The role of TXNIP in the pathophysiology of diabetes and its vascular complications: a concise review






Erol CERASI, MD, PhD
Gil LEIBOWITZ, MD
Endocrinology & Metabolism Service, Department of Medicine
Hadassah University Hospital
Jerusalem, ISRAEL
Alain KTORZA, PhD
Pôle d’Innovation Thérapeutique Métabolisme, Servier
Suresnes, FRANCE

The role of TXNIP in the pathophysiology of diabetes and its vascular complications: a concise review

by G. Leibowitz, A. Ktorza, and E. Cerasi, Israel and France

Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of thioredoxin, an oxidoreductase protein that plays a central role in protecting pancreatic β cells and vascular cells against oxidative stress. Apart from its inhibitory interaction with thioredoxin, TXNIP also impacts systemic glucose homeostasis by inhibiting glucose uptake in muscle and adipose tissue and increasing hepatic glucose production. TXNIP expression is itself increased by glucose, and suppressed by insulin, and hence may contribute to the development and progression of diabetes and its vascular complications. Herein, we discuss the role of TXNIP in the pathophysiology of diabetes, emphasizing its effects on β-cell function, such as apoptosis and the production and secretion of insulin, and on diabetic vascular complications. We also evaluate the implications of recent findings on the regulation and function of TXNIP for future diabetes therapies.

Medicographia. 2014;36:391-397 (see French abstract on page 397)



Type 2 diabetes (T2D) results from failure of the pancreatic βcell to cope with the increased insulin demand of nutrient overload and obesity-associated insulin resistance.1 Although many studies in the 1960s demonstrated clearly diminished insulin secretion in T2D patients,2,3 for a long period thereafter the role of the β cell in the pathogenesis of diabetes was regarded as controversial at best, more often as nonexistent. However, numerous studies in more recent decades have convincingly shown that β-cell dysfunction is the driving force of the metabolic disturbance both in the initiation and the progression of T2D.4 β-Cell dysfunction in diabetes is multifactorial, involving both genetic and environmental factors. The latter include hyperglycemia and elevated levels of free fatty acids (FFA) and inflammatory cytokines, all factors that impair mitochondrial and endoplasmic reticulum (ER) function, leading to mitochondrial and ER stress.4 Accumulation of reactive oxygen species (ROS), ie, oxidative stress, can cause ER stress, and vice versa, thus generating a vicious feedforward cycle which impinges on β-cell function, survival, and differentiation. Figure 1 (page 392) presents a schematic illustration of these events.

The β cell is particularly prone to develop oxidative stress, due to low activities of catalase, selenium-dependent glutathione peroxidase 1 and Cu/Zn-superoxide dismutase 1. By contrast, the NADPH-dependent oxidoreductase thioredoxin is abundant, which suggests that it has an important role inβ-cell defense against cellular stress.5 Thioredoxin partners with thioredoxin reductase and thioredoxin peroxidase to reduce oxidized proteins and scavenge ROS.6


Figure 1
Figure 1. Mechanisms of β-cell stress in type 2
diabetes.

In type 2 diabetes, the β cells are exposed to a noxious environment
including hyperglycemia, elevated free fatty acids, and proinflammatory
cytokines, all leading to cellular stress. This is, in
part, the consequence of excessive reactive oxygen species
(ROS) production, in turn leading to mitochondrial fragmentation
and impairment of adenosine triphosphate (ATP) production.
Alterations in the redox state, as well as other poorly defined
mechanisms, also lead to morphological changes in the endoplasmic
reticulum (ER) that are associated with impaired protein
folding, leading to ER stress. Impaired mitochondrial and ER
functions culminate in β-cell dysfunction and apoptosis, with
worsening of diabetes as a consequence. Thioredoxin (TRX) is
the main antioxidant of β cells, regulating its adaptation to stress.
TRX is inhibited by TRX-interacting protein (TXNIP), whose expression
is markedly stimulated by high glucose concentrations.



Thioredoxin-interacting protein (TXNIP), a member of the arrestin family, binds to the redox-active cysteine (Cys) residues of thioredoxin and inhibits its oxidoreductase activity, thus functioning as an endogenous inhibitor of thioredoxin.7 Importantly, in β cells, as well as in other tissues, TXNIP expression is robustly induced by glucose8; hence, it may play a central role in the pathophysiology of T2D and its vascular complications. Indeed, TXNIP has been implicated in β-cell apoptosis in T2D, diabetic microvascular complications, and atherosclerosis, which is the leading cause of death among diabetic patients. In this concise review, we discuss the regulation of TXNIP in diabetes and its impact on β-cell function, glucose homeostasis, and vascular complications. We also evaluate the implications of these findings for envisaging future diabetes therapies.




TXNIP structure and function

TXNIP, also known as vitamin D3–upregulated protein-1 (VDUP-1) and thioredoxin-binding protein-2 (TBP-2), is a 50-kDa protein that was originally discovered by yeast 2-hybrid screen for thioredoxin-1–interacting proteins.9 An intramolecular disulfide bond between Cys63 and Cys247 in TXNIP is susceptible to disulfide exchange with reduced thioredoxin at Cys247, leading to generation of stable mixed disulfide bonds; this inhibits the ability of thioredoxin to scavenge ROS and to interact with other signaling molecules. The crystal structure of the thioredoxin-TXNIP complex shows that upon binding to thioredoxin, TXNIP undergoes a structural rearrangement that involves intermolecular switching of disulfide domains between different TXNIP molecules that eventually leads to de novo intermolecular interactions between TXNIP Cys247 and the active site of thioredoxin at Cys32.10


Figure 2
Figure 2. Transcriptional regulation of the Txnip gene.

Glucose stimulates the translocation of carbohydrate-response-element–binding protein (ChREBP)
or Mondo from the cytosol to the nucleus and its binding to the carbohydrate response element
(ChoRE) of the Txnip promoter, in complex with Max-like protein X (MLX). Several other factors participate
in the activation of transcription (see text for details). Insulin, cyclic adenosine monophosphate
(cAMP), as well as AMP-activated protein kinase (AMPK) signaling pathways exert negative actions
on Txnip transcription (blue arrows). The inhibition of Txnip involves also the activation of FOXO.
Abbreviations: AMPK, AMP-activated protein kinase; cAMP, cyclic adenosine monophosphate;
ChoRE, carbohydrate response element; ChREBP, carbohydrate-response-element–binding protein;
CREBP, cAMP-response-element–binding protein; FOXO, forkhead transcription factor; GLP-1,
glucagon-like peptide-1; GTF, general transcription factors; HAT, histone acetyltransferase; HDAC,
histone deacetylase; MLX, Max-like protein X; NF-Y, nuclear factor Y; PI3 kinase, phosphatidylinositol
3-kinase; PKB/Akt, protein kinase B (also known as Akt); Pol II, RNA polymerase II; TBP,
TATA-binding protein.



TXNIP is a member of the α-arrestin–protein superfamily that is involved in receptor recycling and endocytosis. The molecular function of the α-arrestin domain of TXNIP, as well as of other proteins belonging to the family, is currently unknown. TXNIP has important effects on glucose homeostasis that are independent of its binding to thioredoxin.11 TXNIP inhibits glucose uptake, including in cells unresponsive to insulin.12 This effect is mediated through enhanced endocytosis of glucose transporter 1 (GLUT1) by plasma membrane–localized TXNIP and by inhibition of GLUT1 transcription.13 In addition to inhibiting glucose uptake, TXNIP may also modify intracellular glucose metabolism; indeed, TXNIP deficiency reduces mitochondrial oxidation while promoting glycolysis,14 thus potentially protecting cells against oxidative stress.

Regulation of TXNIP expression in diabetes

Glucose is the most potent physiological regulator of TXNIP expression. Glucose regulates production of TXNIP by increasing the binding of the transcription factor carbohydrate-response- element–binding protein (ChREBP) to the Txnip promoter, with recruitment of histone acetyltransferase p300 and histone H4 acetylation, thereby stimulating Txnip transcription (Figures 2 and 3).15 Consistently, TXNIP expression was markedly increased in islets of different animal models of T2D. To give an example, in Psammomys obesus, an animal model of nutrition-induced diabetes, TXNIP was undetectable in the islets of normoglycemic animals. When the animals were fed a high-energy diet, they rapidly developed hyperglycemia, which was then accompanied by a rapid and strong induction of TXNIP; this persisted throughout the course of the disease (Figure 3).16 Furthermore, when islets of normoglycemic animals were incubated in vitro, increasing glucose concentrations markedly augmented the expression of TXNIP; this was associated with a strong stimulation of Txnip transcriptional activity (Figure 4).16 In human islets, the expression of TXNIP was robustly increased when incubated in the presence of a high glucose concentration.17 Similarly, TXNIP expression was elevated in muscle tissue of human subjects with impaired glucose tolerance or diabetes.18 No association was found between common genetic variations in the TXNIP gene and T2D, and its expression was not increased in normoglycemic subjects with a family history of diabetes, suggesting that TXNIP is increased in response to glucose dysregulation, rather than being a genetic trait of diabetes.


Figure 3
Figure 3. Effect of glucose on islet thioredoxin-interacting protein
expression in vivo.

Islets were isolated from Psammomys obesus before (Day 0) and 4 days or 2
weeks after switching to a high-caloric diet, which rapidly induced hyperglycemia.
Western blots for thioredoxin-interacting protein (TXNIP) and thioredoxin
(TRX) are shown. No TXNIP could be demonstrated in islets from normoglycemic
animals, while its expression was markedly enhanced with the
beginning of diabetes; TRX expression was unchanged.
After reference 16: Shaked et al. Diabetologia. 2009;52:636-644. © 2009,
Springer-Verlag.



In contrast to glucose, insulin suppresses TXNIP expression in peripheral tissues (muscle and fat) and in β cells.16,18 In T2D, hyperglycemia along with insulin deficiency and insulin resistance may thus be expected to further increase TXNIP expression, and hence markedly exacerbate the oxidative stress of the diabetic state.


Figure 4
Figure 4. Effect of glucose in vitro on Psammomys obesus islet
thioredoxin-interacting protein expression.

Islets were isolated from normoglycemic animals and incubated during 48 hours
at different glucose concentrations. (A) Thioredoxin-interacting protein (TXNIP)
levels determined by Western blot. Note the strong stimulation by 22.2 mM
glucose (G-22.2), compared with 3.3 mM glucose (G-3.3). (B) Dose-dependent
effect of glucose on Txnip messenger RNA (mRNA) concentrations (Northern blots).
After reference 16: Shaked et al. Diabetologia. 2009;52:636-644. © 2009,
Springer-Verlag.


Role of TXNIP in the β-cell dysfunction of T2D

Recent studies have shown that TXNIP is a crucial factor in β-cell biology, and its upregulation is one of the key events leading to β-cell dysfunction and apoptosis in diabetes. β-Cell mass in TXNIP loss-of-function mutant mice was increased, and consequently the mice were resistant to the diabetes inducing effect of streptozotocin (a drug which destroys β cells).19 Moreover, intercrossing TXNIP-deficient mice with an animal model of diabetes (ob/ob mice) prevented the appearance of hyperglycemia and β-cell apoptosis, producing instead a 3-fold increase in β-cell mass.19 TXNIP-deficient islets, and β cells in which TXNIP was knocked down, were completely protected from the apoptosis-inducing effect of high glucose concentrations.16,20 These findings indicate that TXNIP is critical for diabetes-induced β-cell apoptosis. The mechanism of action of TXNIP includes shuttling of the molecule within the β cell between the nucleus and the mitochondria, where it promotes apoptosis by activating the mitochondrial apoptotic pathway.21

In addition to the proapoptotic effects of TXNIP, it also impairs βcell function, and might therefore be an important mediator of the deleterious effects of hyperglycemia (glucotoxicity) on insulin production and secretion.22,23 Of note, overexpression of TXNIP in β cells repressed the expression of genes regulating insulin secretion.24 Recently, TXNIP has been reported to induce the expression of microRNA 204 (miR-204), which inhibits insulin production by directly targeting and down regulating MAFA, a well-established transcription factor involved in proinsulin gene transcription.23 Previous reports showed that decreased MAFA expression is responsible for inhibited insulin production in states of hyperglycemia and high FFA (glucolipotoxicity).25 Thus, the TXNIP–miR-204–MAFA sequence constitutes a novel pathway in the pathogenesis of diabetic β-cell dysfunction.

Finally, in diabetic β cells, ER stress generates a proinflammatory response mediated by the nucleotide-binding domain, leucine-rich-repeat–containing family, pyrin domain–containing 3 (NLRP3) inflammasome, which contributes to β-cell dysfunction and apoptosis in diabetes, both type 1 and type 2.26 Importantly, TXNIP has been reported to serve as a critical link between ER stress and inflammation,27,28 further supporting its prime role in mediating the deleterious effects of the diabetic environment on the β cell. Figure 1 summarizes this section.

TXNIP regulation of insulin sensitivity and hepatic glucose production

In healthy individuals, TXNIP expression is inversely correlated with total body glucose uptake, suggesting that it may have a role in regulating insulin sensitivity.18 Indeed, forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing it with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that TXNIP exerts a detrimental effect on glucose transport.18 Interestingly, TXNIP expression was elevated in ovarian granulosa cells and in the serum of insulin-resistant women with polycystic ovary syndrome,29,30 further supporting its role in regulating insulin sensitivity in human disease.

Noteworthy, TXNIP also regulates hepatic glucose production: HcB-19 mice, which harbor a missense mutation in the TXNIP gene, exhibit fasting hypoglycemia.31 Similarly, conditional knockout of TXNIP in the liver led to lower fasting blood glucose concentrations and impairment of hepatic glucose production.32 Furthermore, forced expression of TXNIP in the liver of normal mice resulted in enhanced gluconeogenesis, along with insulin resistance and impaired glucose tolerance.33


Figure 5
Figure 5. Expected effects of reduction in thioredoxin-interacting
protein (TXNIP) expression on several vascular cell functions.

See text for details.



This was probably mediated by increased expression of the key gluconeogenic enzyme glucose-6-phosphatase and decreased expression of the glycolytic regulator glucokinase. These observations have important implications for the pathophysiology of T2D, as augmented hepatic glucose production is among its fundamental defects, and is considered a determining factor for fasting hyperglycemia in this disease.

Altogether, it is now established that TXNIP is increased in diabetes and has multiple detrimental metabolic effects, including impairment of insulin production and secretion and increased insulin resistance in peripheral tissues and the liver, thus leading to exacerbation of the metabolic disorder in T2D.

The role of TXNIP in vascular complications of diabetes

TXNIP has been implicated in various processes that increase the risk for vascular disease, including metabolic dysregulation, most notably hyperglycemia, oxidative and ER stress, and inflammation. TXNIP has been shown recently to mediate endothelial cell inflammation in response to disturbed blood flow by increasing monocyte adhesion.34 Lipid peroxidation products also inhibit thioredoxin activity by inducing a conformational change; this has been associated with increased ROS production and enhanced monocyte adhesion to vascular endothelial cells.35 Taken together, these studies suggest that the thioredoxin system is important for vascular endothelial cell function and protects against atherosclerosis. We found that TXNIP is an important mediator of oxidative stress– induced cellular dysfunction and senescence in endothelial cells exposed to oxidized low-density lipoprotein (unpublished data, manuscript in preparation). This further supports the hypothesis that increased TXNIP expression results in endothelial cell dysfunction, thereby promoting atherosclerosis. The fact that TXNIP is increased in response to alterations of blood flow may suggest that it plays an important role in the pathophysiology of atherosclerosis, independently of mediating the deleterious effects of hyperglycemia, thus also in the context of diabetes-unrelated atherosclerosis.


Figure 6
Figure 6. Schematic view on the role of thioredoxin-
interacting protein in the pathophysiology
of type 2 diabetes.

Thioredoxin-interacting protein (TXNIP) is markedly increased
by glucose and induces oxidative stress by inhibiting thioredoxin’s
oxidoreductase activity. In addition to scavenging
of free radicals, thioredoxin interacts with signaling molecules
and transcription factors, thereby promoting cell
survival. Increased TXNIP expression in diabetes leads to
β-cell stress and apoptosis, as well as inhibition of insulin
production and secretion. In addition, TXNIP inhibits glucose
uptake in muscle and fat through its arrestin domain
and augments hepatic glucose production. TXNIP induces
inflammation through activation of NLRP3, which may
contribute to β-cell dysfunction, insulin resistance, and
vascular complications (see text for details).
Abbreviations: AP-1, activator protein-1; ASK1, apoptosis
stimulating kinase 1; c32, cysteine residue 32; c35, cysteine
residue 35; IL-1β, interleukin 1β JNK, c-JUN N-terminal
kinase: NF-κB, nuclear factor κB; NLRP3, nucleotidebinding
domain, leucine-rich-repeat–containing family, pyrin
domain–containing 3; Ref-1, redox factor-1; SH, sulfhydryl
group; S-S, disulfide group; TXNIP, thioredoxin-interacting
protein; TRX, thioredoxin.



Hyperglycemia and insulin resistance increase TXNIP expression in vascular tissues of diabetic patients36; this may contribute to the accelerated atherosclerotic process of diabetes. Dysregulation of TXNIP expression by hyperglycemia has also been implicated in diabetes-induced impairment of angiogenesis, probably due to inhibition of vascular endothelial growth factor (VEGF) production and action.37 In addition, TXNIP has been shown to enhance ischemia-reperfusion injury in response to acute hyperglycemia. Indeed, inhibition of TXNIP in the myocardium alleviated oxidative stress and decreased myocardial infarct size.14

Finally, TXNIP may also play a role in the microvascular complications of diabetes, such as retinopathy and nephropathy. This is suggested from work in models of diabetic retinopathy and retinal degeneration, where high glucose concentrations increased the expression of TXNIP, leading to oxidative stress, cellular dysfunction, and death. TXNIP deletion protected against retinal vascular degeneration and preserved retinal function.38 The beneficial effect of reducing TXNIP expression in vascular cells is schematically demonstrated in Figure 5.

TXNIP: a therapeutic target in diabetes

The accumulating data that have been briefly summarized above clearly suggest that TXNIP plays a central role in the pathophysiology of T2D as well as in mediating glucotoxicity, the driving force behind T2D disease progression (Figure 6). Hence, downregulation of TXNIP has potential to become a powerful therapeutic approach in diabetes, capable of improving hyperglycemia and preventing oxidative stress–induced tissue damage, including β-cell apoptosis and diabetic vascular complications.

The regulation of TXNIP is multifactorial, and many agents, including some pharmaceuticals, modify its expression. For example, insulin suppresses TXNIP expression by stimulating the canonical phosphatidylinositol 3-kinase signaling pathway.16,36 Glucagon-like peptide-1 (GLP-1) analogs inhibit TXNIP in β cells by increasing cyclic adenosine monophosphate (cAMP) levels.39 The inhibition of TXNIP by insulin and cAMP is mediated by repression of Txnip transcription and destabilization of the protein. We and others have shown that AMP-activated protein kinase (AMPK) activation also inhibits TXNIP.13,40,41 However, the efficacy by which such medications inhibit TXNIP in vivo is not clear. Therefore, novel TXNIP inhibitors that can specifically and effectively prevent the glucose stimulation of TXNIP expression would be highly desirable; their discovery could pave the way for the development of a new class of antidiabetic medications that target key pathways involved in the pathophysiology of diabetes and its vascular complications. If successful, such an approach may fully satisfy the present requirement for antidiabetic drugs: action not only on hyperglycemia, but on the global pathology of diabetes, including, most importantly, cardiovascular and microvascular morbidity.





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Keywords: glucose; insulin; thioredoxin; thioredoxin-interacting protein; type 2 diabetes; vascular complications