2134/9976241.v1
Sion Parry
Sion
Parry
Mark Turner
Mark
Turner
Rachel Woods
Rachel
Woods
Lewis James
Lewis
James
Richard Ferguson
Richard
Ferguson
Matthew Cocks
Matthew
Cocks
Katie L Whytock
Katie L
Whytock
Juliette A Strauss
Juliette A
Strauss
Sam O Shepherd
Sam O
Shepherd
Anton JM Wagenmakers
Anton JM
Wagenmakers
Gerrit van Hall
Gerrit
van Hall
Carl Hulston
Carl
Hulston
High-fat overfeeding impairs peripheral glucose metabolism and muscle microvascular eNOS Ser1177 phosphorylation
Loughborough University
2019
Endocrinology & Metabolism
Clinical Sciences
Paediatrics and Reproductive Medicine
High-fat diet
Glucose kinetics
Skeletal muscle
Insulin signaling
eNOS
2019-10-14 12:51:36
Journal contribution
https://repository.lboro.ac.uk/articles/journal_contribution/High-fat_overfeeding_impairs_peripheral_glucose_metabolism_and_muscle_microvascular_eNOS_Ser1177_phosphorylation/9976241
Abstract
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.