Lipid News

Acylcarnitines, a warning signal for Type 2 diabetes

Jessica W. Davidson Judith Simcox
By Jessica W. Davidson and Judith Simcox
March 15, 2022

Type 2 diabetes, or T2D, is a chronic disease characterized by insulin resistance that impacts 34.2 million people in the United States. Another 88 million adults are prediabetic, meaning they likely will develop diabetes if they do not receive preventative care. Risk factors for T2D include aging, genetics and obesity. An estimated 89% of adults diagnosed with T2D between 2013 and 2016 were obese.

Acylcarnitines can be measured in blood plasma using mass spectrometry and are associated with insulin resistance, which can serve as a warning sign for development of Type 2 diabetes.
Acylcarnitines can be measured in blood plasma using mass spectrometry and are associated with insulin resistance, which can serve as a warning sign for development of Type 2 diabetes. With stress such as exercise and cold exposure, insulin signaling helps with rapid fuel switching, making acylcarnitines beneficial in these states.

Irregular lipid metabolism associated with obesity and T2D is termed diabetic dyslipidemia, which includes increased plasma triglycerides and low-density lipoprotein cholesterol. This dyslipidemia occurs in 70% of T2D cases and is associated with higher rates of secondary conditions such as cardiovascular disease. Using mass spectrometry, researchers have found that dyslipidemia is associated with increases in more than 300 lipid species in the plasma, and there is mounting evidence that lipids contribute to T2D as signaling molecules.

Acylcarnitines, one of the lipid classes elevated in plasma with diabetic dyslipidemia, function in transport and signaling. In cells, acylcarnitines are made when a fatty acid is bound to carnitine on the outer mitochondria membrane by the enzyme carnitine palmitoyltransferase 1, or CPT1. Then acylcarnitines are transported into the mitochondria matrix, where they are converted back to free carnitines and fatty acid to be broken down by beta-oxidation for energy production. Acylcarnitines also can evade mitochondrial entry and are exported to the blood plasma.

Plasma acylcarnitines contribute to insulin resistance in obesity and T2D. Mice with genetic loss of CPT1 have lower plasma acylcarnitines and greater insulin sensitivity, while mice with a more active form of CPT1 have higher levels of acylcarnitines and insulin resistance. When Mary-Ellen Harper’s lab at the University of Ottawa treated isolated skeletal muscle cells with acylcarnitines, insulin resistance rapidly developed.

So, why would acylcarnitines signal for insulin resistance?

Plasma acylcarnitines increase in diabetes but also with normal stress such as exercise and cold exposure. Deborah Muoio’s lab at Duke University showed that loss of acylcarnitine processing in muscles leads to exercise intolerance, and work from our lab established that mice with a loss of CPT1 are intolerant to cold. A variant of CPT1 is abundant in Inuit populations of Greenland, Alaska and Canada. Work from our laboratory at the University of Wisconsin–Madison describes how this CPT1 variant is constitutively active, leading to higher acylcarnitine levels, which would be beneficial in response to the cold environment inhabited by the Inuit.

Exertion and cold cause organisms to switch fuel sources rapidly from glucose to lipids. Since insulin stimulates glucose uptake, insulin resistance might be advantageous for the switch to lipids. Acylcarnitine signaling could potentiate insulin resistance to facilitate the fuel transition, but the question is how.

As prediabetes and diabetes prevalence increases, we must identify early warning signs and understand the underlying pathobiology. Acylcarnitines are a piece of the puzzle; questions still loom about their transport and regulation in T2D. Understanding how acylcarnitines signal for insulin resistance and their functional role in normal physiology such as cold stress can hold the key to therapeutic intervention for T2D.

Want more lipid research news?

Check out Lipid Trends, a curated collection of hot picks from the world of lipid research, brought to you by LIPID MAPS.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Jessica W. Davidson
Jessica W. Davidson

Jessica W. Davidson is a graduate researcher in Judith Simcox’s laboratory in the Integrative Program in Biochemistry at the University of Wisconsin–Madison.

Judith Simcox
Judith Simcox

Judith Simcox is an assistant professor in the biochemistry department at the University of Wisconsin–Madison.

Related articles

‘Fatty retina’: A root cause of vision loss in diabetes?
Clay Semenkovich & Rithwick Rajagopal
Targeting cardiolipin modification in a genetic disorder
Arianna F. Anzmann, Olivia Sniezek & Hilary Vernon
Hippocampal lipids linked to brain disorders
Luísa Santa–Marinha & Tiago Gil Oliveira

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

From the journals: JLR
Journal News

From the journals: JLR

Sept. 30, 2022

A new site-specific cholesterol control option and a better way to assess vitamin D status in critical care. Read about papers on these topics recently published in the Journal of Lipid Research.

Living in a bubble
Annual Meeting

Living in a bubble

Sept. 29, 2022

This symposium, Protein Machines and Disorder, will be part of #DiscoverBMB 2023.

Keep your friends close and your RNAs closer
Annual Meeting

Keep your friends close and your RNAs closer

Sept. 29, 2022

This symposium, Regulation of RNA, will be part of #DiscoverBMB 2023.

A membrane ATPase without transporter activity
Journal News

A membrane ATPase without transporter activity

Sept. 28, 2022

A classic article in the Journal of Biological Chemistry reflects on Guido Guidotti’s laboratory and the search for CD39.

The era of “smart” organelles
Annual Meeting

The era of “smart” organelles

Sept. 28, 2022

This symposium, Organelles, Mechanisms and Phase Properties of Cellular Quality Control, will be part of #DiscoverBMB 2023.

Lipids, lipids everywhere!
Annual Meeting

Lipids, lipids everywhere!

Sept. 27, 2022

This symposium, Lipid Dynamics and Signals in Membrane and Protein Structure, will be part of #DiscoverBMB 2023.