Sex Differences in Endothelial Function Markers Before Conversion to Pre-Diabetes: Does the Clock Start Ticking Earlier Among Women?

Abstract

OBJECTIVE -We examined whether biomarkers of endothelial function, fibrinolysis/ thrombosis and adiponectin, predict the progression from normal to pre-diabetes more strongly among women than men over 6 years of follow-up from the Western New York Health Study. participants from the Western New York Health Study, who were free of type 2 diabetes and cardiovascular disease at baseline (1996 -2001), were selected for reexamination. An incident case of pre-diabetes was defined as fasting glucose Ͻ100 mg/dl at the baseline examination and Ն100 and Ͻ126 mg/dl at the follow-up examination. Biomarkers of endothelial function (E-selectin and soluble intracellular adhesion molecule-1 [sICAM-1]), fibrinolysis/thrombosis (plasminogen activator inhibitor-1 [PAI-1]), and fasting insulin, adiponectin, and inflammation (high-sensitivity C-reactive protein) were measured in frozen (Ϫ190°C) baseline samples. RESEARCH DESIGN AND METHODSRESULTS -Multivariate analyses revealed higher adjusted mean values of biomarkers of endothelial dysfunction (E-selectin and sICAM-1) and fibrinolysis (PAI-1) and lower mean values of adiponectin only among women who developed pre-diabetes compared with control subjects. Formal tests for interaction between sex and case/control status were statistically significant for E-selectin (P ϭ 0.042), PAI-1 (P ϭ 0.001), sICAM-1 (P ϭ 0.011), and frequency of hypertension (P Ͻ 0.001).CONCLUSIONS -These results support the concept that women who progressed from normoglycemia to pre-diabetes have greater endothelial dysfunction than men as well as more hypertension and a greater degree of fibrinolysis/thrombosis. Whether this relates to the higher risk of heart disease among diabetic women awaits further study. Diabetes Care 30:354 -359, 2007D eath rates from coronary heart disease (CHD) in the U.S. have fallen dramatically over the last several decades; however, the rate of decline has been greater among men than among women (1). The factors underlying this sex difference are unclear (2-6). It has also been suggested that women, especially those with type 2 diabetes, are more likely to have coronary microvascular disease than men (7,8). It is well known that diabetic women have a much higher risk for CHD than their male counterparts, a risk not completely explained by traditional biological and psychosocial factors (9,10).Previous studies have shown that the frequency of nonfatal myocardial infarction is increased before the clinical diagnosis of type 2 diabetes (11) and that women with impaired glucose tolerance tend to have a more atherogenic risk profile than their male counterparts years before the diagnosis of clinical diabetes (12). This observation has led to the "ticking clock" hypothesis (13), wherein the elevated CHD risk among diabetic individuals may be due more to their longstanding atherogenic risk profile than to hyperglycemia per se, which is more strongly associated with the risk of microvascular events (14). Recently, attention has been focused on the role of emerging risk factors including ...

Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women’s Heart Health Study

“…The greater relative risk of CHD associated with diabetes in women may be explained by diabetes producing a more adverse change in the coagulation, inflammation and fibrinolytic system than men [14][15][16][17]; or, as explained above, changes in such pathways are simply greater due to a greater deterioration in insulin resistance in women. We examined several markers of inflammation that have been associated with diabetes and CHD including CRP, IL-6 and WBC [13,23], and all showed differing patterns of associations.…”

“…Recent attention has turned to emerging CV risk factors including endothelial dysfunction, inflammation and fibrinolysis, which have been associated with diabetes risk [13]. Women with type 2 diabetes may be subject to even more adverse changes in coagulation, inflammation and vascular function than men [14][15][16][17]. Insulin resistance, a recognised contributor to hyperglycaemia and diabetes precedes the development of diabetes by years and has been associated with increased CVD risk including dyslipidaemia, hypertension, impaired fibrinolysis, inflammation and coagulation [18,19].…”

Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events

“…Several studies have shown that the difference in both traditional and novel cardiovascular risk factor levels in people with and without diabetes is significantly greater in women than in men [26][27][28][29][30][31][32]. Furthermore, in the prediabetic state where glucose tolerance may already be impaired but does not meet all diagnostic criteria of diabetes, risk factor levels are more elevated in women than in men [33,34]. Several studies have suggested that men develop diabetes at a lower BMI compared with women [32,[35][36][37].…”

Gender Difference in Albuminuria and Ischemic Heart Disease in Type 2 Diabetes

“…They suggested that the cause-effect relationships observed in cross sectional studies may be confounded by unknown variables. 44 Donahue et al 45 showed that women who progress from normoglycemia to prediabetes have greater endothelial dysfunction, a greater degree of fibrinolysis/thrombosis, and are more hypertensive than men. 45 It has been shown that women with hypertension have a higher prevalence of other concomitant cardiovascular risk factors.…”