BACKGROUND AND PURPOSE: Type 2 diabetes is one of the most severe chronic diseases and is an increasingly important public health problem worldwide. Several agonists of the glucagon-like peptide-1 (GLP-1) 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-1 receptor agonist - oral hypoglycaemic peptide 2 (OHP2) - derived from exendin-4 by replacing amino acids. We have also investigated its pharmacokinetic profiles, therapeutic effects and absorption mechanism. EXPERIMENTAL APPROACH: 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-2 cell monolayers. KEY RESULTS: In rats, the absolute bioavailability of orally administered OHP2 was 20-fold greater than that of orally administered exendin-4. In db/db mice, OHP2 dose-dependently exhibits good potential in glucose-lowering 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-2 cells was dependent on caveolae-mediated transcytosis rather than endocytosis mediated by GLP-1 receptors. CONCLUSIONS AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: Type 2 diabetes is one of the most severe chronic diseases and is an increasingly important public health problem worldwide. Several agonists of the glucagon-like peptide-1 (GLP-1) 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-1 receptor agonist - oral hypoglycaemic peptide 2 (OHP2) - derived from exendin-4 by replacing amino acids. We have also investigated its pharmacokinetic profiles, therapeutic effects and absorption mechanism. EXPERIMENTAL APPROACH: 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-2 cell monolayers. KEY RESULTS: In rats, the absolute bioavailability of orally administered OHP2 was 20-fold greater than that of orally administered exendin-4. In db/db mice, OHP2 dose-dependently exhibits good potential in glucose-lowering and weight loss after oral administration. OHP2 also alleviated hyperlipidaemia, ameliorated energy metabolism and promoted tissue repair in diabeticmice. Furthermore, uptake of OHP2 by Caco-2 cells was dependent on caveolae-mediated transcytosis rather than endocytosis mediated by GLP-1 receptors. CONCLUSIONS AND IMPLICATIONS: 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.
Authors: Michael J Curtis; Steve Alexander; Giuseppe Cirino; James R Docherty; Christopher H George; Mark A Giembycz; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Yong Ji; David J MacEwan; Christopher G Sobey; S Clare Stanford; Mauro M Teixeira; Sue Wonnacott; Amrita Ahluwalia Journal: Br J Pharmacol Date: 2018-04 Impact factor: 8.739
Authors: Melanie Davies; Thomas R Pieber; Marie-Louise Hartoft-Nielsen; Oluf K H Hansen; Serge Jabbour; Julio Rosenstock Journal: JAMA Date: 2017-10-17 Impact factor: 56.272
Authors: Eric P Smith; Zhibo An; Constance Wagner; Alfor G Lewis; Eric B Cohen; Bailing Li; Parinaz Mahbod; Darleen Sandoval; Diego Perez-Tilve; Natalia Tamarina; Louis H Philipson; Doris A Stoffers; Randy J Seeley; David A D'Alessio Journal: Cell Metab Date: 2014-05-15 Impact factor: 27.287
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