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Pre-Diabetes Gives Women Head Start on Heart and Diabetes Risk

Feb 27, 2007

The countdown to diabetes and coronary heart disease may start earlier for women with prediabetes than for men.

The "diabetes clock" may start ticking in women years in advance of a medical diagnosis of the disease, new research has shown. Among healthy adults who developed prediabetes during a six-year period, women started off with greater endothelial dysfunction, more hypertension and a greater degree of thrombosis than did men, said Richard P. Donahue, Ph.D., M.P.H., of the State University of New York at Buffalo, and colleagues.



These results support the "ticking clock" hypothesis used to explain the higher coronary heart disease risk seen for women with diabetes than for men with diabetes. This hypothesis says the cardiovascular risk and diabetes may be linked more through longstanding atherogenic risk factors than hyperglycemia alone.

"Although observational studies cannot prove causality, our data add compelling new evidence that the clock may indeed start ticking earlier among women than among men," Dr. Donahue and colleagues wrote.

In the study, female gender was significantly linked to factors emerging as precursors of coronary heart disease and type 2 diabetes, including the endothelial markers E-selectin (P=0.042) and soluble intracellular adhesion molecule-1 (P=0.011), fibrinolysis/thrombosis marker plasminogen activator inhibitor-1 (P=0.001), and frequency of hypertension (P<0.001).
"These novel and important observations support a role for endothelial dysfunction in the progression to pre-diabetes," they added.

The researchers examined these and other factors among 1,455 healthy control subjects from the larger Western New York Health Study of alcohol consumption and cardiovascular risk. None of the participants had pre-diabetes, type 1 or 2 diabetes, or known cardiovascular disease. All were 39 to 79 years old. New-onset prediabetes was defined by normal fasting serum glucose of less than 100 mg/dl at baseline but elevated to between 100 and 125 mg/dl at follow-up a mean of 5.9 years later.

The 52 women and 39 men in the cohort who developed prediabetes were matched to three controls on the basis of sex, ethnicity, and year of study entry. Their frozen blood samples from baseline were used to determine levels of the endothelial markers.

For pre-diabetic women compared with controls, the findings adjusted for age, body mass index and homeostasis model assessment of insulin resistance.

In the same adjusted model, there were no significant differences between pre-diabetic men and their controls. Comparing the pre-diabetic women and men, the significant findings were:

  • Women had higher E-selectin levels (51.2 versus 40.5 ng/ml, P=0.036).
  • Women had higher levels of soluble intracellular adhesion molecule-1 (273.0 versus 254.8 ng/ml, P=0.010).
  • Women had higher plasminogen activator inhibitor-1 levels (34.6 versus 26.8 ng/ml, P=0.001).

The researchers highlighted that insulin resistance "failed to reduce or eliminate the sex differences in the risk factors of interest" though they noted that the measure of insulin resistance used is only modestly correlated with the gold-standard measure of insulin resistance, the hyperinsulinemic-euglycemic clamp method.

Further adjustment for high-sensitivity C-reactive protein levels had no effect, indicating the differences in endothelial function were not moderated by inflammation.

The findings were also unaltered by including weight change, family history of type 2 diabetes, physical inactivity, and use of lipid-lowering medications.

Take Away Information

  • Explain to interested patients that women with diabetes are known to have a higher risk of subsequent coronary heart disease than are men, which this study suggests may be partly due to longstanding endothelial damage.
  • Caution patients that further study will be required to be needed to confirm whether their findings in prediabetes are related to subsequent risk of heart disease.

Donahue RP, et al "Sex Differences in Endothelial Function Markers Before Conversion to Pre-Diabetes: Does the Clock Start Ticking Earlier Among Women?: The Western New York Study" Diabetes Care 2007 30: 354-359.


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