Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats

Meng-Qi Tong; Lan-Zi Luo; Peng-Peng Xue; Yong-Hui Han; Li-Fen Wang; De-Li Zhuge; Qing Yao; Bin Chen; Ying-Zheng Zhao; He-Lin Xu

doi:10.1016/j.actbio.2021.01.007

Glucose-responsive hydrogel enhances the preventive effect of insulin and liraglutide on diabetic nephropathy of rats

Acta Biomater. 2021 Mar 1:122:111-132. doi: 10.1016/j.actbio.2021.01.007. Epub 2021 Jan 11.

Authors

Affiliations

¹ Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
² Department of Ultrasonography, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China.
³ Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; Department of Ultrasonography, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China. Electronic address: pharmtds@163.com.
⁴ Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; Department of Ultrasonography, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China. Electronic address: xhlpharm1214@wmu.edu.cn.

PMID: 33444802
DOI: 10.1016/j.actbio.2021.01.007

Abstract

Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus. The combination of insulin (Ins) with liraglutide (Lir) has a greater potential for preventing DN than monotherapy. However, the renal protective effect of the combined Ins/Lir therapy is largely compromised due to their short half-lives after subcutaneous injection. Herein, a glucose-responsive hydrogel was designed in situ forming the dynamic boronic esters bonds between phenylboronic acid-grafted γ-Polyglutamic acid (PBA-PGA) and konjac glucomannan (KGM). It was hypothesized that the KGM/PBA-PGA hydrogel as the delivery vehicle of Ins/Lir would enhance the combinational effect of the latter on preventing the DN progress. Scan electronic microscopy and rheological studies showed that KGM/PBA-PGA hydrogel displayed good glucose-responsive property. Besides, the glucose-sensitive release profile of either Ins or Lir from KGM/PBA-PGA hydrogel was uniformly displayed at hyperglycemic level. Furthermore, the preventive efficacy of KGM/PBA-PGA hydrogel incorporating insulin and liraglutide (Ins/Lir-H) on DN progress was evaluated on streptozotocin-induced rats with diabetic mellitus (DM). At 6 weeks after subcutaneous injection of Ins/Lir-H, not only the morphology of kidneys was obviously recovered as shown by ultrasonography, but also the renal hemodynamics was significantly improved. Meanwhile, the 24-h urinary protein and albumin/creatinine ratio were well modulated. Inflammation and fibrosis were also largely inhibited. Besides, the glomerular NPHS-2 was obviously elevated after treatment with Ins/Lir-H. The therapeutic mechanism of Ins/Lir-H was highly associated with the alleviation of oxidative stress and activation of autophagy. Conclusively, the better preventive effect of the combined Ins/Lir via KGM/PBA-PGA hydrogel on DN progress was demonstrated as compared with their mixed solution, suggesting KGM/PBA-PGA hydrogel might be a potential vehicle of Ins/Lir to combat the progression of DN.

Keywords: Diabetic nephropathy; Glucose-responsive; Injectable hydrogel; Liraglutide and insulin; Phenylboronic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus*
Diabetic Nephropathies* / drug therapy
Diabetic Nephropathies* / prevention & control
Glucose
Hydrogels / pharmacology
Insulin / pharmacology
Liraglutide / pharmacology
Liraglutide / therapeutic use
Rats

Substances

Hydrogels
Insulin
Liraglutide
Glucose