Diabetes mellitus is a major cause of death and disability worldwide and is a strong risk factor for stroke. Whether and to what extent the excess risk of stroke conferred by diabetes differs between the sexes is unknown. We did a systematic review and meta-analysis to estimate the relative effect of diabetes on stroke risk in women compared with men.
We systematically searched PubMed for reports of prospective, population-based cohort studies published between Jan 1, 1966, and Dec 16, 2013. Studies were selected if they reported sex-specific estimates of the relative risk (RR) for stroke associated with diabetes, and its associated variability. We pooled the sex-specific RRs and their ratio comparing women with men using random-effects meta-analysis with inverse-variance weighting.
Data from 64 cohort studies, representing 775 385 individuals and 12 539 fatal and non-fatal strokes, were included in the analysis. The pooled maximum-adjusted RR of stroke associated with diabetes was 2·28 (95% CI 1·93-2·69) in women and 1·83 (1·60-2·08) in men. Compared with men with diabetes, women with diabetes therefore had a greater risk of stroke-the pooled ratio of RRs was 1·27 (1·10-1·46; I(2)=0%), with no evidence of publication bias. This sex differential was seen consistently across major predefined stroke, participant, and study subtypes.
The excess risk of stroke associated with diabetes is significantly higher in women than men, independent of sex differences in other major cardiovascular risk factors. These data add to the existing evidence that men and women experience diabetes-related diseases differently and suggest the need for further work to clarify the biological, behavioural, or social mechanisms involved.
"been reported to be increased during the course of diabetes (Peters et al., 2014). Moreover, after acute limb ischemia or foot ulcers, diabetics appear to have both higher mortality and an increased rate of amputation (Jeffcoate and Harding, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Impaired angiogenesis and endothelial dysfunction in type 2 diabetes constitute a dominant risk factor for non-healing wounds and most forms of cardiovascular disease. We propose that diabetes shifts the "angiogenic balance" in favor of excessive antiangiogenic phenotype. Herein, we report that diabetes impairs in vivo sponge angiogenic capacity by decreasing VEGF expression/fibrovascular invasion and reciprocally enhances the formation of angiostatic molecules such as thrombospondins, NFκB and FasL. Defective in vivo angiogenesis prompted cellular studies in cultured endothelial cells derived from subcutaneous sponge implants (SIECs) of control and Goto-Kakizaki rats. Ensuing data in diabetic SIECs, demonstrated a marked up-regulation in cAMP-PKA-CREB signaling, possibly stemming from increased and decreased expression of adenylyl cyclase isoforms 3/8 and PDE3, respectively. Mechanistically, we found that oxidative stress and PKA activation in diabetes enhanced CREM/ICERs expression. This reduces IRS2 cellular content by inhibiting CRE transcriptional activity. Consequently, a decrease in the activity of Akt-mTOR is ensued with a concomitant reduction in total and nuclear protein levels of HIF-1α. Limiting HIF-1α availability for the specific HREs in diabetic SIECs elicited a marked reduction in VEGF expression, both at the mRNA and protein levels. These molecular abnormalities were illustrated functionally by a defect in various proangiogenic properties including cell proliferation, migration and tube formation. A genetic-based strategy in diabetic SIECs using CREM/ICER siRNA significantly augmented the PKA-dependent VEGF expression. To this end, the current data identify the criticality of CREM/ICER as a negative regulator of endothelial function and establish a link between CREM/ICER overexpression and impaired angiogenesis during the course of diabetes. Moreover, it may also offer CREM/ICERs as a potential therapeutic target in the treatment of pathological angiogenesis in diseases such as diabetes and cancer.
"This translates to a 44% greater increase in relative risk for coronary heart disease in women with diabetes compared to men . A second meta-analysis examining 64 cohorts with 777,385 individuals by the same author showed a 25% increase in relative risk for stroke in women compared with men with diabetes  emphasizing the differential effects of diabetes on vascular health in women compared with men. The authors further suggest that this difference may be secondary to differences between men and women in level of metabolic changes needed to occur prior to sufficient impairment in glucose tolerance in women for the diagnosis of diabetes, thus more women spend a greater amount of time in the pre-diabetic state when compared with men . "
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