Therapy of type 2 diabetes: development of an agonist of adiponectin receptor

This project is based on the research of a therapeutic agent able to interact with both adiponectin receptors and adjust the insulin sensitivity of muscle and liver, as well as the metabolism of glucose and lipids in type 2 diabetes. This adiponectin receptor (AdipoR) agonist is searched within a combinatorial library of random 12-mer peptides fused to the pIII minor coat protein of M13 bacteriophage, aiming to develop a therapeutic strategy designed for medical care of type 2 diabetes and other obesity-linked disorders.
Adipokines play an important role in the pathophysiology of obesity-related disorders by their ability to regulate inflammatory processes and metabolic disorders. When adiponectin binds to its two receptors, AdipoR1 and AdipoR2, AMPK (AMP-activated protein kinase) is activated and leads to fatty acid oxidation and increased glucose uptake in muscle and a decrease in glucose production in the liver. This receptor is present in two forms, one primarily in muscle (AdipoR1) and the other mainly in the liver (AdipoR2). At the level of pancreatic beta cells (BC), there is evidence that these two receptors are widely expressed and regulate the anti-apoptotic effect of adiponectin through activation of MEK-ERK1 / 2 and PI3K-Akt1. These two proteins are homologous in proportion of 67% and are composed of seven transmembrane domains. At the C-terminal extracellular domain, we identified a sequence of nine amino acids that is homologous to both receptors in humans and mice.
This peptide sequence belonging to the C-terminal domain of both receptors was immobilized on magnetic beads and used as antigen during three rounds of screening (panning) carried by phage display. The selected phage clones were amplified using a bacterial strain of Escherichia coli ER2738. The binding of the phage pools obtained after three rounds of panning was confirmed on both the protein fragment and on AdipoR1 purified protein. The screening of the phage clones isolated from the pool of the third round of panning proves their excellent affinity for the target. Although the studies are incipient, the preliminary data are optimistic for the development of a therapeutic agent with applications in metabolic disorders.