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
Abstract
AIM

To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity.

METHODS

Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment.

RESULTS

Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation (CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-α. Coagonist treatment reduced expression of inflammatory (TNF-α, MCP-1, and MMP-9) and pro-fibrotic (TGF-β, COL1A1, and α-SMA) genes and also improved histological derangement in renal tissue.

CONCLUSION

Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

Keywords: Coagonist; Glucagon; Renal dysfunction; Glucagon-like peptide-1; Insulin sensitivity

Core tip: Nephropathy is a significant complication of diabetes. In this study, we have demonstrated that the coagonist of glucagon-like peptide-1 and glucagon receptors alleviates biochemical and histopathological features of nephropathy in HFSTZ and db/db mice. Coagonist reduces glucotoxicity and lipotoxicity in these animal models, which translates into benefit for prevention of nephropathy. The results provide further evidence that coagonist may be effective in the prevention of diabetic nephropathy.