"We find that offspring of type 2 diabetic parents have endothelial dysfunction, even when they do not have diabetes. If early treatment can prevent progression of atherosclerosis, then identifying groups of persons at risk for diabetes in whom early atherosclerosis may be present is clinically important," said Allison B. Goldfine, M.D. from the Joslin Diabetes Center and Brigham and Women's Hospital in Boston, Massachusetts.
None of the 38 adults (mid- to late-30s) in this study had diabetes, but half of them were the offspring of two diabetic parents. The researchers restricted blood flow in the arms of the participants using a blood pressure cuff. Then, using ultrasound, they compared how blood vessels in the arms of participants responded to the surge in blood flow when the cuff was released. Blood vessel responsiveness was impaired in all 19 participants (9 men and 10 women) whose parents had diabetes.
Diabetes is a leading cause of heart disease. Other studies have linked higher blood sugar levels to impaired responsiveness of the lining of blood vessels (endothelial dysfunction); but this is the first study to demonstrate that even when blood sugar is below the diabetic range, modest increases in blood sugar can contribute to endothelial dysfunction. Endothelial dysfunction in this population shows a predisposition to atherosclerosis.
Type 2 diabetes, also known as adult-onset diabetes, is linked to overweight and obesity. However, obesity and other common risk factors, including age, gender, ethnicity, cholesterol, blood pressure and insulin resistance did not explain the differences observed between participants who had a family history of diabetes and those who did not.
"Persons whose parents both have type 2 diabetes have endothelial dysfunction. This predisposition to atherosclerosis is present even when the offspring do not have diabetes themselves. Insulin resistance has been suggested to be important to both the development of diabetes and cardiovascular disease in large populations. However, in this high-risk group, even the most insulin sensitive offspring had diminished endothelial function," Dr. Goldfine said.
The problem seems to be related to the availability of nitric oxide, a key signaling chemical that triggers blood vessel dilation. The researchers reported that there was no difference between the two groups of participants in how much their blood vessels dilated after treatment with nitroglycerin, which boosts nitric oxide levels in the blood.
While physicians already are told to aggressively combat heart disease risk factors in patients with diabetes, the results of this study suggest even apparently healthy people may have blood vessel problems, if they have a strong family history of diabetes. The researchers did not perform genetic analyses of the participants. In this case, family history includes both genetic inheritance and environmental factors.
"Persons with a strong family history of diabetes are at increased risk of atherosclerosis in addition to risk of diabetes. They may benefit from aggressive cardiovascular risk factor modification, including blood pressure and lipid control, weight management and smoking cessation to reduce their risk of heart attack and stroke," Dr. Goldfine said. "Blood sugar levels, even in the non-diabetic range contribute importantly to endothelial dysfunction and thus the atherosclerotic process. This raises the question of when doctors should recommend interventions to lower glucose levels and what should be the appropriate level of glucose recommended to patients with diabetes."
Dr. Goldfine noted that this study included only a small number of participants. However, she said it did a better job than earlier studies of matching the offspring of diabetics to control subjects; so that the effects of family history could be distinguished from the effects of risk factors such as insulin resistance, obesity, cholesterol and blood pressure.
Ann Marie Schmidt, M.D. from Columbia University Medical Center in New York, NY, who was not connected with this study, said the study was "quite informative," particularly the finding that the participants with a family history of diabetes showed signs of impaired endothelial function in their blood vessels even when they were not only free of diabetes itself, but even when they lacked any insulin resistance, which is one key early sign of a type of diabetes.
"These studies point out that genetic, and perhaps environmental, influences, as the groups were all first-degree relatives, critically impact on endothelial function. Although it is tempting to strictly predict genetic differences underlie this finding, the influence of dietary habits, exercise patterns and perhaps environmental exposures cannot be discounted," Dr. Schmidt said. "Taken together, this fascinating study suggests that irrespective of family history, efforts to limit factors leading to insulin resistance may have frank benefits in enhancing endothelial health and integrity."
Dr. Schmidt noted that the study had only a small number of participants. She also pointed out that the participants with a family history of diabetes had higher fasting glucose levels than the participants without a family history of diabetes.
This research was supported by grants from the National Institutes of Health. Dr. Creager is the Simon C. Fireman Scholar in Cardiovascular Medicine at Brigham and Women's Hospital.
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