Duodenal mucosal mitochondrial gene expression is associated with delayed gastric emptying in diabetic gastroenteropathy.

Susrutha Puthanmadhom Narayanan,Tamas Ordog,Karl Miller,Alfonso Eirin,Peter Adams,João F Passos,Daniel O’Brien,Adil E Bharucha,Mayank Sharma

doi:10.1172/jci.insight.143596

Abstract

Hindered by a limited understanding of the mechanisms responsible for diabetic gastroenteropathy (DGE), management is symptomatic. We investigated the duodenal mucosal expression of protein-coding genes and microRNAs (miRNA) in DGE and related them to clinical features. The diabetic phenotype, gastric emptying, mRNA, and miRNA expression and ultrastructure of duodenal mucosal biopsies were compared in 39 DGE patients and 21 controls. Among 3175 differentially expressed genes (FDR < 0.05), several mitochondrial DNA–encoded (mtDNA-encoded) genes (12 of 13 protein coding genes involved in oxidative phosphorylation [OXPHOS], both rRNAs and 9 of 22 transfer RNAs) were downregulated; conversely, nuclear DNA–encoded (nDNA-encoded) mitochondrial genes (OXPHOS) were upregulated in DGE. The promoters of differentially expressed genes were enriched in motifs for transcription factors (e.g., NRF1), which regulate mitochondrial biogenesis. Seventeen of 30 differentially expressed miRNAs targeted differentially expressed mitochondrial genes. Mitochondrial density was reduced and correlated with expression of 9 mtDNA OXPHOS genes. Uncovered by principal component (PC) analysis of 70 OXPHOS genes, PC1 was associated with neuropathy (P = 0.01) and delayed gastric emptying (P < 0.05). In DGE, mtDNA- and nDNA-encoded mitochondrial genes are reduced and increased — associated with reduced mitochondrial density, neuropathy, and delayed gastric emptying — and correlated with cognate miRNAs. These findings suggest that mitochondrial disturbances may contribute to delayed gastric emptying in DGE.

Highlights

Up to 50% of patients with diabetes mellitus (DM) have delayed gastric emptying [1,2,3]
Diabetic gastroenteropathy (DGE) encompasses dyspepsia; gastroparesis, which is characterized by moderate-to-severe upper gastrointestinal symptoms and markedly delayed gastric emptying; and asymptomatic delay in gastric emptying
A principal component, which was defined by reduced expression of 10 of 12 mtDNA and increased expression of all 58 nDNA oxidative phosphorylation (OXPHOS) genes, was associated with a neuropathy and with delayed GE in DGE

Summary

Introduction

Up to 50% of patients with diabetes mellitus (DM) have delayed gastric emptying [1,2,3]. Derived primarily from animal models and, to a limited extent, in patients with DGE, our insight into the mechanisms responsible for neuronal loss and gut dysmotility (e.g., apoptosis, oxidative stress, advanced glycation end products, reduced expression of neuronal nitric oxide signaling, and neuroimmune mechanisms) [5] lags our understanding of the pathogenesis of other DM complications (e.g., neuropathy) [3, 6]. Only 1 study compared the transcriptome in full-thickness stomach biopsies between DM patients with delayed gastric emptying and DM controls, who were assumed to have normal gastric emptying [7]. Patients with delayed gastric emptying had reduced mRNA expression of several genes related to innate immunity [7].

Methods

Results

Conclusion