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Several agonists of the glucagon\u2010like peptide\u20101 (GLP\u20101) receptor have been developed to treat Type 2 diabetes but most of them are administered by injection. This mode of administration seriously reduces patient compliance and increases the risk of infection. Here, we describe the actions of a novel, orally available, GLP\u20101 receptor agonist \u2010 oral hypoglycaemic peptide 2 (OHP2) \u2010 derived from exendin\u20104 by replacing amino acids. We have also investigated its pharmacokinetic profiles, therapeutic effects and absorption mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Healthy Wistar rats were used for pharmacokinetic analyses. In diabetic db\/db mice. OHP2 was given for 8 weeks to evaluate its effects on hyperglycaemia, dyslipidaemia, basal metabolism and tissue injury. Possible endocytosis and transcytosis mechanisms of OHP2 uptake were explored in Caco\u20102 cell monolayers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In rats, the absolute bioavailability of orally administered OHP2 was 20\u2010fold greater than that of orally administered exendin\u20104. In db\/db mice, OHP2 dose\u2010dependently exhibits good potential in glucose\u2010lowering and weight loss after oral administration. OHP2 also alleviated hyperlipidaemia, ameliorated energy metabolism and promoted tissue repair in diabetic mice. Furthermore, uptake of OHP2 by Caco\u20102 cells was dependent on caveolae\u2010mediated transcytosis rather than endocytosis mediated by GLP\u20101 receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>OHP2 is a potential, orally bioavailable, candidate drug for the treatment of Type 2 diabetes. Its transcytosis mechanism of uptake could help in the development of absorption enhancers of OHP2.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15069","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T15:13:05Z","timestamp":1586963585000},"page":"3473-3488","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An orally available hypoglycaemic peptide taken up by caveolae transcytosis displays improved hypoglycaemic effects and body weight control in db\/db mice"],"prefix":"10.1111","volume":"177","author":[{"given":"Weisheng","family":"Lu","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Tian","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of 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