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

Tsuyoshi Yanagimachi, Yukihiro Fujita, Yasutaka Takeda, Jun Honjo, Kuralay K. Atageldiyeva, Yumi Takiyama, Atsuko Abiko, Yuichi Makino, Timothy J. Kieffer, Masakazu Haneda

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Aims/hypothesis: 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-Ala2]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-Ala2]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-Ala2]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-Ala2]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-Ala2]GIP(1–30)-PEG preserved beta cell area via inhibition of apoptosis in LD-STZ mice. Conclusions/interpretation: 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.

Original languageEnglish
Pages (from-to)533-541
Number of pages9
JournalDiabetologia
Volume59
Issue number3
DOIs
Publication statusPublished - Mar 1 2016
Externally publishedYes

Keywords

  • Alpha cell
  • Beta cell
  • Glucagon
  • Glucose-dependent insulinotropic polypeptide(1–30)
  • Insulin
  • Polyethylene glycol
  • Streptozotocin

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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