Type 2 diabetes is associated with impaired jejunal enteroendocrine GLP-1 cell lineage in human obesity

Céline Osinski,Karine Clément,Armelle Leturque,Corinne Blugeon,Laurent Jourdren,Léa Le Gléau,Agnès Ribeiro,Edwige Ludiwyne Hubert,Magali Fradet,Juan De Toro-Martin,Patricia Serradas,Hédi Antoine Soula,Laurent Genser,Christine Poitou

doi:10.1038/s41366-020-00694-1

Abstract

ObjectivesAltered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes.MethodsEEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals.ResultsThe RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals.ConclusionsThese results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.

Highlights

Enterohormones, such as peptide YY (PYY), glucagon-like peptide-1 (GLP-1) cholecystokinin (CCK) and glucose-These authors contributed : Patricia Serradas, Agnès Ribeiro Prior Presentation
Suspecting that nutritional changes can modulate enteroendocrine cells (EEC) differentiation and contribute to the modulation of gut hormone secretion in metabolic diseases, we previously showed a positive association between GLP-1-positive cell density in jejunum samples and fat-consumption in individuals with severe obesity [23]
Taking advantage of jejunal samples collected during bariatric surgery, we examined the impact of obesity and type 2 diabetes (T2D) on human EEC using an integrated strategy combining transcriptomic profiles, cell lineage gene expression and cell density analysis

Summary

Objectives

Altered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes. Methods EEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals

Methods

Results

Conclusion