The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo
Abstract Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we descr...
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Nature Portfolio
2017
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oai:doaj.org-article:b7cf3b9f7d1d47d2a96769334b00ea7b2021-12-02T16:06:38ZThe dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo10.1038/s41598-017-04633-52045-2322https://doaj.org/article/b7cf3b9f7d1d47d2a96769334b00ea7b2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04633-5https://doaj.org/toc/2045-2322Abstract Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.Yi HuanQian JiangGang LiGuoliang BaiTian ZhouShuainan LiuCaina LiQuan LiuSujuan SunMiaomiao YangNan GuoXing WangShusen WangYaojuan LiuGuanqiao WangHaihong HuangZhufang ShenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Yi Huan Qian Jiang Gang Li Guoliang Bai Tian Zhou Shuainan Liu Caina Li Quan Liu Sujuan Sun Miaomiao Yang Nan Guo Xing Wang Shusen Wang Yaojuan Liu Guanqiao Wang Haihong Huang Zhufang Shen The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| description |
Abstract Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors. |
| format |
article |
| author |
Yi Huan Qian Jiang Gang Li Guoliang Bai Tian Zhou Shuainan Liu Caina Li Quan Liu Sujuan Sun Miaomiao Yang Nan Guo Xing Wang Shusen Wang Yaojuan Liu Guanqiao Wang Haihong Huang Zhufang Shen |
| author_facet |
Yi Huan Qian Jiang Gang Li Guoliang Bai Tian Zhou Shuainan Liu Caina Li Quan Liu Sujuan Sun Miaomiao Yang Nan Guo Xing Wang Shusen Wang Yaojuan Liu Guanqiao Wang Haihong Huang Zhufang Shen |
| author_sort |
Yi Huan |
| title |
The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| title_short |
The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| title_full |
The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| title_fullStr |
The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| title_full_unstemmed |
The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo |
| title_sort |
dual dpp4 inhibitor and gpr119 agonist hbk001 regulates glycemic control and beta cell function ex and in vivo |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/b7cf3b9f7d1d47d2a96769334b00ea7b |
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