Metabolic coupling between schwann cells and axons is functionally distinct from myelination and is disrupted in obesity, prediabetes, and diabetes

Active Project Grant Awarded Last action

Award ID
R01DK130913
Recipient
Awarding agency
Obligated
$3,951,204

Award facts

Completion date 48% complete
Originally
Place of performance
Ann Arbor, MI 48109, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Peripheral neuropathy (PN) is a common complication of type 2 diabetes (T2D), prediabetes, and obesity, conditions that comprise aspects of the metabolic syndrome (METS). Strict glycemic control does not treat PN in METS, and new clinical guidelines instead focus on improving metabolic health by modifying METS components through diet and exercise, though how lifestyle modifications improve PN is unknown. There is a critical need to elucidate the mechanisms underlying PN pathophysiology in METS to establish effective, mechanism-based PN treatments. Metabolically active tissues like muscle and FAT develop insulin resistance (IR) in response to METS; however, diet and/or exercise increase energy consumption and/or decrease IR, reversing METS. Like muscle and FAT, nervous system cells develop IR under METS conditions which is linked to PN in multiple mouse models. We recently reported that dietary reversal (DR) in a high-FAT diet (HFD) mouse model of METS improves PN and corrects PN-induced lipidome and transcriptome changes. Our new preliminary data additionally confirms significant IR in sciatic nerves from this same animal model. Despite our findings in mice and reports of beneficial effects of exercise in individuals with METS and PN, the mechanisms linking improved systemic metabolic health to improved nerve health remain poorly understood. Particularly, the contribution of peripheral nervous system glia, schwann cells (SCS), has not been investigated in metabolically-acquired PN despite the non-cell autonomous nature of PN and a growing importance of SC- axon metabolic crosstalk on nerve health. Our objective is to rigorously evaluate the effects of DR and high- intensity interval training (HIIT) on nerve transcriptomics at a single cell level and on whole nerve bioenergetics, metabolic flux, and function to define the role of neurometabolic coupling and SC-axon metabolic crosstalk in PN. Our central hypothesis is that diet and exercise improve PN by normalizing METS and nerve insulin sensitivity, which restores critical SC-axon metabolic crosstalk and energy substrate transfer from SCS to axons, normalizing peripheral nerve bioenergetics and function. Aim 1 will assess the effects of DR and HIIT on global nerve bioenergetics and PN in HFD METS mice by longitudinally assessing basic metabolic parameters and PN phenotype, performing SC single cell RNA sequencing, and evaluating EX vivo sciatic nerve bioenergetics, energy substrate fluxomics (glycolysis and fatty acid SS-oxidation), and metabolomics. Aim 2 will evaluate SC-axon metabolic crosstalk in in vitro models of METS PN by characterizing SC glycolysis and SS-oxidation, neuron mitochondria dynamics, and global SC-axon bioenergetics. Aim 3 will determine the impact of SC-restricted insulin signaling or energy transfer ablation on PN in HFD METS mice by using inducible SC-restricted insulin receptor/IGF-I receptor or monocarboxylate transporter 1 knockout mice. This research will have a significant impact by elucidating mechanisms underlying how improving systemic metabolic health with diet and exercise in METS patients improves nerve function and ameliorates PN.

Transactions

Action Obligated Date
Amendment $779,340
Amendment Schwann cell senescence and the secretome provide a unifying mechanism for the onset and progression of diabetic neuropathy $0
Amendment $0
Amendment Schwann cell senescence and the secretome provide a unifying mechanism for the onset and progression of diabetic neuropathy $0
Amendment $621,686
Amendment $605,984
Amendment $640,503
Amendment $640,503
Original award $663,188

Subawards

Subrecipient Amount Awarded
University Of North Dakota In this project, the University of North Dakota (UND) Team, led by Dr. Junguk Hur, will perform all bioinformatics, multi-omics integration, and predictive… $207,566
University Of North Dakota In this project, the University of North Dakota Team will be focused on performing bioinformatics analyses on diabetic complication-related high-throughput… $460,654
University Of North Dakota $986,014

Quick answers

Who received award R01DK130913?

R01DK130913 was awarded to Regents Of The University Of Michigan by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on August 23, 2022.

How much is award R01DK130913 worth?

$3,951,204 has been obligated on R01DK130913.

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