1999 年度実績報告書

IDDMにおけるFas依存的膵β細胞傷害機構の解明とその制御による治療法の開発

研究課題

研究課題/領域番号	10833001
研究機関	大阪大学
研究代表者	河野典夫大阪大学, 医学部, 教授 (30093412)
研究分担者	花房俊昭大阪大学, 医学系研究科, 講師 (60164886)
キーワード	1型糖尿病 / 自己免疫 / Fas / Fas-ligand / Betacellulin
研究概要	1.ヒト1型糖尿病の発症におけるFas、Fas-ligand(Fas-L)系の関与の検討ヒト1型糖尿病の発症におけるFas、Fas-ligand系の関与を検討するために、発症早期の1型糖尿病患者より同意のもとで腹腔鏡下に膵組織を採取し免疫組織化学的に検討した。検討を行った患者13人中、6人で膵島へのリンパ球浸潤など膵島炎の所見を認めた。膵島炎の認められた標本では膵β細胞および膵島浸潤細胞にFasの発現を認めた。膵島細胞でのFasの発現はβ細胞で高頻度に認められた。一方、Fas-Lの発現は浸潤細胞でのみ認められた。また、浸潤細胞で最も頻度の高かったものはCD8陽性T細胞であった。膵島炎の認められなかった症例では、Fas、Fas-Lの発現は認められなかった。以上より、1型糖尿病の発症に対して、Fas、Fas-L系の発現が膵島炎の発症とその後のβ細胞破壊に関与している可能性が示唆された。 2.ヒト膵組織および膵島細胞腫におけるBetacellulin発現の検討ヒト膵組織および膵島細胞腫におけるBetacellulin発現を免疫組織化学的に検討した。その結果、Betacellulinは成人ではα細胞、膵管細胞とβ細胞に発現しているのに対して、胎児では未分化な膵管細胞で強い発現が見られることが明らかとなった。またインスリノーマ細胞、グルカゴノーマ細胞ともにBetacellulinの発現が認められた。これらはBetacellulinが膵島の増殖、分化に重要であることを示唆するものである。 3.1型糖尿病の新たな病型に関する検討 1型糖尿病患者について、その発症様式、検査所見、免疫学的異常などを比較検討したところ、急激な発症、血清膵酵素の上昇を認め糖尿病関連自己抗体が検出されない一群の患者の存在を認めたので、新たな病型として提案した。

研究成果
(30件)

すべてその他

すべて文献書誌 (30件)

[文献書誌] K.Yamagata et al.: "Mutation P291 fsins C in the Transcription Factor Hepatocyte Nuclear Fctor-1 α is Dominant Negative"Diabetes. 47・8. 1231-1235 (1998)
[文献書誌] H.Iwahashi et al.: "Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes: Potential targets for preventive therapy"Cytokines, Cellular & Molecular Therapy. 4. 45-51 (1998)
[文献書誌] I.Yoshiuchi et al.: "Mutation/Polymorphism Scanning of Glucose-6-Phosphatase Gene Promoter in Diabetes Mellitus Patients"J. Clin. Endocrinol and Metab. 83・3. 1016-1019 (1998)
[文献書誌] Y.Kamada et al.: "A Case with Prolactinoma Treated with Pergolide and Its Histology"Endocrine J.. 45・4. 605-606 (1998)
[文献書誌] M.Kuwajima et al.: "Characteristics of cardiac hypertrophy in the juvenile visceral steatosis mouse with systemic carnitine deficiency"J. Mol. Cell. Cardiol.. 30・4. 773-781 (1998)
[文献書誌] H.Iwahashi et al.: "Emerging therapeutic strategies in autoimmune diabetes: etiology, prediction, prevention and cure"Emerging Therapeutic Targets. 3・1(in press). (1999)
[文献書誌] J.Miyagawa et al.: "Immunohistochemical localization of Betacellulin, a new member of BGF family, in normal human pancreas and islet tumor cells"Endocrine J.. 46・6. 755-764 (1999)
[文献書誌] A.Imagawa et al.: "Immunological abanormalities in islets at diagnosis paralleled further deterloration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus"Diabetelogia. 42・5. 574-578 (1999)
[文献書誌] H.Iwahashi et al.: "Emerging therapeutic strategies in autoimmune diabetes: aetiology, prediction, prevention and cure"Emerging Therapeutic Targets. 3・1. 177-193 (1999)
[文献書誌] K.Okita et al.: "Human insulin gene is a target of hepatocyte nuclear factoe-1a (HNF-1a)and HNF-1b"Biochem. Biophys. Res. Commun.. 263・2. 566-569 (1999)
[文献書誌] M.Moriwaki et al.: "Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with resent-onset Type I diabetes mellitus"Diabetelogia. 42・11. 1332-1340 (1999)
[文献書誌] T.Ouee et al.: "Risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients --- a 10-vear follow-up study"Diab. Res. Clin. Prac.. 46・10. 47-52 (1999)
[文献書誌] K.Izuka et al.: "Stable overexpression of the glucose-6-phospatase catalytic subunit attenuates glucose sensitivity of insulin secretion from a mouse pancreatic beta cell line"J. Endocrinol.. (in press).
[文献書誌] I.Yoshiuchi et al.: "Three new mutations in the hepatocyte nuclear factor-1a gene in Japanese subjects with diabetes mellitus: Clinical features and functional characterization"Diabetologia. 42・5. 621-626 (1999)
[文献書誌] R.Hamaoka et al.: "Different expression of nitric oxidase synthase isozymes in various gynecological cancers"J. Cancer Res. Clin. Oncol.. 125. 321 (1999)
[文献書誌] R.Hamaoka et al.: "Overexpression of the aldose reductase gene induces apoptosis in pancreatic b-cells by causing a redox imbalance"J. Biochem.. 126・1. 41-47 (1999)
[文献書誌] Q.Yang et al.: "Structure/function studies of hepatocyte nuclear factor-1a, a diatetes-associated transcription factor"Biochem. Biophys. Res. Commun.. 266・1. 196-202 (1999)
[文献書誌] Y.Terauchi et al.: "Increased insulin sensitivity and hypoglycaemina in mice lacking the p85 subunit of phosphoinositide 3-kinase"Nature Genet.. 21. 230 (1999)
[文献書誌] M.Kuwajima et al.: "Cardiomegaly in the juvenile visceral steatosis (JVS) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after L-carnitine injection"FEBS Lett. 443・3. 261-266 (1999)
[文献書誌] S.Yamada et al.: "Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3 band mutation screening in Japanese subjects with MODY"Diabetologia. in press.
[文献書誌] H.Tomura et al.: "Lose-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1b mutations in familial type 2 diabetes mellitus"J. Biol. Chem.. 274. 12975-12978 (1999)
[文献書誌] H.Kaneto et al.: "Antioxidant treatment protects pancreatic b-cells against glucose toxicity in C57BL/Ksj-db/db mouse"Diabetes. 48・12. 2398-2406 (1999)
[文献書誌] A.Imagawa et al.: "A novel subtype of Type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies"New Engl. J. Med.. (in press).
[文献書誌] 河野典夫: "新版臨床化学"講談社. 212 (1998)
[文献書誌] 河野典夫: "最新内科学大系、特別巻3内科臨床リファレンスブック疾患編II"中山書店. 405 (1998)
[文献書誌] 河野典夫: "先天代謝異常症候群-遺伝子解析の進歩と成果(上巻)"日本臨牀社. 512 (1998)
[文献書誌] 河野典夫: "内科学書"中山書店. 2191 (1999)
[文献書誌] 河野典夫、山崎知行: "消化器疾患-state of arts II 肝・胆・膵"医歯薬出版. 562 (1999)
[文献書誌] 河野典夫: "内科学"朝倉書店. 2110 (1999)
[文献書誌] 河野典夫: "総合内科診断学"朝倉書店. 626 (1999)

1999 年度 実績報告書

IDDMにおけるFas依存的膵β細胞傷害機構の解明とその制御による治療法の開発

研究代表者

河野 典夫 大阪大学, 医学部, 教授 (30093412)

研究成果

[文献書誌] K.Yamagata et al.: "Mutation P291 fsins C in the Transcription Factor Hepatocyte Nuclear Fctor-1 α is Dominant Negative"Diabetes. 47・8. 1231-1235 (1998)

[文献書誌] H.Iwahashi et al.: "Molecular mechanisms of pancreatic beta-cell destruction in autoimmune diabetes: Potential targets for preventive therapy"Cytokines, Cellular & Molecular Therapy. 4. 45-51 (1998)

[文献書誌] I.Yoshiuchi et al.: "Mutation/Polymorphism Scanning of Glucose-6-Phosphatase Gene Promoter in Diabetes Mellitus Patients"J. Clin. Endocrinol and Metab. 83・3. 1016-1019 (1998)

[文献書誌] Y.Kamada et al.: "A Case with Prolactinoma Treated with Pergolide and Its Histology"Endocrine J.. 45・4. 605-606 (1998)

[文献書誌] M.Kuwajima et al.: "Characteristics of cardiac hypertrophy in the juvenile visceral steatosis mouse with systemic carnitine deficiency"J. Mol. Cell. Cardiol.. 30・4. 773-781 (1998)

[文献書誌] H.Iwahashi et al.: "Emerging therapeutic strategies in autoimmune diabetes: etiology, prediction, prevention and cure"Emerging Therapeutic Targets. 3・1(in press). (1999)

[文献書誌] J.Miyagawa et al.: "Immunohistochemical localization of Betacellulin, a new member of BGF family, in normal human pancreas and islet tumor cells"Endocrine J.. 46・6. 755-764 (1999)

[文献書誌] A.Imagawa et al.: "Immunological abanormalities in islets at diagnosis paralleled further deterloration of glycaemic control in patients with recent-onset Type I (insulin-dependent) diabetes mellitus"Diabetelogia. 42・5. 574-578 (1999)

[文献書誌] H.Iwahashi et al.: "Emerging therapeutic strategies in autoimmune diabetes: aetiology, prediction, prevention and cure"Emerging Therapeutic Targets. 3・1. 177-193 (1999)

[文献書誌] K.Okita et al.: "Human insulin gene is a target of hepatocyte nuclear factoe-1a (HNF-1a)and HNF-1b"Biochem. Biophys. Res. Commun.. 263・2. 566-569 (1999)

[文献書誌] M.Moriwaki et al.: "Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with resent-onset Type I diabetes mellitus"Diabetelogia. 42・11. 1332-1340 (1999)

[文献書誌] T.Ouee et al.: "Risk factors for the progression of microalbuminuria in Japanese type 2 diabetic patients --- a 10-vear follow-up study"Diab. Res. Clin. Prac.. 46・10. 47-52 (1999)

[文献書誌] K.Izuka et al.: "Stable overexpression of the glucose-6-phospatase catalytic subunit attenuates glucose sensitivity of insulin secretion from a mouse pancreatic beta cell line"J. Endocrinol.. (in press).

[文献書誌] I.Yoshiuchi et al.: "Three new mutations in the hepatocyte nuclear factor-1a gene in Japanese subjects with diabetes mellitus: Clinical features and functional characterization"Diabetologia. 42・5. 621-626 (1999)

[文献書誌] R.Hamaoka et al.: "Different expression of nitric oxidase synthase isozymes in various gynecological cancers"J. Cancer Res. Clin. Oncol.. 125. 321 (1999)

[文献書誌] R.Hamaoka et al.: "Overexpression of the aldose reductase gene induces apoptosis in pancreatic b-cells by causing a redox imbalance"J. Biochem.. 126・1. 41-47 (1999)

[文献書誌] Q.Yang et al.: "Structure/function studies of hepatocyte nuclear factor-1a, a diatetes-associated transcription factor"Biochem. Biophys. Res. Commun.. 266・1. 196-202 (1999)

[文献書誌] Y.Terauchi et al.: "Increased insulin sensitivity and hypoglycaemina in mice lacking the p85 subunit of phosphoinositide 3-kinase"Nature Genet.. 21. 230 (1999)

[文献書誌] M.Kuwajima et al.: "Cardiomegaly in the juvenile visceral steatosis (JVS) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after L-carnitine injection"FEBS Lett. 443・3. 261-266 (1999)

[文献書誌] S.Yamada et al.: "Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3 band mutation screening in Japanese subjects with MODY"Diabetologia. in press.

[文献書誌] H.Tomura et al.: "Lose-of-function and dominant-negative mechanisms associated with hepatocyte nuclear factor-1b mutations in familial type 2 diabetes mellitus"J. Biol. Chem.. 274. 12975-12978 (1999)

[文献書誌] H.Kaneto et al.: "Antioxidant treatment protects pancreatic b-cells against glucose toxicity in C57BL/Ksj-db/db mouse"Diabetes. 48・12. 2398-2406 (1999)

[文献書誌] A.Imagawa et al.: "A novel subtype of Type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies"New Engl. J. Med.. (in press).

[文献書誌] 河野典夫: "新版臨床化学"講談社. 212 (1998)

[文献書誌] 河野典夫: "最新内科学大系、特別巻3内科臨床リファレンスブック 疾患編II"中山書店. 405 (1998)

[文献書誌] 河野典夫: "先天代謝異常症候群-遺伝子解析の進歩と成果(上巻)"日本臨牀社. 512 (1998)

[文献書誌] 河野典夫: "内科学書"中山書店. 2191 (1999)

[文献書誌] 河野典夫、山崎知行: "消化器疾患-state of arts II 肝・胆・膵"医歯薬出版. 562 (1999)

[文献書誌] 河野典夫: "内科学"朝倉書店. 2110 (1999)

[文献書誌] 河野典夫: "総合内科診断学"朝倉書店. 626 (1999)

1999 年度実績報告書

河野典夫大阪大学, 医学部, 教授 (30093412)

[文献書誌] 河野典夫: "最新内科学大系、特別巻3内科臨床リファレンスブック疾患編II"中山書店. 405 (1998)