New research highlights that small cells lining human blood vessels have a significant role in causing insulin resistance, a critical aspect of metabolic disorders such as diabetes. Traditionally seen as mere structural components, these cells actively influence the insulin response. When their energy supply is diminished, they emit distress signals that provoke inflammation, hindering insulin’s effectiveness.
Although diet, exercise and genetics are well-known factors influencing insulin resistance, which is a crucial part of metabolic disorders such as diabetes, researchers have now identified an overlooked component: endothelial cells.
"These cells, which line the inside of blood vessels, extend beyond mere structural roles to actively modulate the body’s insulin response, presenting new therapeutic possibilities,” explains Erik A. Richter, Professor at the August Krogh Section of Molecular Physiology, University of Copenhagen, Denmark.
Lower than in normal control mice
For tissues to take up glucose, it has to leave the blood, and this happens in the smallest blood vessels: the capillaries. The walls of capillaries comprise a single layer of cells, the endothelial cells. The original purpose of the current study was to investigate the mechanisms by which glucose escapes from the blood to the muscles through the capillaries. Capillaries are the place at which nutrients, oxygen and waste products are exchanged between the blood and tissues.
Previous studies have shown that glucose leaves the capillaries primarily, but not entirely, through small pores or channels between the endothelial cells. However, this is not the only route for glucose uptake, and previous studies estimated that about 25% of the glucose is transported through an unknown mechanism.
“An international colleague had shown that endothelial cells express the glucose transporter GLUT1 and take up glucose, so the question was whether these glucose transporters are the ones carrying out the 25% of the glucose transported by an unknown mechanism,” explains Erik A. Richter.
To answer this question, Erik A. Richter reached out to collaborator Katrien De Bock from ETH Zurich in Switzerland, who provided access to specialised GLUT1 endothelial cell–specific knockout mice. In these mice, the endothelial cells do not express GLUT1. If GLUT1 in endothelial cells is important for transporting glucose across the capillary wall, then the concentration of glucose in the space between the capillaries and the muscle cells – the interstitial space – should be lower than in normal control mice, especially when insulin increases glucose uptake by the muscles.
The results showed that the interstitial glucose concentration was similar in the knockout and the control mice, indicating that GLUT1 in the capillary endothelial cells is not important for transporting glucose out of the capillaries and into muscle. Instead, the glucose leaves the capillaries primarily through pores or slits between the endothelial cells.
However, the new study suggests that endothelial cells have a much more active role in regulating glucose.
Manipulation in mouse models
The researchers were surprised to discover that the knockout mice were insulin resistant in their muscles. It turned out that endothelial cells not expressing GLUT1 rewires their metabolism. The lack of GLUT1 reduces the ability of the endothelial cells to take up glucose, and this causes them to release a substance called osteopontin that activates macrophages – immune cells that act like security guards in muscle tissue – already present in the muscle cells.
This activation causes the macrophages to produce more osteopontin, which is known to cause insulin resistance in animal models. This was also shown in the present study, in which preventing osteopontin secretion from endothelial cells prevented insulin resistance in the GLUT1 knockout mice.
“By manipulating GLUT1 expression in our mouse models, we observed that reduced GLUT1, increased osteopontin production and insulin resistance were directly related,” says Richter.
High-fat diet caused a temporary drop
The new findings showed that GLUT1 reduction triggered the endothelial cells to signal distress, a process known as metabolic reprogramming. This shift, much like changing a car’s fuel from gasoline to electricity, involves the cells switching to alternative energy sources, which ends up intensifying osteopontin production.
“This metabolic reprogramming is like the back-up system of the endothelial cells kicking in under stress, but instead of fixing the problem, it cranks up the distress signals even further,” Richter elaborates. “They are not getting their preferred fuel, and their back-up system makes them send out even more SOS signals, creating a vicious cycle.”
A high-fat diet leading to overeating, even over a short period, exacerbated this process. The high-fat overeating caused a temporary drop in GLUT1 levels, which was enough to initiate the distress signals from endothelial cells, significantly affecting insulin sensitivity. This observation highlights how dietary choices directly affect endothelial cell health and metabolic control.
“Our research found that a short-term high-fat diet caused a rapid but transient decrease in GLUT1, leading to a spike in osteopontin production,” Richter explains. “It is surprising that such a dietary change could cause endothelial cells to send out these distress signals.”
How macrophages respond to osteopontin signals
Once endothelial cells start signalling distress through osteopontin, macrophages respond by releasing inflammatory molecules. This inflammatory response is harmful because it interferes with insulin’s ability to stimulate muscles to absorb glucose, a key process for regulating blood glucose.
“Macrophages act almost like vigilant security guards, always patrolling for signs of trouble in the muscles,” Richter says. “When they detect osteopontin, they respond intensely, sparking inflammation that directly hampers the muscle’s insulin response.”
Osteopontin signalling works through a precise lock-and-key mechanism, with osteopontin acting as the key that binds to a receptor on macrophages called ITGA9. This binding triggers the macrophages’ inflammatory response, which intensifies insulin resistance in muscle tissue.
“It is as if osteopontin is broadcasting on a specific channel, and only these resident macrophages are tuned to pick up the signal,” Richter explains. “This precise lock-and-key interaction opens up potential pathways to block the cascade at the molecular level.”
Calming effect for the endothelial cells
The study conclusively demonstrated that targeting the signalling pathway between endothelial cells and macrophages could help to reduce the inflammatory response that leads to insulin resistance. This finding opens the door for new therapies focusing on blocking or adjusting the harmful signals from stressed endothelial cells to prevent or reduce insulin resistance.
“We found that blocking osteopontin or interfering with its pathway can significantly reduce inflammation and improve insulin sensitivity in muscle tissues,” Richter notes, suggesting a promising target for drug development.
To further explore potential treatments, the researchers also tested supplementing with serine, an amino acid. Serine supplementation calmed the GLUT1-deficient endothelial cells, reducing osteopontin production and breaking the cycle of inflammation. In addition, testing a drug called myriocin, which blocks ceramide production (a type of fat that contributes to inflammation), also effectively reduced insulin resistance.
“Adding serine had a calming effect for the glucose-starved endothelial cells, almost like reassuring them that they did not need to keep signalling distress,” Richter explains. “Both serine and myriocin supplementation helped to break the cycle of insulin resistance, providing multiple potential therapeutic pathways.”
Growing potential for new treatments
These findings suggest that targeting the specific behaviour of endothelial cells could develop new therapeutic targets to manage or prevent insulin resistance more effectively. Treatments could focus on controlling endothelial stress signals such as osteopontin, potentially leading to therapies with fewer-side effects than current insulin-sensitising drugs.
“Looking ahead, we envision a scenario in which therapies could be personalised based on individual endothelial cell health, offering a more targeted and effective approach to managing metabolic health,” Richter forecasts.
“And GLUT1 is quite interesting, because in the brain it is a completely different story. There you need GLUT1 to transport glucose across the endothelial cell barrier,” Richter says.
“The new study shows how the unique roles of GLUT1 vary by tissue type. When we reduced their usual energy source, these cells started sending out SOS signals that led to inflammation and then to insulin resistance. But by calming these cells with certain supplements, we found a way to potentially ease this inflammation and help the body to respond better to insulin.”
