Aims/hypothesis Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. Methods ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 −/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1(1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.).Results Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 −/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/ mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with nondiabetic WT mice, the degree of the phosphorylation of mitogenactivated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 −/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1-13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8-13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Conclusions/interpretationOverall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with Christoph Thiemermann and Egle Solito contributed equally to this work.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4469-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Our aim was to explore the burden of dementia in the Cretan Aging Cohort, comprised of 3140 persons aged 60 years (56.8% women, 5.8 + 3.3 years formal education, 86.2% living in rural areas) who attended selected primary health-care facilities on the island of Crete, Greece. In the first study phase, a formal diagnosis of dementia had been reached in 4.0% of the participants. However, when selected 505 participants underwent thorough neuropsychiatric evaluation in the second phase of this study (344 with Mini-Mental State Examination [MMSE] <24 and 161 with MMSE 24), and results were extrapolated to the entire cohort, the prevalence of dementia and mild cognitive impairment was estimated at 10.8% (9.7%-11.9%) and 32.4% (30.8%-34.0%), respectively. Using both the field diagnostic data and the extrapolated data, the highest dementia prevalence (27.2%) was found in the 80-to 84year-old group, who also showed the lowest educational level, apparently due to lack of schooling during World War II.

In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM.

Aims/hypothesis Patients with type 1 diabetes and microalbuminuria are at high risk of cardiovascular disease (CVD) and end-stage renal disease. Soluble Klotho is an anti-ageing circulating hormone involved in phosphate metabolism and vascular homeostasis through protective effects on the endothelium and antioxidant actions.

BackgroundThere is an increasing incidence of type 2 diabetes mellitus (T2DM) in young urban South-Asians. We tested the effect of a pragmatic trimonthly lifestyle modification (LSM) programme (P-LSM) versus a less-intensive 12-monthly control LSM (C-LSM) intervention on a primary composite endpoint of predictors of cardio-metabolic disease (new onset T2DM, hypertension, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and markers of cardio-renal disease) in participants aged 5–40 years with risk factors for T2DM.MethodsThis was a randomised controlled trial performed at the National Diabetes Centre, Sri-Lanka. We individually randomised 4672 participants at risk of T2DM, of whom 3539 (mean age 22.5 (range 6–40 years, 48% males) received either trimonthly (P-LSM n = 1726) or 12-monthly (C-LSM n = 1813) peer educator advice aimed at reducing weight, improving diet, reducing psychological stress and increasing physical activity.ResultsDuring a median follow-up of 3 years, the cumulative incidence of the primary endpoint was n = 479 in P-LSM (74 per 1000 person years) vs. 561 in C-LSM (96 per 1000 person years), with an incident rate ratio (IRR) of 0.89 (95% CI 0.83–0.96, P = 0.02). In post hoc analyses, new onset dysglycaemia (T2DM, IFG and IGT), was the major contributor to the composite and was significantly reduced by P-LSM (IRR 0.9, 95% CI 0.83–0.97, P = 0.01). A significant impact of P-LSM on the incidence of the composite endpoint was noted in 1725 participants (P-LSM n = 850, C-LSM n = 875) aged below 18; P-LSM n = 140 (48 per 1000 person years) versus C-LSM n = 174 (55.4 per 1000 person years), with an IRR of 0.83 (95% CI 0.73–0.94, P = 0.004).ConclusionsIn a young at-risk South-Asian population, a pragmatic LSM programme significantly reduces the incidence of predictors of cardio-metabolic disease. Our results highlight the importance of early intervention in young at-risk subjects.Trial registrationWorld Health Organization international clinical trial registry platform (SLCTR/2008/003). Registration Date: March 28, 2008. Retrospectively registered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0905-6) contains supplementary material, which is available to authorized users.

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Summary The prevalence of mild cognitive impairment (MCI) increases among elderly people and is associated with a high risk of dementia. Identifying factors that may contribute to the progress of MCI to dementia is critical. The objective of this study was to examine the association of objective sleep with cognitive performance in MCI patients. A subsample of 271 participants with a diagnosis of probable Alzheimer's disease (AD; N = 50) or mild cognitive impairment (MCI; N = 121) and 100 persons who were not cognitively impaired (NI) were recruited from a large population‐based cohort in the island of Crete, Greece (3140 older adults aged >60 years). All participants underwent extensive neuropsychiatric/neuropsychological evaluation and a 3‐day 24‐hr actigraphy. Objective sleep variables and their association with neuropsychological performance were examined across the three groups, controlling for demographics, body mass index, depression, sleep apnea symptoms and psychotropic medications. Patients with AD had significantly longer 24‐hr total sleep time (TST) compared to the MCI and NI groups. Long 24‐hr TST was associated with reduced performance on tasks that placed significant demands on attention and processing speed in the MCI group and the AD group. Elderly patients with MCI have similar objective sleep duration to normal controls, whereas AD patients sleep longer. Long sleep duration in patients with multidomain subtypes of MCI is associated with critical non‐memory cognitive domains. It appears that within the MCI group those that sleep longer have more severe cognitive impairment.

There is a high prevalence of features and risk of obstructive sleep apnoea in people with diabetic foot ulcers. A STOP-BANG score ≥4 predicts poor diabetic foot ulcer healing. Obstructive sleep apnoea may be a potential, modifiable risk factor/treatment target to improve diabetic foot ulcer outcomes.