The relationship between free and bound TBC1D1 and TBC1D4 is a crucial factor for the ability of insulin to increase muscle sugar uptake. At least, that is Rasmus Kjøbsted and colleagues’ theory following their work on the study ‘Illumination of the Endogenous Insulin-Regulated TBC1D4 Interactome in Human Skeletal Muscle’, which has just been published in the May issue of Diabetes.

Rasmus Kjøbsted is currently an assistant professor at the University of Copenhagen’s Department of Nutrition, Exercise and Sports, and he is the last author of the article.

In the study, the researchers investigated - in humans and mice - whether there are muscle enzymes that bind to TBC1D4 that may help explain how TBC1D4 affects the muscles’ ability to take up sugar in the presence of insulin.

“We identified both known and novel TBC1D4 binding partners, a subset of which bound to TBC1D4 in the muscles only in the presence of insulin. One of the binding partners was the related enzyme TBC1D1 and impairments in this enzyme has previously been shown to be associated with severe obesity in humans. Interestingly, we observed in our study that the binding between TBC1D4 and TBC1D1 was compromised in muscles from patients with type 2 diabetes and was affected by age,” says Rasmus Kjøbsted.

The researchers’ current hypothesis - that the relationship between free and bound TBC1D1 and TBC1D4 is a crucial factor in insulin’s ability to increase muscle sugar uptake - has to do with the fact that both aging and type 2 diabetes are associated with an impaired effect of insulin in the muscles (muscle insulin resistance).

As Rasmus Kjøbsted notes, everyone is now well aware of that physical activity is healthy. One of the main reasons is that exercise increases the muscles’ ability to take up sugar, because the muscles become more sensitive to insulin following, for example, a run or a ride. This is also one of the reasons why exercise can prevent the development of type 2 diabetes, a disease in which, among other things, the muscles become worse at reacting to the body’s insulin.

One of the enzymes that are important for the ability of muscles to react normally to insulin is TBC1D4.

“We know this,” says Rasmus, “because a mutation in the TBC1D4 gene has been found in the Inuit population of Greenland and Canada that leads to a loss of TBC1D4 in muscles, and this is associated with poor blood sugar regulation and a 10 times greater risk of developing type 2 diabetes.”

In a previous study published in Diabetes, the research group also showed that the TBC1D4 enzyme enhances muscle insulin sensitivity after a short period of physical activity.

“Basically, we found that mice lacking the TBC1D4 enzyme were worse at taking up sugar into the muscles, because physical activity did not make the muscles more sensitive to insulin,” he explains.

Then comes the obvious question: is it possible to develop a drug targeting TBC1D4 that could help patients? Yes it is, says Rasmus, who has been in contact with a major pharmaceutical company that has made an attempt. Unfortunately, though, it has so far not been possible to make a sufficiently good product. “Therefore, it will likely take a bit of time before such a drug is ready for humans”, he says. “But the potential is there.”

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Read the article in Diabetes here: https://pubmed.ncbi.nlm.nih.gov/35192682/
Illumination of the Endogenous Insulin-Regulated TBC1D4 Interactome in Human Skeletal Muscle
Jeppe K. Larsen, Magnus R. Larsen, Jesper B. Birk, Dorte E. Steenberg, Janne R. Hingst, Kurt Højlund, Alexandra Chadt, Hadi Al-Hasani, Atul S. Deshmukh, Jørgen F.P. Wojtaszewski and Rasmus Kjøbsted
Diabetes 2022;71:906–920 | https://doi.org/10.2337/db21-0855

READ MORE HERE:
https://nexs.ku.dk/english/research/the-august-krogh-section-for-molecular-physiology/

CONTACT:
Assistant Professor Rasmus Kjøbsted
Department of Nutrition, Exercise and Sports
University of Copenhagen
rasmus.kjobsted@nexs.ku.dk
+4535321764