title: Pancreatic glucose-dependent insulinotropic polypeptide (GIP) (1-30) expression is upregulated in diabetes and PEGylated GIP(1-30) can suppress the progression of low-dose-STZ-induced hyperglycaemia in mice.
abstract: OBJECTIVE
  Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone released from gut K cells. While the predominant form is GIP(1-42), a shorter form, GIP(1-30), is produced by pancreatic alpha cells and promotes insulin secretion in a paracrine manner. Here, we elucidated whether GIP(1-30) expression is modulated in mouse models of diabetes. We then investigated whether PEGylated GIP(1-30) can improve islet function and morphology as well as suppress the progression to hyperglycaemia in mice treated with low-dose streptozotocin (LD-STZ).
  
  
  METHODS
  We examined pancreatic GIP immunoreactivity in rodent diabetic models. We synthesised [D-Ala(2)]GIP(1-30) and modified the C-terminus with polyethylene glycol (PEG) to produce a dipeptidyl peptidase-4 (DPP-4)-resistant long-acting GIP analogue, [D-Ala(2)]GIP(1-30)-PEG. We performed i.p.GTT and immunohistochemical analysis in non-diabetic and LD-STZ diabetic mice, with or without administration of [D-Ala(2)]GIP(1-30)-PEG.
  
  
  RESULTS
  Pancreatic GIP expression was concomitantly enhanced with alpha cell expansion in rodent models of diabetes. Treatment with DPP-4 inhibitor decreased both the GIP- and glucagon-positive areas and preserved the insulin-positive area in LD-STZ diabetic mice. Body weight was not affected by [D-Ala(2)]GIP(1-30)-PEG in LD-STZ or non-diabetic mice. Treatment with GIP significantly ameliorated chronic hyperglycaemia and improved glucose excursions in LD-STZ mice. Treatment with GIP also reduced alpha cell expansion in the islets and suppressed plasma glucagon levels compared with non-treated LD-STZ mice. Additionally, [D-Ala(2)]GIP(1-30)-PEG preserved beta cell area via inhibition of apoptosis in LD-STZ mice.
  
  
  CONCLUSIONS
  Our data suggest that GIP(1-30) expression is upregulated in diabetes, and PEGylated GIP(1-30) can suppress the progression to STZ-induced hyperglycaemia by inhibiting beta cell apoptosis and alpha cell expansion.
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yanagimachi
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. yfujita@asahikawa-med.ac.jp.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Honjo
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Kuralay K
authors.initials: KK
authors.lastname: Atageldiyeva
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Takiyama
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Abiko
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D005934:Glucagon / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D013311:Streptozocin / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; C549099:gastric inhibitory polypeptide (1-30); D005749:Gastric Inhibitory Polypeptide; D013311:Streptozocin; D005934:Glucagon
keywords: Alpha cell; Beta cell; Glucagon; Glucose-dependent insulinotropic polypeptide(1–30); Insulin; Polyethylene glycol; Streptozotocin