Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jun 15, 2018; 9(6): 80-91
Published online Jun 15, 2018. doi: 10.4239/wjd.v9.i6.80
Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus
Vishal J Patel, Amit A Joharapurkar, Samadhan G Kshirsagar, Brijesh K Sutariya, Maulik S Patel, Hiren M Patel, Dheerendra K Pandey, Rajesh H Bahekar, Mukul R Jain
Vishal J Patel, Amit A Joharapurkar, Samadhan G Kshirsagar, Brijesh K Sutariya, Maulik S Patel, Hiren M Patel, Dheerendra K Pandey, Rajesh H Bahekar, Mukul R Jain, Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad 382210, India
Author contributions: Patel VJ, Joharapurkar AA and Jain MR contributed to the conception of the manuscript, design of experiments, and analysis and interpretation of the data, and writing of the manuscript; Patel VJ, Joharapurkar AA, Kshirsagar SG, Sutariya BK, Patel MS, Patel HM, Pandey DK and Bahekar RH performed the experiments, analyzed the data, and wrote the manuscript; all authors have commented on the initial and final drafts of the manuscript and are responsible for approval of the final version of the manuscript in all aspects.
Institutional review board statement: This study protocol was reviewed and approved by the Institutional Review Board of Zydus Research Centre.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care Committee of Zydus Research Centre, Ahmedabad, India (ZRC/PH/BP/003/03-2K17).
Conflict-of-interest statement: There is no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Amit A Joharapurkar, PhD, Senior Scientist, Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad 382210, India. amitjoharapurkar@zyduscadila.com
Telephone: +91-27-17665555 Fax: +91-27-17665155
Received: April 23, 2018
Peer-review started: April 24, 2018
First decision: May 7, 2018
Revised: May 10, 2018
Accepted: May 15, 2018
Article in press: May 15, 2018
Published online: June 15, 2018
Processing time: 52 Days and 16.3 Hours
ARTICLE HIGHLIGHTS
Research background

Chronic kidney disease is a major complication for diabetes, mainly caused by lipotoxicity and glucotoxicity. More recent discoveries have strengthened the hypothesis that coagonist of glucagon-like peptide receptor (GLP-1R) and glucagon receptor (GCGR) is a novel therapeutic strategy for the treatment of diabetes and obesity. Preclinical and clinical data indicates that coagonist might have a beneficial effect on diabetic complications such as dyslipidemia and non-alcoholic fatty liver disease, but its potential in treating nephropathy and related complications is not yet investigated.

Research motivation

Diabetes and obesity together enhance the deterioration of renal function. Glucose and lipid both are the major causative factors for the progression of nephropathy associated with diabetes and obesity. Because coagonist reduced both glucose and lipids, it is possible that coagonist may attenuate development of nephropathy associated with diabetes and obesity.

Research objectives

We have investigated the effect of coagonist on renal dysfunction in murine model of diabetes and obesity. These models are widely used model to study diabetic complications and have better clinical translations value.

Research methods

Coagonist was administered to streptozotocin-treated and high-fat diet-fed diabetic mice, chronic high-fat diet fed obese and insulin resistant mice and genetically diabetic and obese db/db mice. Biochemical, inflammatory and fibrotic markers of renal dysfunction was assessed. Additionally, histological assessment of kidney was performed.

Research results

Coagonist treatment reduced creatinine and urea in blood, inflammatory cytokines in blood, and expression of inflammation and fibrotic genes in kidney. Coagonist also improved histological abnormality in these mice models.

Research conclusions

Coagonist attenuated the development of renal dysfunction by improving glucose and lipid metabolism in murine model of diabetes.

Research perspectives

The results of this study provide evidence that coagonist could be a promising agent for the treatment of diabetic nephropathy. Further studies that assess the effect of coagonist on kidney structure and function in animal model of nephropathy with and without such comorbidity may substantiate our findings and pave the path for clinical translation of the therapeutic effects of GLP-1R and GCGR coagonist.