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

Abstract

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. Results The 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. Conclusions These 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.

Vertical Sleeve Gastrectomy Induces Enteroendocrine Cell Differentiation of Intestinal Stem Cells Through Farnesoid X Receptor Activation

“…Furthermore, the increase in jejunal GLP-1 + cell number after VSG might have clinical implications. A recent study revealed that jejunal GLP-1 + cell number is decreased in obese patients (even more so in obese patients with T2DM) compared to non-obese individuals 35 . Jejunal EECs isolated from patients with T2DM also demonstrate downregulation in genes involved in EEC differentiation (including PAX4 and FOXA2 ) and in the GCG gene itself 35 , indicating that jejunal GLP-1 + cell differentiation and number are negatively impacted by both obesity and T2DM.…”

Bioinformatics Analysis of Key Genes and Pathways for Obesity Associated Type 2 Diabetes Mellitus as a Therapeutic Target

“…The expression profiling by high throughput sequencing data GSE132831 was downloaded from the GEO database, which was based on the platform of GPL1857 Illumina NextSeq 500 (Homo sapiens). This dataset, including 104 diabetic obese samples and 120 non diabetic obese samples, was deposited by Osinski et al [12].…”

“…Therefore, in this investigation, we downloaded the expression profiling by high throughput sequencing data GSE132831, provided by Osinski et al [12], from Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) [13] database to identify the differentially expressed genes (DEGs) between diabetic obese samples and non diabetic obese samples. With the identified DEGs, we performed Gene Ontology (GO) and pathway enrichment analyses to investigate the functions and pathways enriched by the DEGs.…”

Microbial regulation of enteroendocrine cells

“…31 In humans, postprandial GLP-1 levels are somewhat lowered in obese individuals with or without T2D. 32,33 In addition, the density of GLP-1-positive cells and differentiation of jejunal GLP-1-expressing cells are reduced in obese individuals with T2D, 22 indicating that the function of GLP-1-expressing EECs is affected by diabetic Gut microbiota produces a number of microbial metabolites that interact with intestinal enteroendocrine cells to modulate hormone secretion and expression. Changes in the gut microbiota composition either by consumption of dietary fiber or bariatric surgery procedures (such as Roux-en-Y gastric bypass or vertical sleeve gastrectomy) modulate levels of microbial metabolites, which in turn affect the enteroendocrine cells.…”

“…Enteroendocrine cells (EECs) constitute a highly specialized population of chemosensory intestinal cells 21 and provide a unique platform to study cellular interaction with the gut microbiota. Dysregulation of EECs is evident in metabolic diseases 22 that make them important drug targets. Currently, the gut hormone glucagon-like peptide-1 (GLP-1)-based drugs are approved for treatment of both obesity and type 2 diabetes (T2D), proving therapeutic importance of EECs.…”