Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:431

Article

O'Harte, F. P. M.¹  Ng, M. T.¹  Lynch, A. M.¹  Conlon, J. M.¹  Flatt, P. R.¹ 

[1] Univ Ulster, Sch Biomed Sci, Saad Ctr Pharm & Diabet, Coleraine BT52 1SA, Co Derry, North Ireland

关键词: Dogfish glucagon;    Glucagon-like peptide-1 (GLP-1);    Glucose dependent insulinotropic polypeptide (GIP);    Glucagon;    Dual agonist;    Diabetes;    Acute effects;    Antidiabetic and antihyperglycaemic;   

DOI  :  10.1016/j.mce.2016.05.012

来源: Elsevier

【 摘 要 】

The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 beta-cells (p < 0.001) and reduced acute glycaemic responses following intraperitoneal glucose (25 nmol/kg) in healthy NIH Swiss mice (p < 0.05-p<0.001). The in vitro insulinotropic actions of [S2a]dogfish glucagon, [S2a]dogfish glucagon-exendin-4(31-39) and [S2a]dogfish glucagon-Lys(30)-gamma-glutamyl-PAL, were blocked (p < 0.05-p<0.001) by the specific GLP-1 and glucagon receptor antagonists, exendin-4(9-39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated CAMP production in GLP-1 and glucagon (p < 0.05 -p<0.001) but not GIP-receptor transfected cells. They improved acute glycaemic and insulinotropic responses in high-fat fed diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p < 0.05-p<0.001), but not GLPAR-KO mice, confirming action on GLP-1 but not GIP receptors. Overall, dogfish glucagon analogues have potential for diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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