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01-01-2021 | Obesity | Article

Subcellular localisation and composition of intramuscular triacylglycerol influence insulin sensitivity in humans

Authors: Darcy Kahn, Leigh Perreault, Emily Macias, Simona Zarini, Sean A. Newsom, Allison Strauss, Anna Kerege, Kathleen Harrison, Janet Snell-Bergeon, Bryan C. Bergman

Published in: Diabetologia | Issue 1/2021

Abstract

Aims/hypothesis

Subcellular localisation is an important factor in the known impact of bioactive lipids, such as diacylglycerol and sphingolipids, on insulin sensitivity in skeletal muscle; yet, the role of localised intramuscular triacylglycerol (IMTG) is yet to be described. Excess accumulation of IMTG in skeletal muscle is associated with insulin resistance, and we hypothesised that differences in subcellular localisation and composition of IMTG would relate to metabolic health status in humans.

Methods

We evaluated subcellular localisation of IMTG in lean participants, endurance-trained athletes, individuals with obesity and individuals with type 2 diabetes using LC-MS/MS of fractionated muscle biopsies and insulin clamps.

Results

Insulin sensitivity was significantly different between each group (athletes>lean>obese>type 2 diabetes; p < 0.001). Sarcolemmal IMTG was significantly greater in individuals with obesity and type 2 diabetes compared with lean control participants and athletes, but individuals with type 2 diabetes were the only group with significantly increased saturated IMTG. Sarcolemmal IMTG was inversely related to insulin sensitivity. Nuclear IMTG was significantly greater in individuals with type 2 diabetes compared with lean control participants and athletes, and total and saturated IMTG localised in the nucleus had a significant inverse relationship with insulin sensitivity. Total cytosolic IMTG was not different between groups, but saturated cytosolic IMTG species were significantly increased in individuals with type 2 diabetes compared with all other groups. There were no significant differences between groups for IMTG concentration in the mitochondria/endoplasmic reticulum.

Conclusions/interpretation

These data reveal previously unknown differences in subcellular IMTG localisation based on metabolic health status and indicate the influence of sarcolemmal and nuclear IMTG on insulin sensitivity. Additionally, these studies suggest saturated IMTG may be uniquely deleterious for muscle insulin sensitivity.

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Title: Subcellular localisation and composition of intramuscular triacylglycerol influence insulin sensitivity in humans
Authors: Darcy Kahn
Leigh Perreault
Emily Macias
Simona Zarini
Sean A. Newsom
Allison Strauss
Anna Kerege
Kathleen Harrison
Janet Snell-Bergeon
Bryan C. Bergman
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Obesity
Obesity
Insulins
Insulins
Type 2 Diabetes
Published in: Diabetologia / Issue 1/2021
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05315-0

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