Endogenous GIP ameliorates impairment of insulin secretion in proglucagon-deficient mice under moderate beta cell damage induced by streptozotocin

普吕卡贡 内分泌学 内科学 β细胞 链脲佐菌素 内生 胰岛素 分泌物 BETA(编程语言) 糖尿病 医学 α细胞 胰高血糖素样肽-1 2型糖尿病 小岛 程序设计语言 计算机科学
作者
Atsushi Iida,Yusuke Seino,Ayako Fukami,Ryuya Maekawa,Daisuke Yabe,Shinobu Shimizu,Keita Kinoshita,Yusuke Takagi,Takako Izumoto,Hidetada Ogata,Kota Ishikawa,Nobuaki Ozaki,Shin Tsunekawa,Yoji Hamada,Yutaka Oiso,Hiroshi Arima,Yoshitaka Hayashi
出处
期刊:Diabetologia [Springer Science+Business Media]
卷期号:59 (7): 1533-1541 被引量:22
标识
DOI:10.1007/s00125-016-3935-2
摘要

The action of incretin hormones including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) is potentiated in animal models defective in glucagon action. It has been reported that such animal models maintain normoglycaemia under streptozotocin (STZ)-induced beta cell damage. However, the role of GIP in regulation of glucose metabolism under a combination of glucagon deficiency and STZ-induced beta cell damage has not been fully explored. In this study, we investigated glucose metabolism in mice deficient in proglucagon-derived peptides (PGDPs)—namely glucagon gene knockout (GcgKO) mice—administered with STZ. Single high-dose STZ (200 mg/kg, hSTZ) or moderate-dose STZ for five consecutive days (50 mg/kg × 5, mSTZ) was administered to GcgKO mice. The contribution of GIP to glucose metabolism in GcgKO mice was also investigated by experiments employing dipeptidyl peptidase IV (DPP4) inhibitor (DPP4i) or Gcg–Gipr double knockout (DKO) mice. GcgKO mice developed severe diabetes by hSTZ administration despite the absence of glucagon. Administration of mSTZ decreased pancreatic insulin content to 18.8 ± 3.4 (%) in GcgKO mice, but ad libitum-fed blood glucose levels did not significantly increase. Glucose-induced insulin secretion was marginally impaired in mSTZ-treated GcgKO mice but was abolished in mSTZ-treated DKO mice. Although GcgKO mice lack GLP-1, treatment with DPP4i potentiated glucose-induced insulin secretion and ameliorated glucose intolerance in mSTZ-treated GcgKO mice, but did not increase beta cell area or significantly reduce apoptotic cells in islets. These results indicate that GIP has the potential to ameliorate glucose intolerance even under STZ-induced beta cell damage by increasing insulin secretion rather than by promoting beta cell survival.
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