title: Endogenous GIP ameliorates impairment of insulin secretion in proglucagon-deficient mice under moderate beta cell damage induced by streptozotocin.
abstract: 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.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan. yusuke@med.nagoya-u.ac.jp.|Department of Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. yusuke@med.nagoya-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Fukami
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Ryuya
authors.initials: R
authors.lastname: Maekawa
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.|Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yabe
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.|Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.|Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takagi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Izumoto
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Hidetada
authors.initials: H
authors.lastname: Ogata
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Research Center of Health, Physical Fitness and Sports, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Tsunekawa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.|Department of Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Genetics, Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 4648601, Japan. hayashiy@riem.nagoya-u.ac.jp.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004195:Disease Models, Animal; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052336:Proglucagon / Q000172:deficiency / Q000378:metabolism*; D013311:Streptozocin / Q000633:toxicity
chemical_list: D007328:Insulin; D052336:Proglucagon; D005749:Gastric Inhibitory Polypeptide; D013311:Streptozocin
keywords: Dipeptidyl peptidase IV; GIP; GLP-1; Glucagon; Hyperglycaemia; Insulin; Insulin secretion; Streptozotocin