title: Role of insulin resistance in the pathogenesis and development of type 2 diabetes in WBN/Kob-Lepr(fa) rats.
abstract: WBN/Kob-Lepr(fa) (fa/fa) rats have been identified as a new animal model of type 2 diabetes (T2DM), as they are characterized by impaired pancreatic insulin secretion and severe insulin resistance. Our previous study demonstrated impaired insulin secretion and its involvement in hyperglycemia in fa/fa rats. The present study was aimed at elucidating the role of insulin resistance in the development and progression of diabetes in these animals. Troglitazone (TGZ) was used as an insulin sensitizer. Insulin resistance and insulin secretory capacity were measured by a homeostasis model assessment of insulin resistance and the area under the blood concentration-time curve for plasma insulin levels after intravenous glucose tolerance testing, respectively. The fa/fa rats exhibited marked insulin resistance between 5 and 11 weeks of age, compared with age-matched Wistar rats. The insulin secretory capacity of fa/fa rats was higher than that of Wistar rats at 5 weeks of age, but decreased by 50% between 9 and 11 weeks of age. The fa/fa rats were fed a standard diet, with or without 0.2% w/w TGZ, for 4 weeks. Treatment with TGZ significantly improved insulin resistance, hyperglycemia and hypertriglyceridemia in both prophylactic and therapeutic study groups. These results suggest that insulin resistance is markedly involved in the development and progression of T2DM in fa/fa rats.
authors.affiliation: Shinagawa R&D Center, Daiichi-Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Okuno
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kaji
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Dai
authors.initials: D
authors.lastname: Nagakubo
authors.forename: Kanako
authors.initials: K
authors.lastname: Ohno-Ichiki
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Shirai
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Asai
mesh_terms: D000367:Age Factors; D000818:Animals; D019540:Area Under Curve; D002839:Chromans / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007328:Insulin; D045162:Thiazolidinediones; D000077288:Troglitazone
references.citation: J Vet Med Sci. 2012 Sep;74(9):1185-9
references.pmid: 22571894
references.citation: Metabolism. 2002 Aug;51(8):998-1002
references.pmid: 12145772
references.citation: Curr Diabetes Rev. 2012 Mar;8(2):76-83
references.pmid: 22229253
references.citation: J Vet Med Sci. 2012 Jan;74(1):65-70
references.pmid: 21836382
references.citation: Acta Diabetol. 2005 Dec;42(4):162-70
references.pmid: 16382303
references.citation: Diabetes. 1996 Aug;45(8):1141-3
references.pmid: 8690163
references.citation: J Biol Chem. 2001 Nov 2;276(44):41245-54
references.pmid: 11533050
references.citation: Diabetes Care. 2004 May;27(5):1047-53
references.pmid: 15111519
references.citation: Int J Pancreatol. 1990 Jun;6(4):231-47
references.pmid: 1698893
references.citation: Curr Med Res Opin. 2011 Jul;27(7):1431-8
references.pmid: 21599553
references.citation: Lab Anim. 1985 Jul;19(3):200-7
references.pmid: 4033061
references.citation: J Clin Invest. 1998 Mar 15;101(6):1354-61
references.pmid: 9502777
references.citation: Expert Opin Drug Saf. 2013 Mar;12(2):153-75
references.pmid: 23241069
references.citation: Diabetes. 2002 Oct;51(10):2895-902
references.pmid: 12351424
references.citation: J Clin Invest. 2000 Aug;106(4):459-65
references.pmid: 10953020
references.citation: Diabetes. 1988 Nov;37(11):1549-58
references.pmid: 3053303
references.citation: Ann N Y Acad Sci. 1965 Oct 8;131(1):447-58
references.pmid: 5216982
references.citation: World J Gastroenterol. 2005 Aug 28;11(32):4931-8
references.pmid: 16124041
references.citation: Lipids. 2006 Mar;41(3):241-7
references.pmid: 16711598
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Biochem Biophys Res Commun. 2008 Feb 8;366(2):556-62
references.pmid: 18068663