Prediabetes Gives Women Head Start on Heart and Diabetes Risk

BUFFALO, N.Y., Feb. 22 -- The countdown to diabetes and coronary heart disease may start earlier for women with prediabetes than for men, researchers said here.

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, they wrote in the February issue of Diabetes Care.

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 were:

• Significantly higher soluble intracellular adhesion molecule-1 levels (273.0 versus 254.5 ng/ml, P=0.036).
• Significantly higher plasminogen activator inhibitor-1 (34.6 versus 27.0 ng/ml, P=0.003).
• Significantly more frequent hypertension (44.5% versus 28.8%, P=0.035),
• No difference in waist circumference (P=0.056), inflammatory marker C-reactive protein levels (P=0.056), interleukin-6 (P=0.762), E-selectin (P=0.062), adiponectin (P=0.055), triglycerides (P=0.230), or albumin-to-creatinine ratio (P=0.783).

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.

However, the researchers acknowledged that the study was limited by the single determination of measures of endothelial markers and fasting glucose concentrations used to define pre-diabetes, though they noted their definition is consistent with American Diabetes Association recommendations.

Furthermore, they cautioned that further studies would be needed to confirm whether their findings are related to subsequent risk of heart disease.

"Whether this relates to the higher risk of heart disease among diabetic women awaits further study," they wrote.