Vitamin D deficiency may exacerbate the excess heart disease risk that people with type 2 diabetes face, a new study in the Aug. 25 Circulation suggests. In lab tests, researchers demonstrate that immune cells with very low vitamin D levels turn into soggy, cholesterol-filled baggage that can become building blocks of arterial plaques.
Carlos Bernal-Mizrachi, an endocrinologist at Washington University School of Medicine in St. Louis, and his colleagues found that people with diabetes seem more susceptible than nondiabetics to the negative cardiovascular effects attributable to a vitamin D shortage. Larger studies may clarify whether the shortage’s effects extend to nondiabetics, Bernal-Mizrachi says.
Previous studies have tied vitamin D deficiency to cardiovascular disease risk, but the cell biology underpinning this link has been gauzy. “Now we’re figuring out the mechanisms behind how this works,” Bernal-Mizrachi says.
The team tested blood samples from 76 obese people, average age 55, who had high blood pressure, type 2 diabetes and low vitamin D levels. As a comparison, the scientists tested blood from 15 similar people who had normal vitamin D levels and another 45 people with normal blood pressure.
From these blood samples, the scientists cultured immune cells called macrophages and exposed the cells to an oxidized form of LDL cholesterol (the bad kind). Because macrophages are immune cleanup crews that normally snag and engulf LDL molecules, this test mimicked the goings-on in the walls of a blood vessel.
But in these tests, macrophages from the type 2 diabetes patients were more likely to absorb LDL cholesterol in excess when they were cultured without vitamin D than when they were bathed in vitamin D.
Macrophages low on vitamin D become indiscriminate devourers, gobbling up too much LDL and transforming into foam cells, core constituents of arterial plaques, Bernal-Mizrachi says.
Foam cells cluster with other debris along the sides of blood vessels, eventually forming a fibrous, collagen cap. If that cap becomes unstable, the plaque ruptures and a blood clot forms — a recipe for a heart attack or stroke.
Macrophages from people without diabetes were much less affected by the presence of vitamin D in this study.
In further experiments, the researchers demonstrated that vitamin D protects the endoplasmic reticulum — an organelle that governs a host of cell functions — from stress in diabetic people. Less stress means the macrophages will display fewer receptor proteins that scavenge oxidized LDL cholesterol. “Vitamin D regulates these receptors,” Bernal-Mizrachi says, and that limits how much LDL cholesterol the macrophage can gobble up.
“The central observation here is that, with vitamin D deficiency, diabetic people have more endoplasmic reticulum stress,” says Alan Tall, an internist at Columbia University. That stress results in the snaring of more LDL cholesterol.
Bernal-Mizrachi and his colleagues also show that this stress triggers an inflammatory response. In an artery that has already formed plaques, this can be deadly, says Tall, because some inflammatory proteins degrade collagen. “Inflammation is linked to cap breakdown,” he says.
Until more data are available, people with diabetes might think about their vitamin D levels, Bernal-Mizrachi says. Vitamin D can be stored up from supplements and short sun exposures, he says, but not getting too much is “a matter of moderation.”