European Association for the Study of Diabetes (EASD) 2022 in Stockholm, SE

Dr Allan LANGLOIS presented a project from CeeD entitled "Peptide X, a promising inhibitor of MP001 protein which improves human pancreatic islet survival and function”

The objective of this study conducted in collaboration with Pr Makoto KANZAKI, from Tohoku University in Japan, was to identify a new therapeutic target to treat patients with diabetes and to develop a pharmacological approach. Thus, our laboratory has identified for the first time that the MP001 protein represents a target of major interest for improving insulin secretion and the survival of human pancreatic islets. Finally, we have implemented a promising pharmacological strategy targeting MP001 to treat subjects with diabetes because this new molecule improves the functionality and survival of human pancreatic islets.

This major international congress in the field of diabetology was an opportunity to listen to numerous high-level works and to meet renowned scientists. Furthermore, it was a real opportunity to be able to present my results and discuss them with these experts.

Abstract :

Peptide X, a promising inhibitor of MP001 protein which improves human pancreatic islet survival and function 

A. Langlois1, M. Kanzaki2, G. Bechtluft1, M. Pinget1 and K. Bouzakri1.

1. DIATECH, UMR 7294, Centre Européen d’Etude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France.

2. Department of Biomedical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6-04-110 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, JAPAN. 980-8579.


Background and aims:

Previously, our team identified by proteomics that several proteins are up-regulated in human pancreatic islets upon exposure with conditioned medium derived from insulin-resistant skeletal muscle cell culture induced by incubation with TNF-α. Among them, the MP001 protein which has been identified as being specific for the β-cell. Recently, we demonstrated that MP001 is a key protein involved in insulin granule exocytosis via an impact on the dynamics of actin filaments and cellular remodeling of β-cells. Moreover, its inhibition using siRNA technology improved human pancreatic islet survival and function. The aim of this project was to developed a pharmacological strategy of MP001 inhibition and to evaluate it effect on human islet survival and function. For that we have tested the Peptide X.

Materials and methods:

Studies were carried out on human pancreatic islet. These were incubated for 24h in presence of Peptide X 0.1, 1 or 10µM versus its Peptide control. Islet functionality was assessed using glucose stimulation insulin secretion test. Data were expressed in percentage toward total insulin content. Moreover, the effect of Peptide X on islet survival and function was studied using western blotting targeting Akt, p-Akt, NFκBp65, p-NFκBp65, PGC1α, IRS1, p-IRS1, IRS2, p-IRS2, Tbc1d1, p-Tbc1d1 and AS160. Protein expression was reported as a percentage versus Peptide control. Statistics were performed using non parametric test (Mann Whitney) for molecular study and ordinary one-way ANOVA followed to multiple comparison test for functionality evaluation. Data were reported as mean ± SEM for the indicated number of replicates and a p value of <0.05 was considered statistically significant.

Results:

Firstly, we showed that Peptide X potentiates insulin secretion from 0.1µM in comparison to control with no improvement for higher concentrations (Peptide X 0.1µM 16.7mM glucose = 4.35±0.52%, Peptide X 0.1µM 2.8mM glucose = 1.24±0.33%, p< 0.001 n=13 versus Peptide control 0.1µM 16.7mM glucose = 3.30±0.39%, Peptide X 0.1µM 2.8mM glucose = 1.25±0.28%, p< 0.01 n=13). Thus, for the molecular study we used 0.1µM. Secondly, proteomic demonstrated that Peptide X improves human islet survival increasing Akt activation (p-AKT: 206±67% versus control, p<0.001, n=7), NFkBp65 (139±28% versus control, n=9) and PGC-1α expressions (146±10% versus control, p<0.01, n=5). Finally, Peptide X has a positive action on islet function up-regulating proteins involved in insulin molecular pathway as IRS1 (283±83% versus control, p<0.001, n=10), p-IRS2 (179±42% versus control, p<0.05, n=9), p-Tbc1d1(179±39% versus control, p<0.05, n=7) and AS160 (185±36% versus control, p<0.05, n=9).

Conclusions:

Our study has demonstrated for the first time that Peptide X, inhibiting MP001, improves human pancreatic islet survival and function. Consequently, based on our data, we propose that Peptide X could be a promising therapeutic approach for diabetic patients.