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Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes. Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes. Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease (1Saltiel A.R. Kahn C.R. Nature. 2001; 414: 799-806Crossref PubMed Scopus (3849) Google Scholar, 2Shulman G.I. J. Clin. Investig. 2000; 106: 171-176Crossref PubMed Scopus (2166) Google Scholar). Normal β-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, insulin resistance is further increased and β-cell function progressively deteriorates. The significance of hyperglycemia as a direct cause of these phenomena has been called “glucose toxicity” (3Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50: 154-159Crossref PubMed Google Scholar, 4Robertson R.P. Harmon J. Tran P.O. Poitout V. Diabetes. 2004; 53: 119-124Crossref PubMed Google Scholar).The endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; ORP150, oxygen-regulated protein 150; Ad-S-ORP, adenovirus expressing sense ORP; Ad-AS-ORP, adenovirus expressing antisense ORP; pfu, plaque-forming unit; GFP, green fluorescent protein; HGP, hepatic glucose production; MOPS, 4-morpholinepropanesulfonic acid. 1The abbreviations used are: ER, endoplasmic reticulum; ORP150, oxygen-regulated protein 150; Ad-S-ORP, adenovirus expressing sense ORP; Ad-AS-ORP, adenovirus expressing antisense ORP; pfu, plaque-forming unit; GFP, green fluorescent protein; HGP, hepatic glucose production; MOPS, 4-morpholinepropanesulfonic acid. is an organelle that synthesizes various secretory and membrane proteins. These proteins are correctly folded and assembled by chaperones in the ER. During stressful conditions, such as an increase in the misfolded protein level, the chaperons become overloaded and the ER fails to fold and export newly synthesized proteins, leading to ER stress (5Wang X-Z. Harding H.P. Zhang Y. Jolicoeur E.M. Kuroda M. Ron D EMBO J. 1998; 17: 5708-5717Crossref PubMed Scopus (650) Google Scholar, 6Tirasophon W. Welihinda A.A. Kaufman R.J. Genes Dev. 1998; 12: 1812-1824Crossref PubMed Scopus (729) Google Scholar, 7Harding H.P. Zhang Y. Ron D. Nature. 1999; 397: 271-274Crossref PubMed Scopus (2482) Google Scholar, 8Aridor M. Balch W.E. Nat. Med. 1999; 5: 745-751Crossref PubMed Scopus (255) Google Scholar, 9Don D. J. Clin. Investig. 2002; 110: 1383-1388Crossref PubMed Scopus (727) Google Scholar). We hypothesized that the ER stress provoked in diabetes is involved in various phenomena found in the disease. It has indeed previously been shown that ER stress is involved in pancreatic β-cell dysfunction (10Inoue H. Tanizawa Y. Wasson J. Behn P. Kalidas K. Bernal-Mizrachi E. Mueckler M. Marshall H. Donis-Keller H. Crock P. Rogers D. Mikuni M. Kumashiro H. Higashi K. Sobue G. Oka Y. Permutt M.A. Nat. Genet. 1998; 20: 143-148Crossref PubMed Scopus (580) Google Scholar, 11Harding H.P. Zeng H. Zhang Y. Jungries R. Chung P. Plesken H. Sabatini D.D. Ron D. Mol. Cell. 2001; 7: 1153-1163Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, 12Harding H.P. Ron D. Diabetes. 2002; 51: 455-461Crossref PubMed Google Scholar, 13Oyadomari S. Takeda K. Takiguchi M. Gotoh T. Matsumoto M. Wada I. Akira S. Araki E. Mori M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10845-10850Crossref PubMed Scopus (511) Google Scholar, 14Oyadomari S. Koizumi A. Takeda K. Gotoh T. Akira S. Araki E. Mori M. J. Clin. Investig. 2002; 109: 525-532Crossref PubMed Scopus (778) Google Scholar). Oxygen-regulated protein 150 (ORP150), a molecular chaperone found in the ER, has been shown to protect cells from ER stress (15Kuwabara K. Matsumoto M. Ikeda J. Hori O. Ogawa S. Maeda Y. Kitagawa K. Imuta N. Kinoshita T. Stern D.M. Yanagi H. Kamada T. J. Biol. Chem. 1996; 271: 5025-5032Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 16Tamatani M. Matsuyama T. Yamaguchi A. Mitsuda N. Tsukamoto Y. Taniguchi M. Che Y.H. Ozawa K. Hori O. Nishimura H. Yamashita A. Okabe M. Yanagi H. Stern D.M. Ogawa S. Tohyama M. Nat. Med. 2001; 7: 317-323Crossref PubMed Scopus (171) Google Scholar). Here we report that ORP150 overexpression markedly improves insulin resistance and ameliorates glucose tolerance in diabetic animals, indicating that ER stress plays a crucial role in insulin resistance and could be a potential therapeutic target for diabetes.MATERIALS AND METHODSPreparation of Recombinant Adenoviruses—Recombinant adenoviruses expressing sense ORP (Ad-S-ORP) and antisense ORP (Ad-AS-ORP) were prepared, and the adenovirus titers were increased up to 1 × 108 pfu/ml in the 293 cells. Adenovirus titers were further increased up to 1 × 1010 pfu/ml using Adeno-X™ virus purification kit (Clontech). Control adenovirus expressing green fluorescent protein (Ad-GFP) was also prepared in the same manner. Virus titers were estimated using an Adeno-X™ titer kit (Clontech).Animals and Administration of Recombinant Adenoviruses—Male C57BL6 and C57BL/KsJ-db/db mice were purchased from Japan SLC. Mice (8 weeks old) were injected Ad-S-ORP, Ad-AS-ORP, × 1010 pfu/ml for and 2 × pfu/ml for from the adenovirus glucose levels were a glucose of insulin of mice a were and insulin levels were an kit a mice were injected glucose were various and glucose levels and insulin levels were as a mice were injected insulin for were various and glucose levels were as the study, × 1010 × was injected from the the study, a was the under The which is for in the study, was the of the a and were mice under and a a was to glucose and glucose of a of insulin for C57BL6 for C57BL/KsJ-db/db mice the During this glucose levels were and the of glucose the was to glucose of by HGP, glucose was were and and of were of The was and the was by the of and of were to the and the was for 1 The glucose was by and a × The of glucose was from the by and was by The of and were a of and and from liver were by and to membrane the were in 150 a of and and for 1 in a of to In expression of the of IRS-1 was by using and were by and to of from liver were in 1 × and to a membrane The phosphoenolpyruvate carboxykinase and were using a kit a the were in 2 × The were to an and the was using a are as were for significance using the of the AND in the and in C57BL/KsJ-db/db to ER stress is increased in the liver under diabetic conditions, we ER stress levels in the of obese diabetic C57BL/KsJ-db/db levels of and of which are ER stress were in the obese diabetic mice C57BL6 mice indicating that ER stress is increased under diabetic the of sense ORP150 overexpression insulin resistance and we prepared sense ORP150 expressing × 1010 and a adenovirus (Ad-GFP) and adenovirus to C57BL/KsJ-db/db obese diabetic mice from the we an increase in ORP150 expression in the liver adenovirus but in such as and In expression levels of and in mice were in indicating that ORP150 is to ER stress in the liver was in and and mice C57BL/KsJ-db/db mice were Ad-S-ORP, glucose levels were markedly such were in mice in C57BL6 mice glucose a were also significantly in mice was in insulin the the of ORP150 overexpression in the liver insulin we the insulin tolerance The to insulin was in C57BL/KsJ-db/db mice in mice this we the were mice under and a of a of insulin for C57BL6 for C57BL/KsJ-db/db glucose levels were and the of of a glucose the was to glucose The glucose of mice were significantly mice indicating that ORP150 overexpression in the liver insulin resistance and thus ameliorates glucose tolerance in C57BL/KsJ-db/db We also hepatic glucose in mice using was significantly in mice mice These that the of insulin resistance and of glucose tolerance by overexpression are of the of of sense ORP overexpression in the liver insulin resistance and glucose tolerance in C57BL/KsJ-db/db glucose levels in C57BL/KsJ-db/db mice glucose and insulin levels in C57BL/KsJ-db/db mice 2 weeks insulin resistance in C57BL/KsJ-db/db mice weeks the adenovirus insulin tolerance were a insulin was injected a of and glucose levels were glucose and hepatic glucose in C57BL/KsJ-db/db mice weeks the adenovirus glucose and hepatic glucose were estimated by a ORP150 in the in C57BL6 to the of antisense ORP150 expression in the liver insulin and glucose tolerance in animals, we prepared an antisense adenovirus × and a adenovirus (Ad-GFP) and adenovirus to C57BL6 mice from the we a in ORP150 expression in the liver adenovirus In expression levels of in mice were in C57BL6 was in expression levels was in and the In was in glucose levels and in glucose and insulin levels and mice the glucose tolerance that glucose tolerance is markedly antisense ORP150 expression in the study, the of C57BL6 mice were significantly mice indicating that ER stress in the liver insulin in C57BL6 we in mice using in mice was significantly in mice These that antisense ORP150 expression insulin in by increasing in of antisense ORP overexpression in the liver insulin resistance and glucose tolerance in C57BL6 glucose levels in C57BL6 mice glucose and insulin levels in C57BL6 mice 2 weeks glucose tolerance in C57BL6 mice weeks the adenovirus glucose tolerance were a glucose was injected a of and glucose levels were glucose and hepatic glucose in C57BL6 mice weeks the adenovirus glucose and hepatic glucose were estimated by a in the the of the molecular involved in the of insulin by ER stress in we the phosphorylation state of IRS-1 and in the which are key molecules for insulin IRS-1 phosphorylation was markedly increased in C57BL/KsJ-db/db mice mice an increase in phosphorylation was in C57BL/KsJ-db/db mice mice In IRS-1 phosphorylation was decreased in mice mice in phosphorylation was in C57BL6 mice mice We the expression levels of the key enzymes phosphoenolpyruvate carboxykinase and of which are to be by insulin The expression of and was markedly decreased by in C57BL/KsJ-db/db mice In expression of enzymes was increased in C57BL6 mice These that of ER stress insulin signaling, which leads to a in and of glucose of sense and antisense ORP overexpression insulin and in the of ER stress insulin C57BL/KsJ-db/db mice were and C57BL6 mice were weeks the adenovirus the expression of and of IRS-1 and and of were by were in of ER stress C57BL/KsJ-db/db mice were and C57BL6 mice were weeks the adenovirus levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were by were in sense ORP150 overexpression decreased insulin resistance and markedly improved in diabetic in antisense ORP150 expression insulin resistance in indicating that ER stress plays a crucial role in the insulin resistance found in diabetes. ER stress could thus be a potential therapeutic target for diabetes. Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease (1Saltiel A.R. Kahn C.R. Nature. 2001; 414: 799-806Crossref PubMed Scopus (3849) Google Scholar, 2Shulman G.I. J. Clin. Investig. 2000; 106: 171-176Crossref PubMed Scopus (2166) Google Scholar). Normal β-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, insulin resistance is further increased and β-cell function progressively deteriorates. The significance of hyperglycemia as a direct cause of these phenomena has been called “glucose toxicity” (3Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50: 154-159Crossref PubMed Google Scholar, 4Robertson R.P. Harmon J. Tran P.O. Poitout V. Diabetes. 2004; 53: 119-124Crossref PubMed Google Scholar). The endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; ORP150, oxygen-regulated protein 150; Ad-S-ORP, adenovirus expressing sense ORP; Ad-AS-ORP, adenovirus expressing antisense ORP; pfu, plaque-forming unit; GFP, green fluorescent protein; HGP, hepatic glucose production; MOPS, 4-morpholinepropanesulfonic acid. 1The abbreviations used are: ER, endoplasmic reticulum; ORP150, oxygen-regulated protein 150; Ad-S-ORP, adenovirus expressing sense ORP; Ad-AS-ORP, adenovirus expressing antisense ORP; pfu, plaque-forming unit; GFP, green fluorescent protein; HGP, hepatic glucose production; MOPS, 4-morpholinepropanesulfonic acid. is an organelle that synthesizes various secretory and membrane proteins. These proteins are correctly folded and assembled by chaperones in the ER. During stressful conditions, such as an increase in the misfolded protein level, the chaperons become overloaded and the ER fails to fold and export newly synthesized proteins, leading to ER stress (5Wang X-Z. Harding H.P. Zhang Y. Jolicoeur E.M. Kuroda M. Ron D EMBO J. 1998; 17: 5708-5717Crossref PubMed Scopus (650) Google Scholar, 6Tirasophon W. Welihinda A.A. Kaufman R.J. Genes Dev. 1998; 12: 1812-1824Crossref PubMed Scopus (729) Google Scholar, 7Harding H.P. Zhang Y. Ron D. Nature. 1999; 397: 271-274Crossref PubMed Scopus (2482) Google Scholar, 8Aridor M. Balch W.E. Nat. Med. 1999; 5: 745-751Crossref PubMed Scopus (255) Google Scholar, 9Don D. J. Clin. Investig. 2002; 110: 1383-1388Crossref PubMed Scopus (727) Google Scholar). We hypothesized that the ER stress provoked in diabetes is involved in various phenomena found in the disease. It has indeed previously been shown that ER stress is involved in pancreatic β-cell dysfunction (10Inoue H. Tanizawa Y. Wasson J. Behn P. Kalidas K. Bernal-Mizrachi E. Mueckler M. Marshall H. Donis-Keller H. Crock P. Rogers D. Mikuni M. Kumashiro H. Higashi K. Sobue G. Oka Y. Permutt M.A. Nat. Genet. 1998; 20: 143-148Crossref PubMed Scopus (580) Google Scholar, 11Harding H.P. Zeng H. Zhang Y. Jungries R. Chung P. Plesken H. Sabatini D.D. Ron D. Mol. Cell. 2001; 7: 1153-1163Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, 12Harding H.P. Ron D. Diabetes. 2002; 51: 455-461Crossref PubMed Google Scholar, 13Oyadomari S. Takeda K. Takiguchi M. Gotoh T. Matsumoto M. Wada I. Akira S. Araki E. Mori M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 10845-10850Crossref PubMed Scopus (511) Google Scholar, 14Oyadomari S. Koizumi A. Takeda K. Gotoh T. Akira S. Araki E. Mori M. J. Clin. Investig. 2002; 109: 525-532Crossref PubMed Scopus (778) Google Scholar). Oxygen-regulated protein 150 (ORP150), a molecular chaperone found in the ER, has been shown to protect cells from ER stress (15Kuwabara K. Matsumoto M. Ikeda J. Hori O. Ogawa S. Maeda Y. Kitagawa K. Imuta N. Kinoshita T. Stern D.M. Yanagi H. Kamada T. J. Biol. Chem. 1996; 271: 5025-5032Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 16Tamatani M. Matsuyama T. Yamaguchi A. Mitsuda N. Tsukamoto Y. Taniguchi M. Che Y.H. Ozawa K. Hori O. Nishimura H. Yamashita A. Okabe M. Yanagi H. Stern D.M. Ogawa S. Tohyama M. Nat. Med. 2001; 7: 317-323Crossref PubMed Scopus (171) Google Scholar). Here we report that ORP150 overexpression markedly improves insulin resistance and ameliorates glucose tolerance in diabetic animals, indicating that ER stress plays a crucial role in insulin resistance and could be a potential therapeutic target for diabetes. AND METHODSPreparation of Recombinant Adenoviruses—Recombinant adenoviruses expressing sense ORP (Ad-S-ORP) and antisense ORP (Ad-AS-ORP) were prepared, and the adenovirus titers were increased up to 1 × 108 pfu/ml in the 293 cells. Adenovirus titers were further increased up to 1 × 1010 pfu/ml using Adeno-X™ virus purification kit (Clontech). Control adenovirus expressing green fluorescent protein (Ad-GFP) was also prepared in the same manner. Virus titers were estimated using an Adeno-X™ titer kit (Clontech).Animals and Administration of Recombinant Adenoviruses—Male C57BL6 and C57BL/KsJ-db/db mice were purchased from Japan SLC. Mice (8 weeks old) were injected Ad-S-ORP, Ad-AS-ORP, × 1010 pfu/ml for and 2 × pfu/ml for from the adenovirus glucose levels were a glucose of insulin of mice a were and insulin levels were an kit a mice were injected glucose were various and glucose levels and insulin levels were as a mice were injected insulin for were various and glucose levels were as the study, × 1010 × was injected from the the study, a was the under The which is for in the study, was the of the a and were mice under and a a was to glucose and glucose of a of insulin for C57BL6 for C57BL/KsJ-db/db mice the During this glucose levels were and the of glucose the was to glucose of by HGP, glucose was were and and of were of The was and the was by the of and of were to the and the was for 1 The glucose was by and a × The of glucose was from the by and was by The of and were a of and and from liver were by and to membrane the were in 150 a of and and for 1 in a of to In expression of the of IRS-1 was by using and were by and to of from liver were in 1 × and to a membrane The phosphoenolpyruvate carboxykinase and were using a kit a the were in 2 × The were to an and the was using a are as were for significance using the of the of Recombinant Adenoviruses—Recombinant adenoviruses expressing sense ORP (Ad-S-ORP) and antisense ORP (Ad-AS-ORP) were prepared, and the adenovirus titers were increased up to 1 × 108 pfu/ml in the 293 cells. Adenovirus titers were further increased up to 1 × 1010 pfu/ml using Adeno-X™ virus purification kit (Clontech). Control adenovirus expressing green fluorescent protein (Ad-GFP) was also prepared in the same manner. Virus titers were estimated using an Adeno-X™ titer kit (Clontech). and Administration of Recombinant Adenoviruses—Male C57BL6 and C57BL/KsJ-db/db mice were purchased from Japan SLC. Mice (8 weeks old) were injected Ad-S-ORP, Ad-AS-ORP, × 1010 pfu/ml for and 2 × pfu/ml for from the adenovirus glucose levels were a glucose of insulin of mice a were and insulin levels were an kit a mice were injected glucose were various and glucose levels and insulin levels were as a mice were injected insulin for were various and glucose levels were as the study, × 1010 × was injected from the the study, a was the under The which is for in the study, was the of the a and were mice under and a a was to glucose and glucose of a of insulin for C57BL6 for C57BL/KsJ-db/db mice the During this glucose levels were and the of glucose the was to glucose of by HGP, glucose was were and and of were of The was and the was by the of and of were to the and the was for 1 The glucose was by and a × The of glucose was from the by and was by The of and were a of and and from liver were by and to membrane the were in 150 a of and and for 1 in a of to In expression of the of IRS-1 was by using and were by and to of from liver were in 1 × and to a membrane The phosphoenolpyruvate carboxykinase and were using a kit a the were in 2 × The were to an and the was using a are as were for significance using the of the AND in the and in C57BL/KsJ-db/db to ER stress is increased in the liver under diabetic conditions, we ER stress levels in the of obese diabetic C57BL/KsJ-db/db levels of and of which are ER stress were in the obese diabetic mice C57BL6 mice indicating that ER stress is increased under diabetic the of sense ORP150 overexpression insulin resistance and we prepared sense ORP150 expressing × 1010 and a adenovirus (Ad-GFP) and adenovirus to C57BL/KsJ-db/db obese diabetic mice from the we an increase in ORP150 expression in the liver adenovirus but in such as and In expression levels of and in mice were in indicating that ORP150 is to ER stress in the liver was in and and mice C57BL/KsJ-db/db mice were Ad-S-ORP, glucose levels were markedly such were in mice in C57BL6 mice glucose a were also significantly in mice was in insulin the the of ORP150 overexpression in the liver insulin we the insulin tolerance The to insulin was in C57BL/KsJ-db/db mice in mice this we the were mice under and a of a of insulin for C57BL6 for C57BL/KsJ-db/db glucose levels were and the of of a glucose the was to glucose The glucose of mice were significantly mice indicating that ORP150 overexpression in the liver insulin resistance and thus ameliorates glucose tolerance in C57BL/KsJ-db/db We also hepatic glucose in mice using was significantly in mice mice These that the of insulin resistance and of glucose tolerance by overexpression are of the of ORP150 in the in C57BL6 to the of antisense ORP150 expression in the liver insulin and glucose tolerance in animals, we prepared an antisense adenovirus × and a adenovirus (Ad-GFP) and adenovirus to C57BL6 mice from the we a in ORP150 expression in the liver adenovirus In expression levels of in mice were in C57BL6 was in expression levels was in and the In was in glucose levels and in glucose and insulin levels and mice the glucose tolerance that glucose tolerance is markedly antisense ORP150 expression in the study, the of C57BL6 mice were significantly mice indicating that ER stress in the liver insulin in C57BL6 we in mice using in mice was significantly in mice These that antisense ORP150 expression insulin in by increasing in of antisense ORP overexpression in the liver insulin resistance and glucose tolerance in C57BL6 glucose levels in C57BL6 mice glucose and insulin levels in C57BL6 mice 2 weeks glucose tolerance in C57BL6 mice weeks the adenovirus glucose tolerance were a glucose was injected a of and glucose levels were glucose and hepatic glucose in C57BL6 mice weeks the adenovirus glucose and hepatic glucose were estimated by a in the the of the molecular involved in the of insulin by ER stress in we the phosphorylation state of IRS-1 and in the which are key molecules for insulin IRS-1 phosphorylation was markedly increased in C57BL/KsJ-db/db mice mice an increase in phosphorylation was in C57BL/KsJ-db/db mice mice In IRS-1 phosphorylation was decreased in mice mice in phosphorylation was in C57BL6 mice mice We the expression levels of the key enzymes phosphoenolpyruvate carboxykinase and of which are to be by insulin The expression of and was markedly decreased by in C57BL/KsJ-db/db mice In expression of enzymes was increased in C57BL6 mice These that of ER stress insulin signaling, which leads to a in and of glucose of sense and antisense ORP overexpression insulin and in the of ER stress insulin C57BL/KsJ-db/db mice were and C57BL6 mice were weeks the adenovirus the expression of and of IRS-1 and and of were by were in of ER stress C57BL/KsJ-db/db mice were and C57BL6 mice were weeks the adenovirus levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were by were in sense ORP150 overexpression decreased insulin resistance and markedly improved in diabetic in antisense ORP150 expression insulin resistance in indicating that ER stress plays a crucial role in the insulin resistance found in diabetes. ER stress could thus be a potential therapeutic target for diabetes. ORP150 in the and in C57BL/KsJ-db/db to ER stress is increased in the liver under diabetic conditions, we ER stress levels in the of obese diabetic C57BL/KsJ-db/db levels of and of which are ER stress were in the obese diabetic mice C57BL6 mice indicating that ER stress is increased under diabetic the of sense ORP150 overexpression insulin resistance and we prepared sense ORP150 expressing × 1010 and a adenovirus (Ad-GFP) and adenovirus to C57BL/KsJ-db/db obese diabetic mice from the we an increase in ORP150 expression in the liver adenovirus but in such as and In expression levels of and in mice were in indicating that ORP150 is to ER stress in the liver was in and and mice C57BL/KsJ-db/db mice were Ad-S-ORP, glucose levels were markedly such were in mice in C57BL6 mice glucose a were also significantly in mice was in insulin the the of ORP150 overexpression in the liver insulin we the insulin tolerance The to insulin was in C57BL/KsJ-db/db mice in mice this we the were mice under and a of a of insulin for C57BL6 for C57BL/KsJ-db/db glucose levels were and the of of a glucose the was to glucose The glucose of mice were significantly mice indicating that ORP150 overexpression in the liver insulin resistance and thus ameliorates glucose tolerance in C57BL/KsJ-db/db We also hepatic glucose in mice using was significantly in mice mice These that the of insulin resistance and of glucose tolerance by overexpression are of the of ORP150 in the in C57BL6 to the of antisense ORP150 expression in the liver insulin and glucose tolerance in animals, we prepared an antisense adenovirus × and a adenovirus (Ad-GFP) and adenovirus to C57BL6 mice from the we a in ORP150 expression in the liver adenovirus In expression levels of in mice were in C57BL6 was in expression levels was in and the In was in glucose levels and in glucose and insulin levels and mice the glucose tolerance that glucose tolerance is markedly antisense ORP150 expression in the study, the of C57BL6 mice were significantly mice indicating that ER stress in the liver insulin in C57BL6 we in mice using in mice was significantly in mice These that antisense ORP150 expression insulin in by increasing in ER in the the of the molecular involved in the of insulin by ER stress in we the phosphorylation state of IRS-1 and in the which are key molecules for insulin IRS-1 phosphorylation was markedly increased in C57BL/KsJ-db/db mice mice an increase in phosphorylation was in C57BL/KsJ-db/db mice mice In IRS-1 phosphorylation was decreased in mice mice in phosphorylation was in C57BL6 mice mice We the expression levels of the key enzymes phosphoenolpyruvate carboxykinase and of which are to be by insulin The expression of and was markedly decreased by in C57BL/KsJ-db/db mice In expression of enzymes was increased in C57BL6 mice These that of ER stress insulin signaling, which leads to a in and of glucose tolerance. In sense ORP150 overexpression decreased insulin resistance and markedly improved in diabetic in antisense ORP150 expression insulin resistance in indicating that ER stress plays a crucial role in the insulin resistance found in diabetes. ER stress could thus be a potential therapeutic target for diabetes. We for and for We also for the
Nakatani et al. (Thu,) studied this question.