Thioredoxin‐interacting protein deficiency induces Akt/Bcl‐xL signaling and pancreatic beta‐cell mass and protects against diabetes

Chen, Junqin; Hui, Simon T.; Couto, Francesca M.; Mungrue, Imran N.; Davis, Dawn Belt; Attie, Alan D.; Lusis, Aldons J.; Davis, Roger J.; Shalev, Anath

doi:10.1096/fj.08-111690

Cited by 202 publications

(271 citation statements)

References 39 publications

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“…As would be expected, induction of TXNIP by glucose was shown to promote oxidative stress and apoptosis in vascular smooth muscle cells and in the INS-1 beta cell line [9,12]. Moreover, islets from Txnip mutant mice are protected from glucose-induced apoptosis [13,14]. Thus, TXNIP is emerging as an important mediator of beta cell glucotoxicity.…”

Section: Introductionmentioning

confidence: 70%

“…Nevertheless, we cannot exclude the possibility that suppression of TXNIP to a greater extent than achieved here (~50%) could enhance insulin signal transduction also in beta cells. Moreover, it was recently shown that TXNIP deficiency prevented beta cell apoptosis in vivo, protecting the animals from hyperglycaemia and hypoinsulinaemia and thereby increasing PKB/Akt signalling [14]. Therefore, enhanced insulin signalling may contribute to beta cell survival in TXNIPdeficient animals.…”

Section: Discussionmentioning

confidence: 99%

“…TXNIP deficiency may prevent apoptosis through activation of PKB/Akt [14,20]. Therefore, we studied whether partial Txnip knockdown increased PKB/Akt phosphorylation in beta cells.…”

Section: Insulin Protects Beta Cells From Glucose-induced Apoptosismentioning

confidence: 99%

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Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

et al. 2009

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Aims/hypothesis In type 2 diabetes, glucose toxicity leads to beta cell apoptosis with decreased beta cell mass as a consequence. Thioredoxin-interacting protein (TXNIP) is a critical mediator of glucose-induced beta cell apoptosis. Since hyperglycaemia leads to elevated serum insulin, we hypothesised that insulin is involved in the regulation of TXNIP protein levels in beta cells. Methods We studied the production of TXNIP in INS-1E beta cells and in islets of Psammomys obesus, an animal model of type 2 diabetes, in response to glucose and different modulators of insulin secretion. Results TXNIP production was markedly augmented in islets from diabetic P. obesus and in beta cells exposed to high glucose concentration. In contrast, adding insulin to the culture medium or stimulating insulin secretion with different secretagogues suppressed TXNIP. Inhibition of glucose and fatty acid-stimulated insulin secretion with diazoxide increased TXNIP production in beta cells. Nitric oxide (NO), a repressor of TXNIP, enhanced insulin signal transduction, whereas inhibition of NO synthase abolished its activation, suggesting that TXNIP inhibition by NO is mediated by stimulation of insulin signalling. Treatment of beta cells chronically exposed to high glucose with insulin reduced beta cell apoptosis. Txnip knockdown mimicking the effect of insulin prevented glucose-induced beta cell apoptosis. Conclusions/interpretation Insulin is a potent repressor of TXNIP, operating a negative feedback loop that restrains the stimulation of TXNIP by chronic hyperglycaemia. Repression of TXNIP by insulin is probably an important compensatory mechanism protecting beta cells from oxidative damage and apoptosis in type 2 diabetes.

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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

et al. 2009

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“…15 Thus, by increasing the generation and decreasing the degradation of ROS, HG-induced TxNIP may contribute to glucotoxicity, as observed by others and our group in pancreatic b cells. 13,16,17 To elucidate the role of TxNIP in the pathogenesis of DN in vivo, we explored the action of TxNIP in the diabetic kidney of wild-type (WT) and TxNIP 2/2 (knockout [KO]) mice. In streptozotocin (STZ)-induced diabetic mice we found that, unlike in WT, indicators of renal injury and dysfunction such as albuminuria, proteinuria, serum cystatin C, and serum creatinine levels were not increased in diabetic TxNIP KO mice.…”

mentioning

confidence: 99%

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Shah

Xia

Masson

et al. 2015

Journal of the American Society of Nephrology

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Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogenactivated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP 2/2 , and TxNIP +/2 mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP 2/2 mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP 2/2 mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-b1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1b mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP 2/2 mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O 2 2 generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.

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“…Increased Txnip expression leads to insulin-resistant glucose transport in muscle and in adipocytes (Chutkow et al 2010, Yoshihara et al 2010, and in pancreatic b cells chronic increases in Txnip expression cause apoptosis (Minn et al 2005, Chen et al 2008a,b, Corbett 2008. Hyperglycemiamediated increase in Txnip induces accelerated transcription of interleukin 1b (IL1b), in human and in mouse adipocytes, and the increased production of IL1b likely contributes to the insulin resistance of diabetes (Koenen et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Posttranslational regulation of thioredoxin-interacting protein

Robinson¹,

Brock²,

Buse³

2012

Journal of Molecular Endocrinology

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Thioredoxin-interacting protein (Txnip) is a metabolic regulator, which modulates insulin sensitivity and likely plays a role in type 2 diabetes. We studied the regulation of Txnip in 3T3-L1 adipocytes. Cells were incubated under different conditions and Txnip was measured by immunoblotting. We confirmed that high glucose markedly increases Txnip expression by promoting transcription. Insulin decreases Txnip protein levels. Rapamycin under most conditions decreased Txnip, suggesting that mTOR complex-1 is involved. The acute effects of insulin are mainly posttranscriptional; insulin (100 nM) accelerates Txnip degradation more than tenfold. This effect is cell type specific. It works in adipocytes, preadipocytes and in L6 myotubes but not in HepG2 or in HEK 293 cells or in a pancreatic b-cell line. The ubiquitin/proteasome pathway is involved. Degradation of Txnip occurred within 15 min in the presence of 3 nM insulin and overnight with 0.6 nM insulin. Proteasomal Txnip degradation is not mediated by a cysteine protease or an anti-calpain enzyme. Okadaic acid (OKA), an inhibitor of phosphoprotein phosphatases (pp), markedly reduced Txnip protein and stimulated its further decrease by insulin. The latter occurred after incubation with 1 or 1000 nM OKA, suggesting that insulin enhances the phosphorylation of a pp2A substrate. Incubation with 0.1 mM Wortmannin, a PI3 kinase inhibitor, increased Txnip protein twofold and significantly inhibited its insulin-induced decrease. Thus, while OKA mimics the effect of insulin, Wortmannin opposes it. In summary, insulin stimulates Txnip degradation by a PI3 kinase-dependent mechanism, which activates the ubiquitin/ proteasome pathway and likely serves to mitigate insulin resistance.

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Thioredoxin‐interacting protein deficiency induces Akt/Bcl‐xL signaling and pancreatic beta‐cell mass and protects against diabetes

Cited by 202 publications

References 39 publications

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

Posttranslational regulation of thioredoxin-interacting protein

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