Hulstan_HFD glucose kinetics paper - JCEM - final revised - repository.pdf (1.55 MB)
High-fat overfeeding impairs peripheral glucose metabolism and muscle microvascular eNOS Ser1177 phosphorylation
journal contribution
posted on 2019-10-14, 12:51 authored by Sion Parry, Mark Turner, Rachel Woods, Lewis JamesLewis James, Richard FergusonRichard Ferguson, Matthew Cocks, Katie L Whytock, Juliette A Strauss, Sam O Shepherd, Anton JM Wagenmakers, Gerrit van Hall, Carl HulstonAbstract
Context
The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood.
Objective
To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular eNOS content and activation.
Design
Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS.
Results
High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole body glucose clearance (-16%; P = 0.021) and peripheral insulin sensitivity (-26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion.
Conclusion
High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control.
Funding
National Institute for Health Research (NIHR) Leicester Biomedical Research Centre
History
School
- Sport, Exercise and Health Sciences
Published in
The Journal of Clinical Endocrinology & MetabolismVolume
105Issue
1Pages
1-13Publisher
The Endocrine SocietyVersion
- AM (Accepted Manuscript)
Rights holder
© Endocrine Society 2019Publisher statement
This is a pre-copyedited, author-produced version of an article accepted for publication in The Journal of Clinical Endocrinology & Metabolism following peer review. The version of record PARRY, S. ... et al., (2019). High-fat overfeeding impairs peripheral glucose metabolism and muscle microvascular eNOS Ser1177 phosphorylation. The Journal of Clinical Endocrinology & Metabolism, 105(1), pp. 1-13, is available online at: https://doi.org/10.1210/clinem/dgz018Acceptance date
2019-08-21Publication date
2019-09-12Copyright date
2019ISSN
0021-972XeISSN
1945-7197Publisher version
Language
- en
Depositor
Dr Carl HulstonUsage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC