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

Atsushi Iida,Daisuke Yabe,Nobuaki Ozaki,Ryuya Maekawa,Yoshitaka Hayashi,Yoji Hamada,Keita Kinoshita,Kota Ishikawa,Hiroshi Arima,Ayako Fukami,Yusuke Seino,Hidetada Ogata,Yusuke Takagi,Shinobu Shimizu,Takako Izumoto,Shin Tsunekawa,Yutaka Oiso

doi:10.1007/s00125-016-3935-2

Abstract

Aims/hypothesisThe 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.MethodsIn 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.ResultsGcgKO 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.Conclusions/interpretationThese 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3935-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Highlights

Glucagon is secreted from pancreatic alpha cells and contributes to promoting hepatic glucose production [1]
Severe hyperglycaemia is induced by hSTZ-induced beta cell ablation in glucagon gene knockout (GcgKO) mice To evaluate glucose metabolism under beta cell dysfunction in the GcgKO and control mice, STZ was given at a high dose (200 mg/kg, one shot; Fig. 1)
These findings demonstrate that severe destruction of beta cells causes hyperglycaemia even in GcgKO mice, which lack proglucagon-derived peptides (PGDPs) including glucagon, indicating that glucagon action is not requisite for persistent hyperglycaemia

Summary

Introduction

Glucagon is secreted from pancreatic alpha cells and contributes to promoting hepatic glucose production [1]. Several animal models deficient in glucagon action have been reported, including prohormone convertase 2 knockout mice [4, 5], glucagon receptor knockout (Gcgr−/−) mice [6], mice treated with glucagon receptor antisense oligonucleotide [7] and mice having pancreas-specific Arx ablation [8]. All of these animal models show lower blood glucose levels, suggesting that glucagon plays a major role in hepatic glucose production and the maintenance of blood glucose levels. Several studies demonstrated that such animal models do not develop hyperglycaemia after beta cell destruction by streptozotocin (STZ) treatment [8,9,10,11], suggesting that glucagon plays an indispensable role in hyperglycaemia caused by beta cell destruction

Methods

Results

Conclusion