Platelet-derived microvesicles isolated from type-2 diabetes mellitus patients harbour an altered miRNA signature and drive MDA-MB-231 triple-negative breast cancer cell invasion.

The underlying causes of breast cancer are diverse, however, there is a striking association between type 2 diabetes and poor patient outcomes. Platelet activation is a common feature of both type 2 diabetes and breast cancer and has been implicated in tumourigenesis through a multitude of pathways. Here transcriptomic analysis of type 2 diabetes patient-derived platelet microvesicles revealed an altered miRNA signature compared with normoglycaemic control patients. Interestingly, interrogation of these data identifies a shift towards an oncogenic signature in type 2 diabetes-derived platelet microvesicles, with increased levels of miRNAs implicated in breast cancer progression and poor prognosis. Functional studies demonstrate that platelet microvesicles isolated from type 2 diabetes patient blood are internalised by triple-negative breast cancer cells in vitro, and that co-incubation with type 2 diabetes patient-derived platelet microvesicles led to significantly increased expression of epithelial to mesenchymal transition markers and triple-negative breast cancer cell invasion compared with platelet microvesicles from healthy volunteers. Together, these data suggest that circulating PMVs in type 2 diabetes patients may contribute to the progression of triple-negative breast cancer.

Pregnancy glycaemia and cord-blood levels of insulin and leptin in Pakistani and white British mother-offspring pairs: findings from a prospective pregnancy cohort.

AIMS/HYPOTHESIS: To determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants. METHODS: Analyses were undertaken in a prospective pregnancy cohort study of 1,415 women and their singleton live-born infants (629 white British and 786 Pakistani). Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels. Maternal OGTTs were completed at 26-28 weeks of gestation. RESULTS: Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women. Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants, irrespective of ethnicity. Cord-blood leptin levels were 16% (95% CI 6, 26) higher in Pakistani than in white British infants. After adjustment for fasting glucose levels, this difference attenuated to 7% (-3, 16), and with additional adjustment for cord-blood insulin levels it attenuated further to 5% (-4, 14). Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth, as measured by cord-blood leptin levels; on average, 19% of this mediation involved fetal insulin secretion. Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels. Results were very similar when 130 women with gestational diabetes were removed. CONCLUSIONS/INTERPRETATION: These novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants.

Associations of circulating calcium and 25-hydroxyvitamin D with glucose metabolism in pregnancy: a cross-sectional study in European and South Asian women.

BACKGROUND: Vitamin D deficiency is thought to impair insulin action and glucose metabolism; however, previous studies have not examined ethnic differences or the influence of calcium and parathyroid hormone. We investigated this in a cohort of predominantly white European and south Asian women during pregnancy. METHODS: In this cross-sectional study from an urban population in northern England (53.8°N), 1467 women were recruited when undergoing glucose tolerance testing (75 g oral glucose tolerance test) at 26 weeks' gestation. RESULTS: Gestational diabetes mellitus (GDM) was diagnosed in 137 women (9.3%). Median 25-hydroxyvitamin D concentration for the study population was 9.3 ng/mL (interquartile range 5.2, 16.9) and was higher in European [15.2 ng/mL (10.7, 23.5)] than in south Asian women [5.9 ng/mL (3.9, 9.4), P < .001]. After appropriate adjustment for confounders, 25-hydroxyvitamin D showed a weak inverse association with fasting plasma glucose (FPG; mean difference 1.0% per 1 SD; the ratio of geometric means (RGM) 0.99, 95% confidence interval (CI) 0.98, 1.00), and PTH was weakly associated with FPG (RGM 1.01, 95% CI 1.00, 1.02), but neither was associated with fasting insulin, postchallenge glucose, or GDM. Serum calcium (albumin adjusted) was strongly associated with fasting insulin (RGM 1.06; 95% CI 1.03, 1.08), postchallenge glucose (RGM 1.03, 95% CI 1.01, 1.04), and GDM (odds ratio 1.33, 95% CI 1.06, 1.66) but not with FPG. Associations were similar in European and south Asian women. CONCLUSIONS: These findings do not indicate any important association between vitamin D status and glucose tolerance in pregnancy. Relationships between circulating calcium and glucose metabolism warrant further investigation.

Outcomes of pregnancies in women with pre-existing type 1 or type 2 diabetes, in an ethnically mixed population.

OBJECTIVE: To compare the outcomes of pregnancies in women with pre-existing, type 1 and type 2, diabetes and to examine the influence of ethnicity on these outcomes. DESIGN: Prospective cohort study. SETTING: Large district hospital in Yorkshire with an ethnically mixed population. SAMPLE: Case series of all 202 pregnancies in women with pre-existing diabetes, ending in miscarriage, termination of pregnancy or delivery between January 1994 and December 2002. METHODS: Univariate and multivariate logistic regression analysis comparing outcomes in type of diabetes and in ethnic group. MAIN OUTCOME MEASURES: Fetal loss, perinatal and infant mortality and congenital anomaly. RESULTS: All 14 stillbirths and infant deaths and 13 of the 15 congenital malformations were to Asian women. Analysis within this ethnic group showed a very high rate of adverse birth outcome for type 1 diabetic women and for type 2 diabetic women on insulin before the pregnancy. Total pregnancy loss among type 1 diabetic women was 156 per 1000 and among type 2 diabetic women on insulin was 167 per 1000. Congenital abnormality rates were 156 per 1000 for type 1 diabetic women and 261 per 1000 for type 2 diabetic women on insulin. Asian type 2 diabetic women not on insulin prior to pregnancy had significantly better outcomes: Total pregnancy loss was 123 per 1000 and congenital abnormality rate was 32 per 1000. After adjustment for confounders, including type of diabetes, Asian women had significantly worse outcomes (combined perinatal loss and malformation) than Caucasian women [odds ratio (OR) 4.96, 95% confidence interval (CI) 1.16-21.1]. CONCLUSION: Ethnicity has a significant impact on the outcome of diabetic pregnancies, with worse outcomes for babies born to Asian mothers compared with Caucasian mothers. The use of insulin pre-pregnancy rather than type of diabetes appears to predict adverse outcome.