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 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.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…A significant number of GPR119 agonists took part in clinical trials, from which the majority was discontinued [239]. However, multi-target drugs may be a promising strategy, as a dual GPR119 agonist and dipeptidyl peptidase 4 (DPP4) inhibitor, HBK001 (30 mg/kg), was demonstrated to meaningfully improve glucose homeostasis and β-cell function in the rodent model [240].…”

DPP‐4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high‐glucose conditions, potentially through the SIRT1/HIF‐1/VEGF pathway

“…We treated the induced cells in the model control with linagliptin and berberine, and assessed the effects of these established DPP‐4 inhibitors on the cell proliferation. The doses of inhibitors used in current work are determined on the basis of previous reports and our preliminary experiments that concentration‐dependent inhibitory effects of selected compounds on DPP‐4 activity were evaluated individually (data not shown). Solvent DMSO was used as vehicle control.…”

“…treated the induced cells in the model control with linagliptin and berberine, and assessed the effects of these established DPP-4inhibitors on the cell proliferation. The doses of inhibitors used in current work are determined on the basis of previous reports7,25,26 and our preliminary experiments that concentration-dependent inhibitory effects of selected compounds on DPP-4 activity were F I G U R E 2 DPP-4 inhibitors linagliptin and berberine attenuated the inhibition of cell proliferation and migration of rBMVECs by the induction of hypoxic/high-glucose conditions. A, MTT experiment results for different groups showing cell proliferation of rBMVECs was inhibited by the induction of hypoxic/high-glucose treatment (model control), which was attenuated to a large extent by the administration of DPP-4 inhibitors, for example, linagliptin and berberine.…”

Human Islet Isolation and Distribution Efforts for Clinical and Basic Research

“…To the best of our knowledge, there are no coordinating efforts or networks that facilitate the distribution of human islets in a country or to other countries in Asia. In China, a number of facilities, such as the Tianjin First Center Hospital, are known to isolate human islets for both research and clinical transplantation [71,72]. However, the list in Table 1 is likely to be an underestimate, especially for China, as information regarding certain centers in China may not be well-documented in English.…”