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Antidiabetic effects and sustained metabolic benefits of sub-chronic co-administration of exendin-4/gastrin and xenin-8-Gln in high fat fed mice.

Abstract：

:The present study has examined the antidiabetic effects of 21 days co-administration of xenin-8-Gln with the dual-acting fusion peptide, exendin-4/gastrin, as well as persistence of beneficial metabolic benefits, in high fat fed (HFF) mice. Xenin-8-Gln, exendin-4 and gastrin represent compounds that activate receptors of the gut-derived hormones, xenin, glucagon-like peptide-1 (GLP-1) and gastrin, respectively. Twice-daily administration of exendin-4/gastrin, xenin-8-Gln or a combination of both peptides significantly reduced circulating glucose, HbA1c and cumulative energy intake. Combination therapy with xenin-8-Gln and exendin-4/gastrin increased circulating insulin. All HFF mice treated with exendin-4/gastrin presented with body weight similar to lean control mice on day 21. Each treatment improved glucose tolerance and the glucose-lowering actions of glucose dependent insulinotropic polypeptide (GIP), as well as augmenting glucose- and GIP-induced insulin secretion, with benefits being most prominent in the combination group. Administration of exendin-4/gastrin alone, and in combination with xenin-8-Gln, increased pancreatic insulin content and improved the insulin sensitivity index. Pancreatic beta-cell area was significantly increased, and alpha cell area decreased, by all treatments, with the combination group also displaying enhanced overall islet area. Notably, metabolic benefits were generally retained in all groups of HFF mice, and especially in the combination group, following discontinuation of the treatment regimens for 21 days. This was associated with maintenance of increased islet and beta-cell areas. Together, these data confirm the antidiabetic effects of co-activation of GLP-1, gastrin and xenin cell signalling pathways, and highlight the sustainable benefits this type of treatment paradigm can offer in T2DM.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Hasib A,Khan D,Craig SL,Gault VA,Flatt PR,Irwin N

doi

10.1016/j.ejphar.2019.172733

subject

Has Abstract

pub_date

2019-12-15 00:00:00

pages

172733

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(19)30685-5

journal_volume

865

pub_type

杂志文章

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Antidiabetic effects and sustained metabolic benefits of sub-chronic co-administration of exendin-4/gastrin and xenin-8-Gln in high fat fed mice.