, arginine, and cysteine residues.^79,80,82 The eventual protein adducts are a variety of AGEs that could be structurally distinct.^83,84 It has also been reported that MGO can have profound detrimental effects in diabetes.^79,85 For example, MGO can impair mitochondrial function in diabetes via modifications of a variety of mitochondrial proteins.⁸³

Protein Carbonylation

Protein carbonylation is an irreversible process.^39,86 Protein carbonyls can be formed directly by ROS attack or indirectly by conjugating to lipid peroxidation byproducts, such as hydroxynonenal.^20,87,88 Protein carbonylation can be formed on a variety of amino acid residues’ including histidine’ cysteine’ lysine’ arginine’ proline’ and threonine.⁸⁷ Protein carbonyls not only have been used as a biomarker for protein oxidation in aging and disease⁸⁹ but have also been shown to impair protein structure and function.^90,91 In diabetes, it has been shown that protein carbonylation is increased in red blood cell membranes in diabetic retinopathy.⁹² It has also been reported that more plasma proteins show elevated protein carbonyl content in type 2 diabetes.⁹³ In our own studies’ we have shown that mitochondrial complex I isolated from diabetic kidneys exhibited selective protein carbonylation via the conjugation with lipid peroxidation product hydroxynonenal that contains a carbonyl group.²⁰ As protein carbonyls are toxic protein adducts impairing protein function and carbonylation can occur to proteins involved in insulin signaling,⁹⁴ insulin signaling pathways can be disrupted.⁹⁴ Indeed’ protein carbonylation has been suggested to be implicated in insulin resistance,^94–96 which is an early event in the development of type 2 diabetes.^97–99

Protein Nitration

Protein nitration is also an irreversible protein modification. It occurs on protein tyrosine residues due to attack by peroxynitrite.^100,101 As peroxynitrite is formed by reaction between superoxide and nitric oxide,^102,103 this modification is related to both ROS and reactive nitrogen species. Glucose is known to be implicated in the formation of nitrotyrosine.^104,105 Elegant studies by Koeck et al^104,105 have demonstrated that glucose can mediate tyrosine nitration in both adipocytes and β-cells, suggesting a role of glucose-modulated nitration in obesity, insulin resistance, and β-cell dysfunction. Importantly, in both adipocytes and β-cells, specific proteins that underwent nitration have been identified; many of them are involved in glucose metabolism and bioenergetics.^104,105

O-GlcNAcylation

This posttranslational modification is a reversible modification occurring on serine or threonine residues.¹⁰⁶ The substrate for this modification is uridine diphospho-N-acetylglucosamine, the end product of the hexosamine pathway.^{59,60,107,108} As glucose level becomes higher in diabetes, more glucose is fluxed into the hexosamine pathway, resulting in elevated levels of uri-dine diphospho-N-acetylglucosamine that can attach to proteins.^107,109 Protein O-GlcNAcylation has been found to be involved in numerous biological processes, such as transcription, redox signaling, apoptosis, autophagy, and protein degradation.^110–112 Many proteins involved in insulin signaling can undergo this modification. Moreover, O-GlcNAcylation can worsen glucotoxicity in the liver. For example, O-GlcNAcylation of FoxO1 in hepatocytes can increase its transcriptional activity that then upregu-lates the expression of glucose 6-phosphotase, leading to hyperglycemia by increasing hepatic glucose production.¹¹³ Therefore, protein O-GlcNAcylation has been regarded as a major factor in the development of insulin resistance and diabetes and diabetic complications.^109,114,115

Protein S-nitrosylation

This modification occurs on cysteine residues and is also a reversible modification.⁷¹ As cysteine oxidation status can reflect cellular redox status, this modification is tightly linked to oxidative stress and glutathione content.⁶⁵ As the modification is reversible, it can regulate protein function either beneficially or detrimentally.^65,116 In fact, many studies are now being conducted to explore the beneficial role of this modification in aging and disease.^117–121 Nonetheless, S-nitrosylation can play a deleterious role in diabetes.¹²² For example, it has been reported that in the early phase of diabetes, the level of protein S-nitrosylation is increased that might lead to mitochondrial dysfunction.¹²³ It has also been reported that S-nitrosylation is involved in insulin resistance via the modification and inactivation of protein kinase B.¹²⁴ It should be mentioned that, similar to this modification, other types of cysteine modifications, such as S-glutathionylation, have also been shown to be involved in the pathogenesis of diabetes and its complications.^125,126 For example, hemoglobin shows increased levels of glutathionylation in type 2 diabetes.¹²⁷

Protein Acetylation

Protein acetylation is the attachment of an acetyl group onto a lysine side chain in a target protein, and the acetyl group usually comes from acetyl-CoA,^128,129 which is a central molecule in metabolism. As shown in Figure 4, acetyl-CoA can be derived from combustion of glucose, fatty acids, alcohol, and amino acids. Under normal condition, acetyl-CoA is channeled into the Krebs cycle for ATP production and is also used for the synthesis of cholesterol and fatty acids. Excess acetyl-CoA usually leads to ketone body production^130–132 and nonenzymatic protein acetylation.¹³³ This modification often occurs on lysine residues^134,135 and has been referred to as carbon stress.^{108,136–138} Except histone acetylation and enzyme-catalyzed acetylation that are well-regulated processes,¹³⁹ protein acetylation occurring in cytosol and mitochondria has been widely considered as a pure chemical, nonenzymatic reaction,^{128,129,133,140,141} although the removal of the lysine-conjugated acetyl groups requires deacetylating enzymes, such as sirtuins.^142–144 When the glucose level is high, so is acetyl-CoA that is used as the substrate of acetylation. Hence, proteins can be highly acetylated under hyperglycemic or overnutritional conditions.^145,146 When cells switch to use fatty acids as their major energy source, such as under the condition of insulin resistance, whereby glucose cannot enter the cells,¹⁴⁷ the levels of acetyl-CoA can increase dramatically (Fig. 5) and protein acetylation can concomitantly increase.¹⁴⁶ Thus, it has been reported that increased fatty acid oxidation leads to elevation in protein acetylation in the diabetic heart.¹⁴⁸ Additionally, over consumption of alcohol that fuels the production of acetyl-CoA can also elevate protein acetylation.^133,149 It should be noted that removal of the acetyl group by enzymes, such as sirtuins, requires the presence of NAD⁺, which is used as the substrate for deacetylases.^150,151 Therefore, a lower level of NAD⁺ would inhibit protein deacetylation and increase protein acetylation.¹⁵² Hence, protein acetylation is a modification that is highly governed by the availability of fuels and NAD⁺, the latter being tightly linked to cellular redox balance.^153–155 In this regard, it is no surprising that aldose reductase can increase protein acetylation via diminishing the NAD⁺ levels.¹⁵⁶

Figure 4.

Fates of acetyl-CoA, a central molecule in fuel metabolism. Acetyl-CoA can be derived by combustion of glucose, fatty acids, proteins or amino acids, and alcohol. In normal condition, acetyl-CoA is mainly channeled into the Krebs cycle for energy production. In overnutrition state, acetyl-CoA can be used to store excess energy by forming fatty acids. Acetyl-CoA is also the source for cholesterol synthesis. In starved state, acetyl-CoA is converted into ketone bodies. Acetyl-CoA is also the substrate used for protein acetylation.

Figure 5.

Excess acetyl-CoA drives nonenzymatic protein acetylation. For noninsulin-dependent cells, diabetic hyperglycemia can overload them with glucose, causing the oversupply of acetyl-CoA. For insulin-dependent tissues in diabetes, the cell cannot get enough glucose and will have to use fatty acids as the source of energy. Because oxaloacetate cannot be continuously formed due to lack of glucose, the level of acetyl-CoA could be extremely high, leading to ketone body production and protein acetylation.

Protein Succination

This modification, along with protein acetylation, has also been categorized under carbon stress.¹³⁸ Protein succination is due to a conjugation reaction between fumerate and proteins and often occurs on protein cysteine residues.^157,158 Any fuel source that would elevate the level of fumerate, an intermediate in the Krebs cycle, would theoretically facilitate protein succination.^158–161 Similar to S-nitrosylation, protein succination has been shown to increase in diabetes and its complications.^161,162 Protein succination can also impair protein function and cellular redox signaling.^{38,65,71,163–167} Indeed, it has been reported that protein succination is a manifestation of glucotoxicity in both the glycolytic pathway and the mitochondrial bioenergetics pathway.^158,161

Protein Sumoylation

This posttranslational modification refers to the attachment of a small protein, called small ubiquitin-like modifier (SUMO) protein.^168,169 SUMOs are covalently attached onto target proteins and can also be detached.^170,171 Hence, sumoylation is also a reversible process. Protein sumoylation is known to be involved in protein translocation, protein stabilization, inflammation, redox imbalance, and oxidative stress.¹⁷² In diabetes, SUMO-4 has been implicated in the development of diabetes.¹⁷³ The target proteins of SUMO-4 include IKBα, STAT, AP-1, and heat shock transcription factors.¹⁷⁴ Moreover, SUMO-4 seems to restrict its action in pancreas and immune systems as well as in kid-neys.^175,176 With respect to regulation of blood glucose levels, sumoylation is known to occur in Glut4, thereby facilitating its translocation onto cell membranes.¹⁷⁷ Sumoylation is also known to occur in protein-tyrosine phosphatase 1B (PTP1B), whereby PTP1B function is inhibited.¹⁷⁸ As PTP1B is involved in a negative regulation of insulin receptor, PTP1B sumoylation is considered to positively regulate insulin signaling.¹⁶⁹ While some of these studies indicate the beneficial role of protein sumoylation, the modification has also been shown to be involved in diabetic pathogenesis.^176,179,180 For example, high glucose has been shown to induce sumoylation of Smad4 in mesangial cells, a process likely involved in renal fibrosis in diabetic kidney.¹⁸¹ Additionally, protein sumoylation has been linked to increased endothelial inflammation, a process known to occur in diabetes and its complications.¹⁸²

Protein ADP-ribosylation

This posttranslational modification occurring in several amino acid residues, such as cysteine, arginine, and asparagine, is the transfer of the ADP-ribose moiety of the NAD⁺ molecule onto a target protein,^183,184 and either mono-ADP-ribosylation or poly-ADP-ribosylation can occur.¹⁸⁵ Because NAD⁺ is used as a substrate for ADP-ribosylases, the process is also highly dependent on NAD⁺ availability, and activation of ADP-ribosylases can actually deplete NAD⁺.^41–44 This is indeed the case in diabetes as over-activation of poly-ADP-ribosylases and NAD⁺ depletion have been observed.^41,186,187 Accordingly, inhibition of poly-ADP-ribosylases has been demonstrated to prevent the development of diabetes and its complications.^188–190 As ROS-induced DNA damage can activate poly-ADP-ribosylases, ADP-ribosylation is thought to be deeply involved in oxidative stress and glucotoxicity.¹⁹¹

Conclusion

In this review, we have summarized the evidence that post-translational protein modifications can manifest glucotoxicity in diabetes. We have discussed the types of protein modifications that have been, and are still being, intensively investigated in the field of diabetes research. These modifications, including carbonylation, nitration, glycation, O-GlcNAcylation, nitro-sylation, succination, acetylation, and ADP-ribosylation, can affect or modulate the function of the modified proteins’ with consequences that are more often detrimental than beneficial. Importantly, the driving force behind all these modifications is dysregulation of glucose metabolism in diabetes that results in persistent hyperglycemia. Further studies on these protein modifications in diabetes will continue to help our understanding of the pathogenic mechanisms of diabetes and its complications.

Author Contributions

Conceived the idea and wrote the first draft of the article: L-JY. Contributed to the preparation and design of the article and reviewed and approved the final form of the article: HZ, JW, ZJ, L-JY. All authors reviewed and approved of the final manuscript.

References

Kaiser

, Leibowitz

, Nesher

Glucotoxicity and beta-cell failure in type 2 diabetes mellitus.

J Pediatr Endocrinol Metab. 2003; 16(1): 5–22.

Del Prato

Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies.

Diabet Med. 2009; 26(12): 1185–1192.

Brunner

, Schvartz

, Priego-Capote

, Coute

, Sanchez

J.C.

Glucotoxicity and pancreatic proteomics.

J Proteomics. 2009; 71(6): 576–591.

Tuch

, Dunlop

, Proietto

Diabetes Research: A Guide for Postgraduates. Har-wood Academic Publishers, Amsterdam, The Netherland; 2000.

Funk

S.D.

, Yurdagul

Jr , Orr

A.W.

Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes.

Int J Vasc Med. 2012; 2012: 569654.

Eiselein

, Schwartz

H.J.

, Rutledge

J.C.

The challenge of type 1 diabetes mellitus.

ILAR J. 2004; 45(3): 231–236.

Leibowitz

, Kaiser

, Cerasi

Beta-cell failure in type 2 diabetes.

J Diabetes Investig. 2011; 2(2): 82–91.

Butler

A.E.

, Janson

, Bonner-Weir

, Ritzel

, Rizza

R.A.

, Butler

P.C.

Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.

Diabetes. 2003; 52(1): 102–110.

Chang-Chen

K.J.

, Mullur

, Bernal-Mizrachi

Beta-cell failure as a complication of diabetes.

Rev Endocr Metab Disord. 2008; 9(4): 329–343.

10.

Larsen

M.O.

Beta-cell function and mass in type 2 diabetes.

Dan Med Bull. 2009; 56(3): 153–164.

11.

Abdul-Ghani

M.A.

, DeFronzo

R.A.

Oxidative stress in type 2 diabetes. In: Miwa

, Beckman

K.B.

, Muller

F.L.

, eds. Oxidative Stress in Aging. Humana Press, Totowa, New Jersey, USA; 2008: 191–212.

12.

DeFronzo

R.A.

Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis.

Neth J Med. 1997; 50(5): 191–197.

13.

Maedler

, Donath

M.Y.

Beta-cells in type 2 diabetes: a loss of function and mass.

Horm Res. 2004; 62(Suppl 3): 67–73.

14.

Muoio

D.M.

, Newgard

C.B.

Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes.

Nat Rev Mol Cell Biol. 2008; 9(3): 193–205.

15.

Lee

S.A.

, Lee

W.J.

, Kim

E.H.

. Progression to insulin deficiency in Korean patients with type 2 diabetes mellitus positive for anti-GAD antibody. Diabet Med. 2011; 28(3): 319–324.

16.

Gallwitz

, Kazda

, Kraus

, Nicolay

, Schernthaner

Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes.

Acta Diabetol. 2013; 50(1): 39–45.

17.

Cnop

, Welsh

, Jonas

J.C.

, Jorns

, Lenzen

, Eizirik

D.L.

Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.

Diabetes. 2005; 54(Suppl 2): S97–S107.

18.

Szendroedi

, Phielix

, Roden

The role of mitochondria in insulin resistance and type 2 diabetes mellitus.

Nat Rev Endocrinol. 2012; 8(2): 92–103.

19.

Gholap

N.N.

, Davies

M.J.

, Mostafa

S.A.

, Khunti

Diagnosing type 2 diabetes and identifying high-risk individuals using the new glycated haemoglobin (HbA1c) criteria.

Br J Gen Pract. 2013; 63(607): e165–e167.

20.

, Luo

, Yan

L.J.

Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE).

Front Physiol. 2015; 6: 98.

21.

Korsgren

, Jansson

, Sandler

, Andersson

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

J Clin Invest. 1990; 86(6): 2161–2168.

22.

Poitout

, Robertson

R.P.

Minireview: secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity.

Endocrinology. 2002; 143(2): 339–342.

23.

Roseman

H.M.

Progression from obesity to type 2 diabetes: lipotoxicity, glucotox-icity, and implications for management.

J Manag Care Pharm. 2005; 11(6 suppl B): S3–S11.

24.

Weir

G.C.

, Marselli

, Marchetti

, Katsuta

, Jung

M.H.

, Bonner-Weir

Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes.

Diabetes Obes Metab. 2009; 11(Suppl 4): 82–90.

25.

, Yan

L.J.

Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic beta cell glucotoxicity.

Diabetes Metab Syndr Obes. 2015; 8: 181–188.

26.

Chung

S.S.

, Chung

S.K.

Aldose reductase in diabetic microvascular complications.

Curr Drug Targets. 2005; 6(4): 475–486.

27.

Dunlop

Aldose reductase and the role of the polyol pathway in diabetic nephropathy.

Kidney Int Suppl. 2000; 77: S3–S12.

28.

Hodgkinson

A.D.

, Sondergaard

K.L.

, Yang

, Cross

D.F.

, Millward

B.A.

, Demaine

A.G.

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.

Kidney Int. 2001; 60(1): 211–218.

29.

Iwata

, Nishinaka

, Matsuno

. The activity of aldose reductase is elevated in diabetic mouse heart. J Pharmacol Sci. 2007; 103(4): 408–416.

30.

Fantus

I.G.

The pathogenesis of the chronic complications of the diabetes mel-litus.

Endocrinol Rounds. 2002; 2(4): 1–8.

31.

Yasunari

, Kohno

, Kano

, Minami

, Yoshikawa

Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose.

Hypertension. 2000; 35(5): 1092–1098.

32.

Yasunari

, Kohno

, Kano

, Yokokawa

, Horio

, Yoshikawa

Aldose reductase inhibitor prevents hyperproliferation and hypertrophy of cultured rat vascular smooth muscle cells induced by high glucose.

Arterioscler Thromb Vasc Biol. 1995; 15(12): 2207–2212.

33.

Reddy

A.B.

, Ramana

K.V.

Aldose reductase inhibition: emerging drug target for the treatment of cardiovascular complications.

Recent Pat Cardiovasc Drug Discov. 2010; 5(1): 25–32.

34.

A.C.

, Cheung

A.K.

, Hung

V.K.

. Deletion of aldose reductase leads to protection against cerebral ischemic injury. J Cereb Blood Flow Metab. 2007; 27(8): 1496–1509.

35.

Luo

, Li

, Yan

L.J.

Roles of pyruvate, NADH, and mitochondrial complex I in redox balance and imbalance in β cell function and dysfunction.

J Diabetes Res. 2015; 2015: 512618.

36.

Yabe-Nishimura

Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications.

Pharmacol Rev. 1998; 50(1): 21–33.

37.

Tang

W.H.

, Martin

K.A.

, Hwa

Aldose reductase, oxidative stress, and diabetic mellitus.

Front Pharmacol. 2012; 3: 87.

38.

Yan

L.J.

Positive oxidative stress in aging and aging-related disease tolerance.

Redox Biol. 2014; 2C: 165–169.

39.

Yan

L.J.

, Christians

E.S.

, Liu

, Xiao

, Sohal

R.S.

, Benjamin

I.J.

Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage.

EMBO J. 2002; 21(19): 5164–5172.

40.

De Mattia

, Laurenti

, Bravi

, Ghiselli

, Iuliano

, Balsano

Effect of aldose reductase inhibition on glutathione redox status in erythrocytes of diabetic patients.

Metabolism. 1994; 43(8): 965–968.

41.

Dolle

, Rack

J.G.

, Ziegler

NAD and ADP-ribose metabolism in mitochondria.

FEBS J. 2013; 280(15): 3530–3541.

42.

Ying

NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences.

Antioxid Redox Signal. 2008; 10(2): 179–206.

43.

Szabados

, Fischer

G.M.

, Gallyas

Jr , Kispal

, Sumegi

Enhanced ADP-ribosylation and its diminution by lipoamide after ischemia-reperfusion in perfused rat heart.

Free Radic Biol Med. 1999; 27(9-10): 1103–1113.

44.

Szabo

Roles of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and its complications.

Pharmacol Res. 2005; 52(1): 60–71.

45.

Pittelli

, Felici

, Pitozzi

. Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol Pharmacol. 2011; 80(6): 1136–1146.

46.

Szabo

, Zanchi

, Komjati

. Poly(ADP-ribose) polymerase is activated in subjects at risk of developing type 2 diabetes and is associated with impaired vascular reactivity. Circulation. 2002; 106(21): 2680–2686.

47.

Pacher

, Liaudet

, Soriano

F.G.

, Mabley

J.G.

, Szabo

The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes.

Diabetes. 2002; 51(2): 514–521.

48.

Boesten

D.M.

, von Ungern-Sternberg

S.N.

, den Hartog

G.J.

, Bast

Protective pleiotropic effect of flavonoids on NAD(+) levels in endothelial cells exposed to high glucose.

Oxid Med Cell Longev. 2015; 2015: 894597.

49.

Pacher

, Szabo

Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme.

Antioxid Redox Signal. 2005; 7(11-12): 1568–1580.

50.

Obrosova

I.G.

, Drel

V.R.

, Pacher

. Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy: the relation is revisited. Diabetes. 2005; 54(12): 3435–3441.

51.

Chiu

, Xu

B.Y.

, Chen

, Feng

, Chakrabarti

Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications.

Can J Physiol Pharmacol. 2008; 86(6): 365–372.

52.

Puthanveetil

, Zhang

, Wang

. Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1. J Mol Cell Cardiol. 2012; 53(5): 677–686.

53.

Patti

M.E.

, Corvera

The role of mitochondria in the pathogenesis of type 2 diabetes.

Endocr Rev. 2010; 31(3): 364–395.

54.

Beaudry

J.L.

, Riddell

M.C.

Effects of glucocorticoids and exercise on pancreatic beta-cell function and diabetes development.

Diabetes Metab Res Rev. 2012; 28(7): 560–573.

55.

Bergman

R.N.

The two-edged sword.

Endocrinol Nutr. 2009; 56(Suppl 4): 5–7.

56.

Chung

S.S.

, Ho

E.C.

, Lam

K.S.

, Chung

S.K.

Contribution of polyol pathway to diabetes-induced oxidative stress.

J Am Soc Nephrol. 2003; 14(8 suppl 3): S233–S236.

57.

Vlassara

, Striker

G.E.

Advanced glycation endproducts in diabetes and diabetic complications.

Endocrinol Metab Clin North Am. 2013; 42(4): 697–719.

58.

Wolff

S.P.

, Jiang

Z.Y.

, Hunt

J.V.

Protein glycation and oxidative stress in diabetes mellitus and ageing.

Free Radic Biol Med. 1991; 10(5): 339–352.

59.

Beyer

A.M.

, Weihrauch

Hexosamine pathway activation and O-linked-N-acetylglucosamine: novel mediators of endothelial dysfunction in hyperglycemia and diabetes.

Vascul Pharmacol. 2012; 56(3-4): 113–114.

60.

Schleicher

E.D.

, Weigert

Role of the hexosamine biosynthetic pathway in diabetic nephropathy.

Kidney Int Suppl. 2000; 77: S13–S18.

61.

Xia

, Wang

, Munk

. Reactive oxygen species, PKC-beta1, and PKC-zeta mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells. Am J Physiol Endocrinol Metab. 2007; 293(5): E1280–E1288.

62.

Xia

, Wang

, Munk

. High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-beta1 signaling in mesangial cells. Am J Physiol Renal Physiol. 2008; 295(6): F1705–F1714.

63.

Yan

L.J.

Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress.

J Diabetes Res. 2014; 2014: 137919.

64.

Robertson

R.P.

Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.

J Biol Chem. 2004; 279(41): 42351–42354.

65.

Yan

L.J.

Protein redox modification as a cellular defense mechanism against tissue ischemic injury.

Oxid Med Cell Longev. 2014; 2014: 12.

66.

Knorre

D.G.

, Kudryashova

N.V.

, Godovikova

T.S.

Chemical and functional aspects of posttranslational modification of proteins.

Acta Naturae. 2009; 1(3): 29–51.

67.

Walsh

C.T.

Posttranslational Modification of Proteins: Expanding Natures Inventory. Eaglewood, CO: Robert and Company Publishers; 2006.

68.

Berlett

B.S.

, Stadtman

E.R.

Protein oxidation in aging, disease, and oxidative stress.

J Biol Chem. 1997; 272(33): 20313–20316.

69.

Stadtman

E.R.

Protein oxidation in aging and age-related diseases.

Ann NY Acad Sci. 2001; 928: 22–38.

70.

Chakravarti

, Chakravarti

D.N.

Oxidative modification of proteins: age-related changes.

Gerontology. 2007; 53(3): 128–139.

71.

Cai

, Yan

L.J.

Protein oxidative modifications: beneficial roles in disease and health.

J Biochem Pharmacol Res. 2013; 1(1): 15–26.

72.

Nass

, Bartling

, Navarrete Santos

. Advanced glycation end products, diabetes and ageing. Z Gerontol Geriatr. 2007; 40(5): 349–356.

73.

Nass

, Kukat

, Seibel

. Advanced glycation end product accumulation in rho(0) cells without a functional respiratory chain. Biol Chem. 2009; 390(9): 915–919.

74.

Chetyrkin

, Mathis

, Pedchenko

. Glucose autoxidation induces functional damage to proteins via modification of critical arginine residues. Biochemistry. 2011; 50(27): 6102–6112.

75.

Wolff

S.P.

, Dean

R.T.

Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes.

Biochem J. 1987; 245(1): 243–250.

76.

Lyons

T.J.

, Jenkins

A.J.

Glycation, oxidation, and lipoxidation in the development of the complications of diabetes: a carbonyl stress hypothesis.

Diabetes Rev (Alex). 1997; 5(4): 365–391.

77.

Takagi

, Kashiwagi

, Tanaka

, Asahina

, Kikkawa

, Shigeta

Significance of fructose-induced protein oxidation and formation of advanced glycation end product.

J Diabetes Complications. 1995; 9(2): 87–91.

78.

Dmitriev

L.F.

, Dugin

S.F.

Aldehydes and disturbance of carbohydrate metabolism: some consequences and possible approaches to its normalization.

Arch Physiol Biochem. 2007; 113(2): 87–95.

79.

Allaman

, Belanger

, Magistretti

P.J.

Methylglyoxal, the dark side of glycolysis.

Front Neurosci. 2015; 9: 23.

80.

Maessen

D.E.

, Stehouwer

C.D.

, Schalkwijk

C.G.

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases.

Clin Sci (Lond). 2015; 128(12): 839–861.

81.

Queisser

M.A.

, Yao

, Geisler

. Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes. 2010; 59(3): 670–678.

82.

hornalley

P.J.

, Langborg

, Minhas

H.S.

Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose.

Biochem J. 1999; 344(Pt 1): 109–116.

83.

Rosca

, Mustata

T.G.

, Kinter

M.T.

. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol. 2005; 289(2): F420–F430.

84.

Ozdemir

A.M.

, Hopfer

, Rosca

M.V.

, Fan

X.J.

, Monnier

V.M.

, Weiss

M.F.

Effects of advanced glycation end product modification on proximal tubule epithelial cell processing of albumin.

Am J Nephrol. 2008; 28(1): 14–24.

85.

Turk

Glycotoxines, carbonyl stress and relevance to diabetes and its complications.

Physiol Res. 2010; 59(2): 147–156.

86.

Yan

L.J.

Analysis of oxidative modification of proteins.

Curr Protoc Protein Sci. 2009; Chapter 14: Unit 14.4.

87.

Stadtman

E.R.

, Levine

R.L.

Free radical-mediated oxidation of free amino acids and amino acid residues in proteins.

Amino Acids. 2003; 25(3-4): 207–218.

88.

Yan

L.J.

, Sohal

R.S.

Mitochondrial adenine nucleotide translocase is modified oxidatively during aging.

Proc Natl Acad Sci USA. 1998; 95: 12896–12901.

89.

Yan

L.J.

, Levine

R.L.

, Sohal

R.S.

Oxidative damage during aging targets mitochondrial aconitase.

Proc Natl Acad Sci USA. 1997; 94: 11168–11172.

90.

Dalle-Donne

, Aldini

, Carini

, Colombo

, Rossi

, Milzani

Protein carbonylation, cellular dysfunction’ and disease progression.

J Cell Mol Med. 2006; 10(2): 389–406.

91.

Fedorova

, Bollineni

R.C.

, Hoffmann

Protein carbonylation as a major hallmark of oxidative damage: update of analytical strategies.

Mass Spectrom Rev. 2014; 33(2): 79–97.

92.

Margetis

P.I.

, Antonelou

M.H.

, Petropoulos

I.K.

, Margaritis

L.H.

, Papassideri

I.S.

Increased protein carbonylation of red blood cell membrane in diabetic retinopathy.

Exp Mol Pathol. 2009; 87(1): 76–82.

93.

Bollineni

R.C.

, Fedorova

, Bluher

, Hoffmann

Carbonylated plasma proteins as potential biomarkers of obesity induced type 2 diabetes mellitus.

J Proteome Res. 2014; 13(11): 5081–5093.

94.

Boden

, Homko

, Barrero

C.A.

. Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men. Sci Transl Med. 2015; 7(304): 304re307.

95.

Ruskovska

, Bernlohr

D.A.

Oxidative stress and protein carbonylation in adipose tissue—implications for insulin resistance and diabetes mellitus.

J Proteomics. 2013; 92: 323–334.

96.

Mendez

, Pazos

, Molinar-Toribio

. Protein carbonylation associated to high-fat, high-sucrose diet and its metabolic effects. J Nutr Biochem. 2014; 25(12): 1243–1253.

97.

Taganis

Reactive oxygen species and insulin resistance: the good, the bad and the ugly.

Trends Pharmacol Sci. 2011; 32(2): 82–89.

98.

Henriksen

E.J.

, Diamond-Stanic

M.K.

, Marchionne

E.M.

Oxidative stress and the etiology of insulin resistance and type 2 diabetes.

Free Radic Biol Med. 2011; 51(5): 993–999.

99.

Barnett

A.H.

Type 2 Diabetes. 2nd ed. Oxford University Press, Oxford, United Kindom; 2012.

100.

Radi

Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects.

Acc Chem Res. 2013; 46(2): 550–559.

101.

Radi

, Cassina

, Hodara

, Quijano

, Castro

Peroxynitrite reactions and formation in mitochondria.

Free Radic Biol Med. 2002; 33(11): 1451–1464.

102.

Ferrer-Sueta

, Radi

Chemical biology of peroxynitrite: kinetics, diffusion, and radicals.

ACS Chem Biol. 2009; 4(3): 161–177.

103.

Goldstein

, Merenyi

The chemistry of peroxynitrite: implications for biological activity.

Methods Enzymol. 2008; 436: 49–61.

104.

Koeck

, Corbett

J.A.

, Crabb

J.W.

, Stuehr

D.J.

, Aulak

K.S.

Glucose-modulated tyrosine nitration in beta cells: targets and consequences.

Arch Biochem Biophys. 2009; 484(2): 221–231.

105.

Koeck

, Willard

, Crabb

J.W.

, Kinter

, Stuehr

D.J.

, Aulak

K.S.

Glucose-mediated tyrosine nitration in adipocytes: targets and consequences.

Free Radic Biol Med. 2009; 46(7): 884–892.

106.

Lima

V.V.

, Spitler

, Choi

, Webb

R.C.

, Tostes

R.C.

O-GlcNAcylation and oxidation of proteins: is signalling in the cardiovascular system becoming sweeter?

Clin Sci (Lond). 2012; 123(8): 473–486.

107.

Yki-Jarvinen

, Vogt

, Iozzo

. UDP-N-acetylglucosamine transferase and glutamine: fructose 6-phosphate amidotransferase activities in insulinsensitive tissues. Diabetologia. 1997; 40(1): 76–81.

108.

Luo

, Wu

, Jing

, Yan

L.J.

Hyperglycemic stress and carbon stress in diabetic glucotoxicity.

Aging Dis. 2016; 7(1): 90–110.

109.

, Hart

G.W.

Protein O-GlcNAcylation in diabetes and diabetic complications.

Expert Rev Proteomics. 2013; 10(4): 365–380.

110.

Zachara

N.E.

, Hart

G.W.

Cell signaling, the essential role of O-GlcNAc!

Biochim Biophys Acta. 2006; 1761(5-6): 599–617.

111.

Hart

G.W.

Three decades of research on O-GlcNAcylation—a major nutrient sensor that regulates signaling, transcription and cellular metabolism.

Front Endocrinol (Lausanne). 2014; 5: 183.

112.

Hardiville

, Hart

G.W.

Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation.

Cell Metab. 2014; 20(2): 208–213.

113.

Kuo

, Zilberfarb

, Gangneux

, Christeff

, Issad

O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon?

Biochimie. 2008; 90(5): 679–685.

114.

Banerjee

P.S.

, Ma

, Hart

G.W.

Diabetes-associated dysregulation of O-GlcNAcylation in rat cardiac mitochondria.

Proc Natl Acad Sci USA. 2015; 112(19): 6050–6055.

115.

Fardini

, Masson

, Boudah

. O-GlcNAcylation of FoxO1 in pancreatic beta cells promotes Akt inhibition through an IGFBP1-mediated autocrine mechanism. FASEB J. 2014; 28(2): 1010–1021.

116.

Tong

, Aponte

A.M.

, Kohr

M.J.

, Steenbergen

, Murphy

, Sun

Postconditioning leads to an increase in protein S-nitrosylation.

Am J Physiol Heart Circ Physiol. 2014; 306(6): H825–H832.

117.

Sun

, Murphy

Protein S-nitrosylation and cardioprotection.

Circ Res. 2010; 106(2): 285–296.

118.

Sun

, Morgan

, Shen

R.F.

, Steenbergen

, Murphy

Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport.

Circ Res. 2007; 101(11): 1155–1163.

119.

Lima

, Forrester

M.T.

, Hess

D.T.

, Stamler

J.S.

S-nitrosylation in cardiovascular signaling.

Circ Res. 2010; 106(4): 633–646.

120.

Nakamura

, Lipton

S.A.

Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases.

Trends Pharmacol Sci. 2016; 37(1): 73–84.

121.

Chouchani

E.T.

, Methner

, Nadtochiy

S.M.

. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med. 2013; 19(6): 753–759.

122.

Kaneki

, Shimizu

, Yamada

, Chang

Nitrosative stress and pathogenesis of insulin resistance.

Antioxid Redox Signal. 2007; 9(3): 319–329.

123.

Noriega-Cisneros

, Cortes-Rojo

, Manzo-Avalos

. Mitochondrial response to oxidative and nitrosative stress in early stages of diabetes. Mitochondrion. 2013; 13(6): 835–840.

124.

Yasukawa

, Tokunaga

, Ota

, Sugita

, Martyn

J.A.

, Kaneki

S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance.

J Biol Chem. 2005; 280(9): 7511–7518.

125.

Mieyal

J.J.

, Gallogly

M.M.

, Qanungo

, Sabens

E.A.

, Shelton

M.D.

Molecular mechanisms and clinical implications of reversible protein S-glutathionylation.

Antioxid Redox Signal. 2008; 10(11): 1941–1988.

126.

Sanchez-Gomez

F.J.

, Espinosa-Diez

, Dubey

, Dikshit

, Lamas

S-glutathionylation: relevance in diabetes and potential role as a biomarker.

Biol Chem. 2013; 394(10): 1263–1280.

127.

Sampathkumar

, Balasubramanyam

, Sudarslal

, Rema

, Mohan

, Balaram

Increased glutathionylated hemoglobin (HbSSG) in type 2 diabetes subjects with microangiopathy.

Clin Biochem. 2005; 38(10): 892–899.

128.

Wagner

G.R.

, Payne

R.M.

Widespread and enzyme-independent NΕ-acetylation and NΕ-succinylation of proteins in the chemical conditions of the mitochondrial matrix.

J Biol Chem. 2013; 288(40): 29036–29045.

129.

Baeza

, Smallegan

M.J.

, Denu

J.M.

Site-specific reactivity of nonenzymatic lysine acetylation.

ACS Chem Biol. 2015; 10(1): 122–128.

130.

Prins

M.L.

Cerebral metabolic adaptation and ketone metabolism after brain injury.

J Cereb Blood Flow Metab. 2008; 28(1): 1–16.

131.

White

, Venkatesh

Clinical review: ketones and brain injury.

Crit Care. 2011; 15(2): 219.

132.

Cotter

D.G.

, Schugar

R.C.

, Crawford

P.A.

Ketone body metabolism and cardiovascular disease.

Am J Physiol Heart Circ Physiol. 2013; 304(8): H1060–H1076.

133.

Fritz

K.S.

, Galligan

J.J.

, Hirschey

M.D.

, Verdin

, Petersen

D.R.

Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice.

J Proteome Res. 2012; 11(3): 1633–1643.

134.

Iyer

, Fairlie

D.P.

, Brown

Lysine acetylation in obesity, diabetes and metabolic disease.

Immunol Cell Biol. 2012; 90(1): 39–46.

135.

Kosanam

, Thai

, Zhang

. Diabetes induces lysine acetylation of intermediary metabolism enzymes in the kidney. Diabetes. 2014; 63(7): 2432–2439.

136.

Fernandes

, Weddle

, Kinter

C.S.

. Lysine acetylation activates mitochon-drial aconitase in the heart. Biochemistry. 2015; 54(25): 4008–4018.

137.

Muoio

D.M.

Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock.

Cell. 2014; 159(6): 1253–1262.

138.

Wagner

G.R.

, Hirschey

M.D.

Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases.

Mol Cell. 2014; 54(1): 5–16.

139.

Pham

T.X.

, Lee

Dietary regulation of histone acetylases and deacetylases for the prevention of metabolic diseases.

Nutrients. 2012; 4(12): 1868–1886.

140.

Paik

W.K.

, Pearson

, Lee

H.W.

, Kim

Nonenzymatic acetylation of histones with acetyl-CoA.

Biochim Biophys Acta. 1970; 213(2): 513–522.

141.

Ramponi

, Manao

, Camici

Nonenzymatic acetylation of histones with acetyl phosphate and acetyl adenylate.

Biochemistry. 1975; 14(12): 2681–2685.

142.

Wang

Molecular links between caloric restriction and Sir2/SIRTl activation.

Diabetes Metab J. 2014; 38(5): 321–329.

143.

Ramis

M.R.

, Esteban

, Miralles

, Tan

D.X.

, Reiter

R.J.

Caloric restriction, resveratrol and melatonin: role of SIRT1 and implications for aging and related-diseases.

Mech Ageing Dev. 2015; 146–148C: 28–41.

144.

Kincaid

, Bossy-Wetzel

Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration.

Front Aging Neurosci. 2013; 5: 48.

145.

Verdin

, Ott

50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond.

Nat Rev Mol Cell Biol. 2015; 16(4): 258–264.

146.

Seely

, Olefsky

J.M.

Potential cellular and genetic mechanisms for insulin resistance in the common disorders of diabetes and obesity. In: Moller

D.E.

, ed. Insulin resistance. New York: Wiley; 1993: 187–252.

147.

Lieberman

, Marks

A.D.

Marks’ Basic Medical Biochemistry: A Clinical Approach. 4th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2013.

148.

Vazquez

E.J.

, Berthiaume

J.M.

, Kamath

. Mitochondrial complex I defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart. Cardiovasc Res. 2015; 107(4): 453–465.

149.

Fritz

K.S.

, Green

M.F.

, Petersen

D.R.

, Hirschey

M.D.

Ethanol metabolism modifies hepatic protein acylation in mice.

PLoS One. 2013; 8(9): e75868.

150.

Huynh

F.K.

, Hershberger

K.A.

, Hirschey

M.D.

Targeting sirtuins for the treatment of diabetes.

Diabetes Manag (Lond). 2013; 3(3): 245–257.

151.

Jing

, Emanuelli

, Hirschey

M.D.

. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci USA. 2011; 108(35): 14608–14613.

152.

Morris

B.J.

Seven sirtuins for seven deadly diseases of aging.

Free Radic Biol Med. 2013; 56: 133–171.

153.

Nikiforov

, Kulikova

, Ziegler

The human NAD metabolome: functions, metabolism and compartmentalization.

Crit Rev Biochem Mol Biol. 2015; 50(4): 284–297.

154.

Turkmen

, Karagoz

, Kucuk

Sirtuins as novel players in the pathogenesis of diabetes mellitus.

World J Diabetes. 2014; 5(6): 894–900.

155.

Yang

, Sauve

A.A.

NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity.

AAPS J. 2006; 8(4): E632–E643.

156.

Vedantham

, Thiagarajan

, Ananthakrishnan

. Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of pro-inflammatory and prothrombotic signals. Diabetes. 2014; 63(2): 761–774.

157.

Nagai

, Brock

J.W.

, Blatnik

. Succination of protein thiols during adipocyte maturation: a biomarker of mitochondrial stress. J Biol Chem. 2007; 282(47): 34219–34228.

158.

Frizzell

, Thomas

S.A.

, Carson

J.A.

, Baynes

J.W.

Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity.

Biochem J. 2012; 445(2): 247–254.

159.

Merkley

E.D.

, Metz

T.O.

, Smith

R.D.

, Baynes

J.W.

, Frizzell

The succinated proteome.

Mass Spectrom Rev. 2014; 33(2): 98–109.

160.

Yang

, Ternette

, Su

. The succinated proteome of FH-mutant tumours. Metabolites. 2014; 4(3): 640–654.

161.

Blatnik

, Thorpe

S.R.

, Baynes

J.W.

Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes.

Ann NY Acad Sci. 2008; 1126: 272–275.

162.

Frizzell

, Lima

, Baynes

J.W.

Succination of proteins in diabetes.

Free Radic Res. 2011; 45(1): 101–109.

163.

Winterbourn

C.C.

, Hampton

M.B.

Thiol chemistry and specificity in redox signaling.

Free Radic Biol Med. 2008; 45(5): 549–561.

164.

Ying

, Clavreul

, Sethuraman

, Adachi

, Cohen

R.A.

Thiol oxidation in signaling and response to stress: detection and quantification of physiological and pathophysiological thiol modifications.

Free Radic Biol Med. 2007; 43(8): 1099–1108.

165.

Forman

H.J.

, Fukuto

J.M.

, Torres

Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers.

Am J Physiol Cell Physiol. 2004; 287(2): C246–C256.

166.

Fomenko

D.E.

, Marino

S.M.

, Gladyshev

V.N.

Functional diversity of cysteine residues in proteins and unique features of catalytic redox-active cysteines in thiol oxidoreductases.

Mol Cells. 2008; 26(3): 228–235.

167.

Biswas

, Chida

A.S.

, Rahman

Redox modifications of protein-thiols: emerging roles in cell signaling.

Biochem Pharmacol. 2006; 71(5): 551–564.

168.

Feligioni

, Brambilla

, Camassa

. Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury. PLoS One. 2011; 6(12): e28185.

169.

Feligioni

, Nistico

SUMO: a (oxidative) stressed protein.

Neuromolecular Med. 2013; 15(4): 707–719.

170.

Heo

K.S.

, Chang

, Le

N.T.

. De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis. Circ Res. 2013; 112(6): 911–923.

171.

Huang

C.J.

, Wu

, Khan

F.A.

, Huo

L.J.

DeSUMOylation: an important therapeutic target and protein regulatory event.

DNA Cell Biol. 2015; 34(11): 652–660.

172.

Zhao

Sumoylation regulates diverse biological processes.

Cell Mol Life Sci. 2007; 64(23): 3017–3033.

173.

Guo

, Li

, Zhang

. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet. 2004; 36(8): 837–841.

174.

Guo

, Han

, Adam

B.L.

. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. Biochem Biophys Res Commun. 2005; 337(4): 1308–1318.

175.

, Guo

, Isales

C.M.

. SUMO wrestling with type 1 diabetes. J Mol Med (Berl). 2005; 83(7): 504–513.

176.

Bohren

K.M.

, Nadkarni

, Song

J.H.

, Gabbay

K.H.

, Owerbach

A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.

J Biol Chem. 2004; 279(26): 27233–27238.

177.

Giorgino

, de Robertis

, Laviola

. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. Proc Natl Acad Sci USA. 2000; 97(3): 1125–1130.

178.

Dadke

, Cotteret

, Yip

S.C.

. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol. 2007; 9(1): 80–85.

179.

Wang

C.Y.

, She

J.X.

SUMO4 and its role in type 1 diabetes pathogenesis.

Diabetes Metab Res Rev. 2008; 24(2): 93–102.

180.

Lin

H.Y.

, Wang

C.L.

, Hsiao

P.J.

. SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes. Diabetes. 2007; 56(4): 1177–1180.

181.

Zhou

, Gao

, Huang

. High glucose induces sumoylation of Smad4 via SUMO2/3 in mesangial cells. Biomed Res Int. 2014; 2014: 782625.

182.

N.T.

, Corsetti

J.P.

, Dehoff-Sparks

J.L.

, Sparks

C.E.

, Fujiwara

, Abe

Reactive oxygen species, SUMOylation, and endothelial inflammation.

Int J Inflam. 2012; 2012: 678190.

183.

Mueller-Dieckmann

, Kernstock

, Lisurek

. The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation. Proc Natl Acad Sci USA. 2006; 103(41): 15026–15031.

184.

Hassa

P.O.

, Haenni

S.S.

, Elser

, Hottiger

M.O.

Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going?

Microbiol Mol Biol Rev. 2006; 70(3): 789–829.

185.

Butepage

, Eckei

, Verheugd

, Luscher

Intracellular mono-ADP-ribosylation in signaling and disease.

Cells. 2015; 4(4): 569–595.

186.

Horvath

E.M.

, Magenheim

, Kugler

. Nitrative stress and poly(ADP-ribose) polymerase activation in healthy and gestational diabetic pregnancies. Diabetologia. 2009; 52(9): 1935–1943.

187.

, Matsumura

, Edelstein

. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112(7): 1049–1057.

188.

Masutani

, Suzuki

, Kamada

. Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999; 96(5): 2301–2304.

189.

Pieper

A.A.

, Brat

D.J.

, Krug

D.K.

. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999; 96(6): 3059–3064.

190.

Virag

, Szabo

The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.

Pharmacol Rev. 2002; 54(3): 375–429.

191.

Daniels

C.M.

, Ong

S.E.

, Leung

A.K.

The promise of proteomics for the study of ADP-ribosylation.

Mol Cell. 2015; 58(6): 911–924.

192.

Brownlee

Biochemistry and molecular cell biology of diabetic complications.

Nature. 2001; 414(6865): 813–820.

193.

Brownlee

The pathobiology of diabetic complications: a unifying mechanism.

Diabetes. 2005; 54(6): 1615–1625.