Fetal glucocorticoid overexposure is a key mechanism linking early development with later-life disease. In humans, low birth weight associates with increased fasting cortisol, hypothalamic-pituitary-adrenal (HPA) axis reactivity, and with cardiovascular risk and cognitive decline. As there are sex differences in these adult diseases, we hypothesized that there may be sex differences in programming of the HPA axis in response to prenatal stressors. We conducted a systematic review following Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched Embase, MEDLINE and Web of Science from inception to 31 October 2016. We included studies related to sex differences, prenatal exposures and HPA axis. We excluded studies investigating specific disease states. The 23 included studies investigated the consequences of low birth weight, preterm birth and maternal stressors of asthma, psychosocial stress and glucocorticoid medications on HPA axis outcomes of placental glucocorticoid biology and offspring HPA axis function in early life and later life. Female offspring exposed to stressors had increased HPA axis reactivity compared with males. Furthermore, the female placenta increased its permeability to maternal glucocorticoids following maternal stress with changes in the expression of 11β-hydroxysteroid dehydrogenase enzymes in response to maternal glucocorticoid exposure or asthma. Among males there was some evidence of altered diurnal cortisol secretion. We conclude that although there is some evidence of male vulnerability leading to altered diurnal cortisol secretion, the female HPA axis is more vulnerable to programming, particularly in terms of its reactivity; this suggests a mechanism underlying sex differences in later-life diseases.

Background The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non‐alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non‐invasive markers of fibrosis for risk‐stratification and guiding onward referral. Aims To test the ability of individual fibrosis scores and the European screening algorithm to predict 11‐year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. Methods The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60–75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow‐up, cases of cirrhosis and HCC were identified. Results Forty‐three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk‐stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low‐positive predictive values (5‐46%) and high false‐negative and ‐positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. Conclusions In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

Aims/hypothesis We aimed to determine the association of depression with dementia risk in people with type 2 diabetes, and to explore the possible mediating role of inflammation in this relationship. Methods The Edinburgh Type 2 Diabetes Study is a prospective cohort of 1066 men and women with type 2 diabetes aged 60–75 years. Cox proportional hazards regression analysis was used to investigate the association between depression, assessed at baseline, and subsequent risk of dementia over 10 years. Depression was defined using the Hospital Anxiety and Depression Scale, while incident dementia was defined using medical records, prescription data and death certificates. The potential mediating effect of systemic inflammation was assessed by adjusting models for a generalised inflammation factor, derived from four inflammatory markers measured at baseline (C-reactive protein, IL-6, TNF-α and fibrinogen), and carrying out an exploratory mediation analysis. Results Dementia developed in 105 participants over a median follow-up of 10.6 years. After adjusting for age and sex, depression was associated with over a 2.5-fold increase in risk of dementia (HR 2.59 [95% CI 1.62, 4.15]). Additional adjustment for the generalised inflammation factor and other covariates did not attenuate the size of association between depression and incident dementia and mediation analysis showed that it was not a mediator. Adjusted logistic regression models showed cross-sectional associations of C-reactive protein and IL-6 with depression. Conclusions/interpretation Depression is an important risk factor for dementia in people with type 2 diabetes. Some inflammatory markers were associated with depression, but systemic inflammation does not appear to mediate the relationship between depression and dementia.

Aims/hypothesis Our aim was to determine whether a range of prespecified retinal vessel traits were associated with incident diabetic retinopathy in adults with type 2 diabetes. Methods In the prospective observational cohort Edinburgh Type 2 Diabetes Study of 1066 adults with type 2 diabetes, aged 60–75 years at recruitment, 718 were free from diabetic retinopathy at baseline. Baseline retinal traits including vessel widths, tortuosity (curvature) and fractal dimensions (network complexity), were quantified using fundus camera images and semiautomated software, and analysed using logistic regression for their association with incident diabetic retinopathy over 10 years. Results The incidence of diabetic retinopathy was 11.4% (n = 82) over 10 years. After adjustment for a range of vascular and diabetes-related risk factors, both increased venular tortuosity (OR 1.51; 95% CI 1.15, 1.98; p = 0.003) and decreased fractal dimension (OR 0.75; 95% CI 0.58, 0.96; p = 0.025) were associated with incident retinopathy. There was no evidence of an association with arterial tortuosity, and associations between measurements of vessel widths and retinopathy lost statistical significance after adjustment for diabetes-related factors and vascular disease. Adding venular tortuosity to a model including established risk factors for diabetic retinopathy (HbA1c, BP and kidney function) improved the discriminative ability (C statistic increased from 0.624 to 0.640, p = 0.013), but no such benefit was found with fractal dimension. Conclusions/interpretation Increased retinal venular tortuosity and decreased fractal dimension are associated with incident diabetic retinopathy, independent of classical risk factors. There is some evidence that venular tortuosity may be a useful biomarker to improve the predictive ability of models based on established retinopathy risk factors, and its inclusion in further risk prediction modelling is warranted. Graphical abstract