系統
系統:  GK (Goto-Kakizaki rat) 
キーワード:  2 型糖尿病、非肥満、インスリン分泌不全、インスリン抵抗性、糖尿病 
由来:  Goto と Kakizaki によって、日本クレア社のWistarラットを起源として、経口ブドウ糖負荷試験 (OGTT) で耐糖能の低下している個体を選抜し交配するという操作を第8代まで繰り返し行い、第9代からは兄妹交配を行うことで確立された。第15代から安定して糖尿病を発症するようになった。 
表現型・病態:  糖尿病の発症率は性差なくほぼ100%であり、雄は雌より若干血糖が高い。GTT におけるインスリン分泌が悪く、特に初期分泌が障害されている。膵島は変形し、線維性間質が膵島内に出現するなど膵島が線維化した組織像がみられるが、膵島にアミロイド沈着は認められない。  合併症として、網膜症、腎症および末梢神経障害が認められる。腎症は、腎糸球体基底膜肥厚、尿中微量アルブミンをみる糖尿病性初期腎症の特徴を持つ。神経障害は、有髄神経面積低下、軸索面積低下、神経伝導速度の遅延および神経内ポリオール沈着亢進などを認め、糖尿病性末梢神経障害の特徴を有する。 
病因(原因遺伝子):  QTL 解析により、様々の表現型に対する複数の遺伝子座が報告されている。その他、ADP-ribosyl cyclase活性をもつII型膜タンパクであるCD38遺伝子の発現が膵島で障害されていること、adenylyl cyclase (AC)-III遺伝子プロモーターの2カ所の点突然変異に伴い、AC-III mRNAの過剰発現、それによるcAMP過剰産生が膵島に認められることも報告されている。 
臨床への応用、有用性:  GKラットは日本人の2型糖尿病に多い非肥満、インスリン分泌低下型のよいモデルであり、成因の解明および治療法の開発において極めて有用である。 
維持機関:  富山医科薬科大学 東北厚生年金病院 (2001年5月24日現在) 
文献:  Yagihashi, S., Goto, Y., Kakizaki, M., et al Thickening of glomerular basement membrane in spontaneously diabetic rats. Diabetologia 15:309-312,1978. Yagihashi, S., Tonosaki, A., Yamada, K., et al Peripheral neuropathy in selectively-inbred spontaneously diabetic rats: Electrophysiological , morphometrical and freeze-replica studies. Tohoku J. exp. Med. 138:39-48, 1982. Suzuki, K., Yen-Chung, H., Toyota, T., et al The significance of nerve sugar levels for the peripheral nerve impairment of spontaneously diabetic GK(Goto-Kakizaki) rats. Diabetes Res. 14:21-25, 1990. Portha, B., Serradas, P., Bailbe, D., et al β-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for typeⅡdiabetes. Diabetes 40:486-491, 1991. Ostenson, C.G., Khan, A., Abdel-Halim, S.M., et al Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK-rat. Diabetologia 36:3-8, 1993. Suzuki, K., Goto, Y., Toyota, T. Spontaneously diabetic GK(Goto-Kakizaki) rats. In Lessons from animal diabetesⅣ, ed by E Shafrir Smith-Gordon, Great Britain, 107-111, 1993. Ohneda, M., Johnson, J.H., Inman, L.R., et al GLUT2 expression and function inβ-cells of GK rats with NIDDM: dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. Diabetes 42:1065-1072, 1993. Matsuoka, T., Kajimoto, Y., Watada, H., et al Expression of CD38 gene but not of mitochondrial glycerol-3-phosphate dehydrogenase gene is impaired in pancreatic islets of GK rats. Biochem. Biophys. Res. Commun. 214:239-246, 1995. Kato, S., Ishida, H., Tsuura, Y., et al Altered functions of ion channels in diabetic beta cells. Obes. Res. 3:(Suppl 5) 637S-638S, 1995. Zhou, Y.P., Ostenson, C.G., Ling, Z.C., et al Deficiency of pyruvate dehydrogenase activity in pancreatic islets of diabetic GK rats. Endocrinol .136:3546-3551, 1995. Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau MT, Portha B, James MR, Penicaud L, Lathrop M, Ktorza A. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet. 1996 Jan;12(1):38-43. Galli J, Li LS, Glaser A, Ostenson CG, Jiao H, Fakhrai-Rad H, Jacob HJ, Lander ES, Luthman H. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet. 1996 Jan;12(1):31-7. Abdel-Halim, S.M., Guenifi, A., Khan, A. Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. Diabetes 45:934-940, 1996. Kato, S., Ishida, H., Tsuura, Y., et al Alterations in basal and glucose-stimulated voltage-dependent Ca2 +channel activities in pancreatic beta cells of non-insulin-dependent diabetes mellitus GK rats. J. Clin. Invest. 97:2417-2425, 1996. Miyamoto, K., Ogura, Y., Nishiwaki, H., et al Evaluation of retinal microcirculatory alterations in the Goto-Kakizaki rat. A spontaneous model of non-insulin-dependent diabetes. Invest. Ophthalmol. Vis. Sci. 37:898-905, 1996. Avignon, A., Yamada, K., Zhou, X., et al Chronic activation of protein kinase C in soleus muscles and other tissues of insulin-reeistant typeⅡdiabetic Goto-Kakizaki(GK), obese/aged, and obese/zucker rats. A mechanism for inhibiting glyeogen synthesis. Diabetes 45:1396-1404, 1996. Picarel-Blanchot, F., Berthelier, C., Bailbe, D., et al Impaired insulin secretion and excessive hepatic glucose production are both early events in the diabetic GK rat. Am. J. Physiol. 271:E755-762, 1996. Koike G, Van Vooren P, Shiozawa M, Galli J, Li LS, Glaser A, Balasubramanyam A, Brown LJ, Luthman H, Szpirer C, MacDonald MJ, Jacob HJ. Genetic mapping and chromosome localization of the rat mitochondrial glycerol-3-phosphate dehydrogenase gene, a candidate for non-insulin-dependent diabetes mellitus. Genomics. 1996 Nov 15;38(1):96-9. Hoog, A., Hu, W., Abdel-Halim, S.M., et al Ultrastructural localization of insulin-like growth factor-2(IGF-2) to the secretory granules of insulin cells: a study in normal and diabetic(GK) rats. Ultrastruct. Pathol. 21:457-466, 1997. Carlsson, P.O., Jansson, L., Ostenson, C.G., et al Islet capillary blood pressure increase mediated by hyperglycemia in NIDDM GK rats. Diabetes 46:947-952,1997. Sone, H., Kawakami, Y., Okuda, Y., et al Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes. Diabetologia 40:726-730,1997. Berthelier, C., Kergoat, M., Portha, B. Lack of deterioration of insulin action with aging in the GK rats contrasted adaptation as compared with nondiabetic rats. Metabolism 46:890-896, 1997. Krook, A., Kawano, Y., Song, X.M., et al Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats. Diabetes 46:2110-2114, 1997. Begum N, Ragolia L. Altered regulation of insulin signaling components in adipocytes of insulin-resistant type II diabetic Goto-Kakizaki rats. Metabolism. 1998 Jan;47(1):54-62. Abdel-Halim, S.M., Guenifi, A., He, B. Mutations in the promoter of adenylyl cyclase (AC)-Ⅲ gene, overexpression of AC-Ⅲ mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of typeⅡdiabetes. Diabetes 47:498-504, 1998. Galli J, Fakhrai-Rad H, Kamel A, Marcus C, Norgren S, Luthman H. Pathophysiological and genetic characterization of the major diabetes locus in GK rats. Diabetes. 1999 Dec;48(12):2463-70. Fakhrai-Rad H, Nikoshkov A, Kamel A, Fernstrom M, Zierath JR, Norgren S, Luthman H, Galli J. Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. Hum Mol Genet. 2000 Sep 1;9(14):2149-58. Lin JM, Ortsater H, Fakhrai-Rad H, Galli J, Luthman H, Bergsten P. Phenotyping of individual pancreatic islets locates genetic defects in stimulus secretion coupling to Niddm1i within the major diabetes locus in GK rats. Diabetes. 2001 Dec;50(12):2737-43. 
執筆者記録:  横井伯英(千葉大学)2001年5月24日, TS:4/22/03 
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