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  3. Evolution of GCGR family ligand-receptor extensive cross-interaction systems suggests a therapeutic direction for hyperglycemia in mammals

Evolution of GCGR family ligand-receptor extensive cross-interaction systems suggests a therapeutic direction for hyperglycemia in mammals

  • Acta Biochim Biophys Sin (Shanghai). 2023 Nov 15;55(12):1855-1863. doi: 10.3724/abbs.2023133.
Jian Liu 1,  Xue Wang 2,  Wenli Zhang 1,  Guangneng Liao 3,  Zhenhua Shao 4,  Juergen Brosius 2,  Cheng Deng 1 2,  Shanshan Lai 1,  Enwu Long 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • 2 Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Sichuan University West China Hospital, Department of Experimental Animal Center, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 4 Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
PMID: 37969012 DOI: 10.3724/abbs.2023133
Abstract

Glucose is essential to the physiological processes of vertebrates. Mammalian physiological stability requires a relatively stable blood glucose level (~5 mM), whereas other vertebrates have greater flexibility in regulating blood glucose (0.5-25 mM). GCGR family receptors play an important role in vertebrate glucose regulation. Here, we examine the evolution of the GCGR family ligand-receptor systems in different species. Comparatively, we discover that the conserved sequences among GCG family ligands lead to the non-specific activation of ligands across species. In particular, we observe that glucagon-like peptide 1 receptor (GLP1R), glucagon-like peptide 2 receptor (GLP2R), and glucagon-like receptor (GCGLR, also called GCRPR) are arbitrarily activated by other members of the ligand family in birds. Moreover, we reveal that Gallus gallus GLP2 (gGLP2) effectively activates mammalian GLP1R and improves glucose tolerance in diabetic mice. Our study has important implications for understanding blood glucose stabilization in vertebrates and demonstrates that gGLP2 may be a potential drug for treating type 2 diabetes.

Keywords

GLP1R; GLP2; cross stimulation; diabetes treatment; glucagon receptor family.

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