Mitochondrial uncoupling has no effect on microvascular complications in type 2 diabetes

Lucy M Hinder,Hongyu Zhang,Steven F Abcouwer,Sumathi Shanmugam,Amy E Rumora,Phillipe D O’Brien,Kelli M Sas,Eva L Feldman,John M Hayes,Pradeep Kayampilly,Carey Backus,Cheng-Mao Lin,Subramaniam Pennathur,Frank C Brosius

doi:10.1038/s41598-018-37376-y

Lucy M Hinder, Hongyu Zhang + Show 12 more

Open Access

https://doi.org/10.1038/s41598-018-37376-y

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Journal: Scientific Reports	Publication Date: Jan 29, 2019
Citations: 21	License type: open-access

Affiliation: University of Michigan–Ann Arbor

Abstract

Diabetic peripheral neuropathy (DPN), diabetic kidney disease (DKD), and diabetic retinopathy (DR) contribute to significant morbidity and mortality in diabetes patients. The incidence of these complications is increasing with the diabetes epidemic, and current therapies minimally impact their pathogenesis in type 2 diabetes (T2D). Improved mechanistic understanding of each of the diabetic complications is needed in order to develop disease-modifying treatments for patients. We recently identified fundamental differences in mitochondrial responses of peripheral nerve, kidney, and retinal tissues to T2D in BKS-db/db mice. However, whether these mitochondrial adaptations are the cause or consequence of tissue dysfunction remains unclear. In the current study BKS-db/db mice were treated with the mitochondrial uncoupler, niclosamide ethanolamine (NEN), to determine the effects of mitochondrial uncoupling therapy on T2D, and the pathogenesis of DPN, DKD and DR. Here we report that NEN treatment from 6–24 wk of age had little effect on the development of T2D and diabetic complications. Our data suggest that globally targeting mitochondria with an uncoupling agent is unlikely to provide therapeutic benefit for DPN, DKD, or DR in T2D. These data also highlight the need for further insights into the role of tissue-specific metabolic reprogramming in the pathogenesis of diabetic complications.

Highlights

In the United States, 30 million adults[1] and 200,000 youth[2] have type 2 diabetes (T2D), and this number is expected to double by 20501,3
We report that niclosamide ethanolamine (NEN) treatment of db/db mice from 6–24 wk of age had little effect on the development of T2D and diabetic complications
We recently identified fundamental differences in mitochondrial responses of peripheral nerve, kidney, and retinal tissues to T2D in BKS-db/db mice[10,13]

Summary

Introduction

In the United States, 30 million adults[1] and 200,000 youth[2] have type 2 diabetes (T2D), and this number is expected to double by 20501,3. A high incidence of cardiovascular disease and stroke, commonly classified as diabetic macrovascular disease, contributes to significant patient morbidity and mortality[1] More common than these macrovascular complications are the microvascular complications of diabetes, which are disabling and poorly understood. In db/db mice lead to distinct differences in each end-organ[13], associated with differential transcriptional regulation of mitochondrial lipid and oxidative pathways in the three different tissues[10]. These data highlight fundamental differences in mitochondrial responses within the nerve, kidney and retina, but whether these mitochondrial adaptations are the cause or consequence of tissue dysfunction remains unclear

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