Thioredoxin-interacting Protein (Txnip) Is a Critical Regulator of Hepatic Glucose Production

Thioredoxin-interacting protein (Txnip) has been recently described as a possible link between cellular redox state and metabolism; Txnip binds thioredoxin and inhibits its disulfide reductase activity in vitro, while a naturally occurring strain of Txnip-deficient mice has hyperlipidemia, hypoglycemia, and ketosis exacerbated by fasting. We generated Txnip-null mice to investigate the role of Txnip in glucose homeostasis. Txnip-null mice were hypoglycemic, hypoinsulinemic, and had blunted glucose production following a glucagon challenge, consistent with a central liver glucose-handling defect. Glucose release from isolated Txnip-null hepatocytes was 2-fold lower than wild-type hepatocytes, whereas β-hydroxybutyrate release was increased 2-fold, supporting an intrinsic defect in hepatocyte glucose metabolism. While hepatocyte-specific gene deletion of Txnip did not alter glucose clearance compared with littermate controls, Txnip expression in the liver was required for maintaining normal fasting glycemia and glucose production. In addition, hepatic overexpression of a Txnip transgene in wild-type mice resulted in elevated serum glucose levels and decreased ketone levels. Liver homogenates from Txnip-null mice had no significant differences in the glutathione oxidation state or in the amount of available thioredoxin. However, overexpression of wild-type Txnip in Txnip-null hepatocytes rescued cellular glucose production, whereas overexpression of a C247S mutant Txnip, which does not bind thioredoxin, had no effect. These data demonstrate that Txnip is required for normal glucose homeostasis in the liver. While available thioredoxin is not changed in Txnip-null mice, the effects of Txnip on glucose homeostasis are abolished by a single cysteine mutation that inhibits binding to thioredoxin. Thioredoxin-interacting protein (Txnip) has been recently described as a possible link between cellular redox state and metabolism; Txnip binds thioredoxin and inhibits its disulfide reductase activity in vitro, while a naturally occurring strain of Txnip-deficient mice has hyperlipidemia, hypoglycemia, and ketosis exacerbated by fasting. We generated Txnip-null mice to investigate the role of Txnip in glucose homeostasis. Txnip-null mice were hypoglycemic, hypoinsulinemic, and had blunted glucose production following a glucagon challenge, consistent with a central liver glucose-handling defect. Glucose release from isolated Txnip-null hepatocytes was 2-fold lower than wild-type hepatocytes, whereas β-hydroxybutyrate release was increased 2-fold, supporting an intrinsic defect in hepatocyte glucose metabolism. While hepatocyte-specific gene deletion of Txnip did not alter glucose clearance compared with littermate controls, Txnip expression in the liver was required for maintaining normal fasting glycemia and glucose production. In addition, hepatic overexpression of a Txnip transgene in wild-type mice resulted in elevated serum glucose levels and decreased ketone levels. Liver homogenates from Txnip-null mice had no significant differences in the glutathione oxidation state or in the amount of available thioredoxin. However, overexpression of wild-type Txnip in Txnip-null hepatocytes rescued cellular glucose production, whereas overexpression of a C247S mutant Txnip, which does not bind thioredoxin, had no effect. These data demonstrate that Txnip is required for normal glucose homeostasis in the liver. While available thioredoxin is not changed in Txnip-null mice, the effects of Txnip on glucose homeostasis are abolished by a single cysteine mutation that inhibits binding to thioredoxin. Tight regulation of glucose homeostasis is fundamental to all higher life forms, and dysregulated glucose metabolism is a significant medical problem (1Engelgau M.M. Geiss L.S. Saaddine J.B. Boyle J.P. Benjamin S.M. Gregg E.W. Tierney E.F. Rios-Burrows N. Mokdad A.H. Ford E.S. Imperatore G. Narayan K.M. Ann. Intern. Med. 2004; 140: 945-950Crossref PubMed Scopus (545) Google Scholar, 2Mokdad A.H. Ford E.S. Bowman B.A. Dietz W.H. Vinicor F. Bales V.S. Marks J.S. J. Am. Med. Assoc. 2003; 289: 76-79Crossref PubMed Scopus (4547) Google Scholar). The liver has a major role in determining glucose levels through its control of both hepatic glucose uptake and glucose release. During fasting states the liver is particularly important, as it is the primary organ for maintaining blood glucose levels by up-regulating gluconeogenesis and glycogenolysis to increase glucose release (3Cahill Jr., G.F. N. Engl. J. Med. 1970; 282: 668-675Crossref PubMed Google Scholar, 4Hultman E. Bergstrom J. Nilsson L.H. Acta Anaesthesiol. Scand. 1974; : 28-49Crossref Scopus (10) Google Scholar). These processes are coordinated by hormonal control, primarily through the reciprocal actions of glucagon and insulin, as well as through glucocorticoid and adipokine cues (5Exton J. Park C. Interaction of Insulin and Glucagon in the Control of Liver Metabolism. Williams and Wilkins, Baltimore1972Google Scholar, 6Herman M.A. Kahn B.B. J. Clin. Investig. 2006; 116: 1767-1775Crossref PubMed Scopus (266) Google Scholar). Downstream effectors of hormonal inputs include transcription factors and coactivators that act as master regulators of metabolic transcriptional programs, such as PGC1α, 3The abbreviations used are: PGC1αperoxisome proliferator-activated receptor-γ coactivator 1αcyclic AMPresponse element-binding proteinTORC2transducer of regulated CREB activity 2Foxo1forkhead box O1Txnipthioredoxin-interacting proteinGFPgreen fluorescent proteinTxnipfl/flcontrol mice with Txnip flanked by loxP sitesliver KOTxnipfl/fl mice overexpressing Cre recombinase driven by an albumin promoterELISAenzyme-linked immunosorbent assayKOknock-outPEPCKphosphoenolpyruvate carboxykinaseGlc-6-Paseglucose-6-phosphatase. 3The abbreviations used are: PGC1αperoxisome proliferator-activated receptor-γ coactivator 1αcyclic AMPresponse element-binding proteinTORC2transducer of regulated CREB activity 2Foxo1forkhead box O1Txnipthioredoxin-interacting proteinGFPgreen fluorescent proteinTxnipfl/flcontrol mice with Txnip flanked by loxP sitesliver KOTxnipfl/fl mice overexpressing Cre recombinase driven by an albumin promoterELISAenzyme-linked immunosorbent assayKOknock-outPEPCKphosphoenolpyruvate carboxykinaseGlc-6-Paseglucose-6-phosphatase. CREB, TORC2, and Foxo1 (7Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1128) Google Scholar, 8Koo S.H. Flechner L. Qi L. Zhang X. Screaton R.A. Jeffries S. Hedrick S. Xu W. Boussouar F. Brindle P. Takemori H. Montminy M. Nature. 2005; 437: 1109-1111Crossref PubMed Scopus (796) Google Scholar, 9Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1511) Google Scholar, 10Matsumoto M. Pocai A. Rossetti L. Depinho R.A. Accili D. Cell Metab. 2007; 6: 208-216Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar). Other mechanisms governing hepatic carbohydrate metabolism include changes in substrate availability (11Jahoor F. Peters E.J. Wolfe R.R. Am. J. Physiol. 1990; 258: E288-E296PubMed Google Scholar), changes in mitochondrial respiration (12Pryor H.J. Smyth J.E. Quinlan J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar), and cellular redox state N. J. M. C. A. C.R. J. 2006; PubMed Scopus Google Scholar, Jr., J. Full Text PDF PubMed Google Scholar). proliferator-activated receptor-γ coactivator element-binding protein of regulated CREB activity box protein fluorescent protein control mice with Txnip flanked by loxP mice overexpressing Cre recombinase driven by an albumin immunosorbent proliferator-activated receptor-γ coactivator element-binding protein of regulated CREB activity box protein fluorescent protein control mice with Txnip flanked by loxP mice overexpressing Cre recombinase driven by an albumin immunosorbent The redox state of the is as an of metabolism B.A. 2003; PubMed Scopus Google Scholar, Cell 2003; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, 1990; Google Scholar). is thioredoxin, a in all life in maintaining a cellular through the of its A. M. PubMed Scopus Google Scholar). described as an thioredoxin with transcription factors and it to as a of redox L. M. J. R. H. H. R. 2004; PubMed Scopus Google Scholar, E.J. D. M. A. G. 2004; PubMed Scopus Google Scholar, H. F. M. H. PubMed Scopus Google Scholar). The role of thioredoxin in carbohydrate in is well thioredoxin and thioredoxin in the by of protein B.B. 2005; PubMed Scopus Google Scholar). Thioredoxin-interacting protein as or with thioredoxin its of Txnip inhibits the activity of thioredoxin, and H. F. M. H. PubMed Scopus Google Scholar, E. S.H. E.W. D.K. Rhee J. PubMed Scopus Google Scholar, A. M. S. H. H. H. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Full Text Full Text PDF PubMed Scopus Google Scholar). and J.S. A. J. J. Wu C. K.M. J. M. P. P. PubMed Scopus Google Scholar, R.A. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. J.S. P. J. 2005; Full Text Full Text PDF PubMed Scopus Google a link between thioredoxin and metabolism through the actions of that a naturally occurring strain with or has a mutation that a of Txnip J.S. A. J. J. Wu C. K.M. J. M. P. P. PubMed Scopus Google Scholar). of the a and fasting with a ketosis J.S. A. J. J. Wu C. K.M. J. M. P. P. PubMed Scopus Google Scholar, R.A. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). from Txnip-null mice generated by deletion the of Txnip for the metabolic to the fasting mice from organ of fasting. mice are rescued by a not a S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google Scholar), a defect in or in the and release of link between thioredoxin redox state and metabolism has it is not the Txnip-null is by the of of thioredoxin. is possible that Txnip has thioredoxin Txnip has to the that bind to and 2005; PubMed Scopus Google Scholar). In to Txnip, of which not bind thioredoxin P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). the gene has recently been to in G. J. G. J. J. E. 2005; Scholar). the that the of is a of metabolic regulators are not to thioredoxin binding P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). We recently that mutation of a single Txnip cysteine the of Txnip to bind thioredoxin and to thioredoxin activity in P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). We generated and hepatocyte-specific Txnip gene deletion in mice to the of Txnip in We used mice to the role of Txnip in glucose homeostasis and that in the of Txnip the liver is in maintaining blood glucose levels through glucose production and release. We that the effects of Txnip on glucose regulation are abolished by a single cysteine mutation that is required for the These Txnip as a of hepatic glucose production and glucose homeostasis. Txnip and of an Txnip and Txnip gene deletion is described J. J. C. E. 2007; PubMed Scopus Google Scholar). Txnip gene deletion was by mice to a overexpressing the Cre recombinase an C. M. Chen J. M.A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). used for were and for Cre and and Glucagon blood were with and serum was by through a serum and β-hydroxybutyrate levels were available and levels were by and and serum glucagon levels were by blood glucose levels were from blood an and Glucagon or glucagon was the of fasting mice for glucose for and for glucagon blood glucose levels were by as was isolated from the of was by and with a to the Txnip and were from mice and in in for to were in and by were primary to or was the and was was isolated the was from of and the was in a were in and by The amount of in was to levels. are in the and hepatocytes were isolated by a Cell PubMed Scopus Google Scholar, Cell PubMed Scopus Google Scholar). In mice were through the hepatic the and the with the the and were and for The liver was and to release the which were and in and with in for by a with were in Williams with insulin, and for and in with for a of C. R. Kahn were in with and Glucose on or were with and The following the were with no glucose or to for in in the with the of and or the was and for The glucose of the was by a glucose and for Txnip and Txnip C247S were as described P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of for liver was on in primary hepatocyte of with was to primary hepatocytes in and were mice, were with of with the or was levels were a with were and in the or of glutathione was from the homogenates with and to the available thioredoxin in liver homogenates was by the from and A. M. PubMed Scopus Google Scholar). increase the of the to thioredoxin of the or protein the and the with P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). were in a with and of the of protein were with insulin, liver thioredoxin reductase and for in was and the was by data are as was with were significant for Txnip-null and generated mice with gene deletion of Txnip a for deletion as described in J. J. C. E. 2007; PubMed Scopus Google Scholar). mice were with mice to for Txnip which were to for in and of gene expression in and Txnip-null mice were and normal in and significant differences were in compared with wild-type littermate Txnip-null and wild-type did not significant differences in the Txnip-null mice had higher levels of and lower blood glucose levels The lower blood glucose was exacerbated by Txnip-null mice had glucose than wild-type an and a for both In addition, Txnip-null mice had a ketosis with levels higher than littermate increased fasting was The hypoglycemia, and increase in exacerbated by fasting are consistent with the for the R.A. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. J.S. P. J. 2005; Full Text Full Text PDF PubMed Scopus Google and the Txnip-null mice by S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google Scholar). Txnip-null Glucose and to investigate the defect in glucose homeostasis in the Txnip-null mice, the of serum glucose clearance an glucose in The in serum glucose levels was decreased for the Txnip-null mice compared with wild-type in of both and to an of glucose clearance by the glucose clearance was the of glucose compared the blood glucose levels in to an a Txnip-null mice glucose clearance consistent with glucose by of hepatic glucose production, or a liver defect to the increased glucose mice for were with an glucagon the serum glucose levels were blunted in the Txnip-null mice a primary defect in metabolism or a to to a primary defect in and a to glucose are possible hormonal mechanisms that both glucose clearance as well as hepatic glucose production. However, serum levels were by in the Txnip-null mice compared with wild-type and by in the fasting state in Txnip-null is a from the of the mice and the by S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google Scholar), which described a higher serum levels or compared with control mice R.A. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. J.S. P. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google Scholar). available on of mice, and the with from an We compared and fasting serum glucagon levels between the Txnip-null mice and littermate by significant differences were the Txnip-null mice were hypoinsulinemic, the glucagon to in mice was elevated in both the and fasting The elevated is consistent with a to by the and M.A. PubMed Scopus Google Scholar). and and In addition, no in the of to between wild-type and Txnip-null mice data an to hypoglycemia, a defect in a Txnip-null Glucose the in Txnip-null mice had a defect in hepatic glucose and hepatocytes isolated from the Txnip-null mice an intrinsic defect in glucose and ketone production. hepatocytes were isolated from Txnip-null mice and wild-type littermate mice, in the of the and the levels of glucose and the were hepatocytes from the Txnip-null mice as glucose as hepatocytes isolated from wild-type mice to In addition, Txnip-null primary hepatocytes than 2-fold the levels of β-hydroxybutyrate than wild-type isolated hepatocytes, from the of and the in metabolic and the for an intrinsic defect in regulation of hepatocyte metabolism. in the Txnip-null that Txnip in an intrinsic defect in hepatocyte glucose production, the in or Liver levels from Txnip-null mice were to wild-type of of glycogenolysis were in primary hepatocytes from wild-type and Txnip-null mice, with and glucose release following a of glucagon and Txnip-null hepatocytes had higher levels of and glucose release to wild-type hepatocytes and to Txnip-null hepatocytes had elevated levels of to wild-type hepatocytes was used to glycogenolysis in production was of following a and glucagon were for wild-type and Txnip-deficient hepatocytes, as was the for glucagon These data that hepatic glucose production following Txnip deletion is not the of decreased or glucagon the of the in Txnip no were in on a of hepatic the in hepatocyte metabolism was to a in transcriptional on isolated from Txnip-null and wild-type glucose metabolism is by the coordinated transcriptional regulation of such as and Granner D.K. Physiol. PubMed Scopus Google Scholar), as well as master such as proliferator-activated receptor-γ and element-binding protein (7Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1128) Google Scholar, 8Koo S.H. Flechner L. Qi L. Zhang X. Screaton R.A. Jeffries S. Hedrick S. Xu W. Boussouar F. Brindle P. Takemori H. Montminy M. Nature. 2005; 437: 1109-1111Crossref PubMed Scopus (796) Google Scholar, 9Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1511) Google Scholar). significant differences were in the levels of in Txnip-null compared with wild-type We and transcriptional in primary hepatocytes with glucagon and wild-type and Txnip-deficient hepatocytes a in a Txnip-null hepatocytes had a lower increase levels were increased in both of expression levels in liver of wild-type and mice by expression in a Liver following of in the to a that is by The of are by and and levels and by which of the a in gene expression in the Txnip-null However, no significant differences were in the metabolic and ketone and and or the element-binding protein decreased levels of the hepatic glucose in Txnip-null and a increased levels of hepatic were the differences were not The of significant differences in the transcriptional for or that the primary metabolic defect in Txnip-null hepatocytes in regulation of the of or in substrate availability from metabolic such as mitochondrial We activity for and following a We a increase in activity from Txnip liver to wild-type that activity is not in Txnip-deficient activity was from both and mitochondrial no in the of or the mitochondrial from wild-type and Txnip-null data that Txnip does not gluconeogenesis by changes or of a defect in gluconeogenesis to the hepatic glucose production in primary hepatocyte from wild-type and Txnip-deficient mice and that through the compared with which does not through the and the the R.A. D. S. A. D. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Txnip-null hepatocytes had glucose production from a and to no significant was was used as a to reciprocal was the and overexpression of a Txnip transgene by overexpressing Txnip glucose to from and did not glucose with to with the that Txnip-null hepatocytes the gluconeogenesis with not Txnip deletion mitochondrial with of than with of Txnip and a to isolated Txnip-null hepatocytes had in glucose production, the in in glucose homeostasis resulted from a liver defect in gluconeogenesis in mice a hepatocyte-specific deletion of mice were with mice a Cre recombinase transgene the control of the albumin C. M. Chen J. M.A. J. Full Text Full Text PDF PubMed Scopus Google to mice with hepatocyte-specific gene deletion of Txnip mice had hepatic Txnip expression levels by and as well as normal and glucose compared with wild-type and were used as littermate not that Txnip gene was to the liver in liver mice with Txnip-null mice, liver mice lower blood glucose in the fasting state the of was not as as for Txnip-null mice the liver mice had elevated fasting ketone levels to not as as for the In an glucose the in blood glucose was not between liver and littermate and fasting and glucagon levels for liver Txnip mice were from wild-type These data that Txnip expression in the liver is required for regulation of the fasting glucose whereas Txnip in glucose glucose production in liver mice was by glucagon in mice for with control liver mice a blunted increase in glucose levels in to to the blunted of the Txnip-null mice We primary hepatocytes isolated from Txnip-null mice the intrinsic defect in glucose production in the Txnip-null from the of and hepatocytes from the liver mice as glucose as hepatocytes isolated from wild-type to a in glucose with that in of Txnip Glucose and the role of Txnip in liver glucose homeostasis in by overexpressing a Txnip transgene in the liver of wild-type mice were in with Txnip or an both with of and by in to liver and the in of overexpression to the liver J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. Newgard C.B. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1511) Google Scholar, M. H. B. Wu L. Chen Med. 2005; PubMed Scopus Google Scholar, D. R. W. S. W. C.B. 6: Full Text Full Text PDF PubMed Scopus Google Scholar). of or an of of of the hepatocytes were as by of the of was to the liver as by from from the mice the transgene in the liver had a increase in fasting blood glucose levels compared with mice the In addition, fasting serum ketone levels were by and by Txnip isolated a defect in liver glucose metabolism in the Txnip-null mice, defect to an increase in amount of available thioredoxin in the of The the and overexpression of Txnip in the amount of available thioredoxin as by the E. S.H. E.W. D.K. Rhee J. PubMed Scopus Google Scholar, A. M. S. H. H. H. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Full Text Full Text PDF PubMed Scopus Google Scholar). S. C. J.S. P. J. 2005; Full Text Full Text PDF PubMed Scopus Google no differences in amount of thioredoxin in liver homogenates from the Txnip-deficient the of and A. M. PubMed Scopus Google Scholar). We the to increase its to of thioredoxin to P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), and available thioredoxin was increased in liver from the Txnip-null We no in available thioredoxin between of Txnip-null and wild-type control mice an no differences were in of glutathione to glutathione between the of mice These that the changes in metabolism in the Txnip-null mice are not to changes in cellular redox state or in levels of available thioredoxin. of Txnip Txnip C247S Glucose that a single mutation in Txnip inhibits the of Txnip to bind to thioredoxin P. J. J. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). We Txnip C247S gene the Txnip-null in glucose metabolism. primary hepatocytes from Txnip-null mice were with an wild-type Txnip, or the Txnip was by expression levels of the while thioredoxin expression levels were not Glucose production from Txnip-null hepatocytes was increased by expression of Txnip compared with hepatocytes In expression of Txnip C247S to hepatocyte glucose production. the role of Txnip cysteine on glucose metabolism in the Txnip in the liver of wild-type mice by the transgene increased fasting blood glucose levels the C247S mutant had no on fasting blood glucose levels compared with the mice with the control These data demonstrate the role of Txnip in hepatocyte glucose data that the between Txnip and thioredoxin is in the of Txnip on hepatocyte demonstrate that Txnip is a of glucose and that hepatic gluconeogenesis is on Txnip and Txnip deletion in mice fasting and blunted glucose production, and isolated Txnip-null hepatocytes had glucose an intrinsic hepatocyte the of mitochondrial than to hormonal or of Txnip Txnip-null hepatocytes rescued glucose production, its of Txnip did not thioredoxin activity or the glutathione oxidation the of Txnip on glucose metabolism was on the of the Txnip which is required for binding of Txnip to thioredoxin. The of Txnip on liver glucose regulation to of the of is to the of on hepatic glucose production S. E. R.A. J. Clin. Investig. PubMed Scopus Google Scholar, A. N. F. J. PubMed Google Scholar). Txnip is of the in to glucose and its expression is regulated by and such as A.H. C. A. 2005; PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar, J. Z. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. F. 2006; PubMed Scopus Google Scholar), which are with and Clin. PubMed Scopus Google Scholar, B.M. Full Text PDF PubMed Scopus Google Scholar). Txnip increase glucose its expression is increased a that increase Txnip expression hepatic glucose production, to and in Txnip hepatic glucose production. the of and in Txnip-null is from both the mutant and the Txnip deletion described by S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google Scholar). for the of in in through of a transcriptional PubMed Scopus Google Scholar). to ketone by the liver with R.A. J. 2004; Full Text Full Text PDF PubMed Scopus Google as of the The for the in between the is of Txnip, in The deletion of Txnip by S. W. H. H. S. H. J. J. 2006; PubMed Scopus Google the the gene fasting We gene effects from strain differences between or to the Txnip a role in the in from the hormonal fasting and ketosis are consistent all and a primary defect in the of for hepatocyte metabolism for a of the in of Txnip on glucose homeostasis. The glucose clearance of the Txnip-null mice, not for the liver mice, glucose clearance by is in the of is by glucose a for Txnip-null mice are consistent with a primary defect in both and glucose In with a significant increase in both and and glucose uptake in following Txnip gene H. E. H. P. R. C. C.B. A. M. H. M. D. A. Med. 2007; PubMed Scopus Google Scholar), blunted and glucose uptake with overexpression of Txnip H. E. H. P. R. C. C.B. A. M. H. M. D. A. Med. 2007; PubMed Scopus Google Scholar), and glucose uptake in Txnip-null mice J. J. C. E. 2007; PubMed Scopus Google Scholar). of the of the for the of Txnip from in overexpression had that Txnip to thioredoxin and increase cellular redox However, did not in the glutathione redox in of Txnip-null In addition, S. C. J.S. P. J. 2005; Full Text Full Text PDF PubMed Scopus Google significant changes in the amount of available thioredoxin. data that Txnip does not in to the redox state of the levels of Txnip are not to bind thioredoxin to thioredoxin is possible that Txnip thioredoxin activity in the to such as the or Clin. PubMed Scopus Google thioredoxin binding to thioredoxin in the of Txnip, maintaining the levels of available thioredoxin that Txnip the thioredoxin redox the activity is not by thioredoxin redox However, the that the effects of Txnip not changes in the amount of available thioredoxin, that the for the of Txnip with thioredoxin for the of thioredoxin with its binding such as J.S. A. J. J. Wu C. K.M. J. M. P. P. PubMed Scopus Google Scholar). Txnip binding that for such as is possible than Txnip thioredoxin, thioredoxin is for an through the role of the overexpression of Txnip to an in of glucose production, A. P. J. and R. consistent with its not abolished to bind thioredoxin. However, the Txnip the of the and binding In that Txnip is a significant of glucose homeostasis and demonstrate its central role in hepatic glucose metabolism. In addition, data the that Txnip through its with thioredoxin, not by thioredoxin. of mice the Txnip deletion in that such as and the the of Txnip to in glucose metabolism. We for and for with with