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Blocking the Blood Vessel Dysfunctions That Occur in Diabetes

 

Too much circulating sugar and fat can cause the endothelial lining to become inflamed….
Dr. Eric Belin de Chantemele, physiologist at the Medical College of Georgia at Georgia Regents University, stated that, “When the endothelial lining of our blood vessels becomes inflamed and unable to dilate properly, it drives blood pressure up, which multiplies the problem and sets the stage for vascular disease.”
Now researchers suspect a protein, which is already a hot therapeutic target for the prevention of obesity and diabetes, may be one as well for the disabling and potentially deadly endothelial dysfunction.
A new one-year study of human arteries and veins removed during heart surgery will help determine if they’re right.
A major factor in the vascular dysfunction that can result from diabetes as well as obesity and hypertension is reduced production of nitric oxide by the endothelial cells that line blood vessels. This short-lived gas is the body’s most powerful blood vessel dilator, enabling the 60,000-mile vasculature to dilate, and instantaneously increasing blood flow.

Nitric oxide also decreases excretion of cytokines, immune cells that promote inflammation, so less of it means increased blood flow turbulence, which promotes cytokine secretion, so — rather than just attacking invaders such as bacteria — larger numbers of the immune cells attack the blood vessel lining, helping lay a solid foundation for vascular disease.

Belin de Chantemele, lead author in the study, added that that is why blocking PTP1B may help. It’s known that PTP1B expression is increased in the fat, muscle, and livers of people with diabetes. MCG scientists were looking at the effect of PTP1B on the whole body when they noted that mice missing it had higher blood pressure but not the endothelial dysfunction they would expect. They also found that when they induced type 1 diabetes in mice missing the protein, the mice also didn’t experience endothelial dysfunction.

“We know that diabetes increases PTP1B expression in all those tissues, the muscle, the liver, fat, and what we want to see now is if diabetes also increases PTP1B in endothelial cells and if that increased expression leads to the endothelial dysfunction,” Belin de Chantemele said.

Drug companies are having trouble developing PTP1B inhibitors because of side effects from blocking the multipurpose protein. Belin de Chantemele hopes his lab’s additional findings about the roles of PTP1B will aid development of a more targeted inhibitor.

The protein’s laundry list of functions includes controlling the body’s sensitivity to insulin and leptin which is known as the satiety hormone. Although inhibitors cause the body to make less of both, it becomes more sensitive to both. As an example, PTP1B blocks the action of insulin, which basically tells fat, liver, and muscle to take up circulating glucose so it can be used for energy later. When that doesn’t happen as it should, high glucose levels circulating throughout the body damage cells. That’s why PTP1B inhibitors likely will be effective with weight loss and diabetes: people will take up more glucose and have more energy. “If you have more leptin secretion and your brain is less sensitive, you will continue to eat and become more obese,” Belin de Chantemele said.

Practice Pearls:
  • Too much circulating sugar and fat can cause the endothelial lining to become inflamed and cause problems.
  • PTPB1, a protein, which is already a hot therapeutic target for the prevention of obesity and diabetes, may be one as well for the disabling and potentially deadly endothelial dysfunction.
  • PTP1B blocks the action of insulin, which basically tells fat, liver, and muscle to take up circulating glucose so it can be used for energy later.

Adapted media release, from the Medical College of Georgia at Georgia Regents University, Dec 5, 2014.  Funding by the U.S. Diabetic Complications Consortium of the National Institute of Diabetes and Digestive and Kidney Diseases