It is well known that diabetes wreaks havoc on the vascular system. In fact, vascular complications arising from diabetes are the leading cause of blindness, kidney failure and cardiovascular problems in the U.S. And yet, the physiological mechanisms that link diabetes, which afflicts 26 million Americans, to sickly blood vessels are poorly understood.
Researchers have now identified key interactions among two enzymes that may help connect the dots between insulin control and the integrity of blood vessels. The two enzymes work in tandem to regulate the production of nitric oxide, a gas that relaxes blood vessels. The findings, shown in mice, could provide targets for drugs that would be designed to prevent and offset vascular damage.
"Sadly, most people with diabetes will die from vascular complications," says Clay Semenkovich of Washington University in Saint Louis School of Medicine, co-author of the study published January 28 in The Journal of Biological Chemistry. Diabetes contributes to large blood vessel damage associated with common cardiovascular problems such as stroke and heart disease, but diabetes also deteriorates small blood vessels found in the eyes, kidneys and around nerves. "Small-vessel disease is fairly specific for diabetes, while large-vessel disease also occurs in people without diabetes, especially smokers," Semenkovich says.
As a metabolic disease, diabetes causes a cascade of problems, many linked to high blood levels of glucose and lipids. "Increased sugars and fats promote oxidative stress—the production of excessive amounts of oxygen-derived free radicals that can damage blood vessels," according to Semenkovich. The damage manifests as inflammation. Nitric oxide, produced by the enzyme nitric-oxide synthase (NOS), helps reduce inflammation. NOS functions, however, only when attached to a blood vessel's endothelium (inner membrane) by a common fatty acid called palmitate.
"This fatty acid is abundant, so it was assumed that NOS would use any available palmitate to anchor itself to the membrane," Semenkovich says. "Surprisingly, we found that this is not correct," Instead, the researchers found that NOS requires palmitate synthesized by the fatty-acid synthase (FAS), an enzyme that is regulated by insulin. Without FAS, NOS cannot properly attach to the endothelium. People with diabetes have low levels of FAS due to insulin deficiency or resistance, and this FAS deficit may be at the root of their increased vulnerability to blood vessel damage.
The researchers teased out the association by studying knockout mice (genetically engineered to turn off a specific gene) that lack FAS in their endothelial cells. These so-called FASTie mice had normal overall levels of NOS but were deficient in endothelium-attached NOS. Molecular studies confirmed that FAS and NOS physically bind to each other.
FASTie mice had "leaky" blood vessels and impaired angiogenesis, meaning they were less able to restore blood flow after injury to an artery. In people with diabetes defective angiogenesis is implicated in peripheral vascular disease, which often leads to limb amputations.
"These findings provide a surprisingly simple mechanism underlying blood vessel damage in diabetes," Semenkovich says. He suggests that restoring FAS activity would be a novel therapeutic approach to countering vascular damage in diabetes.
"The identification of new treatment for the vascular complications of diabetes is critical since the risk of developing diabetes is increasing at epidemic proportions," says George King, chief scientific officer for the Joslin Diabetes Center in Boston, who was not involved in the study. The role of FAS and lipid abnormalities is an "exciting new idea" in understanding endothelial dysfunction, according to King, but their specific contribution to the microvascular complications of diabetes is less clear.
There are steep hurdles to overcome in upgrading these proof-of-principle findings into therapeutic applications. The diabetic mouse model has not always translated well to humans, and commonly used knockout mice represent an extreme condition. The question remains, King says, "Can you make smaller changes and still be effective?"
What is clear is that the FAS–NOS mechanism is just one of multifarious contributing factors. In addition to investigating causal mechanisms, research teams are also studying protective agents, such as antioxidants, that help the body fight damage.
The difficulty in understanding and treating diabetes-related vascular disease reflects the labyrinthine complexity of diabetes itself. It is a disease that affects a large number of metabolites, which are the foundation of the body's fuels. On top of that, diabetes also affects many tissues, which handle fuel metabolism differently. "It is unlikely that one single pathway will cause all complications," King says.