SUMMARY Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-Chi monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/A9, via an interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions and promotes regression. In patients with type I diabetes plasma S100A8/A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and thus promotes atherogenesis in diabetes.

Aims/hypothesis The FinnDiane Study has reported that mortality in type 1 diabetes is not increased over a 7 year follow-up in the absence of renal disease (RD). Using the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study population (n= 658) of childhood-onset type 1 diabetes (age <17 years), the present study sought to replicate and expand these findings to a 20 year follow-up (as of 1 January 2008) and examine cause of death by renal status. Methods At baseline (1986)(1987)(1988), mean age and duration of diabetes were 28 and 19 years, respectively. RD was defined as an albumin excretion rate ≥20 μg/min from multiple samples and grouped as microalbuminuria (MA; 20-200 μg/min), overt nephropathy (ON; >200 μg/min), or end stage renal disease (ESRD; dialysis or renal transplantation). Results At baseline, 311 (47.3%) individuals had RD (MA 21.3%, ON 22.2% and ESRD 3.8%). During a median 20 year follow-up, there were 152 deaths (23.1%). Mortality was 6.2 (95% CI 5.2-7.2) times higher than expected, with standardised mortality ratios of 2.0 (1.2-2.8) for normoalbuminuria (NA); 6.4 (4.4-8.4) for MA; 12.5 (9.5-15.4) for ON; and 29.8 (16.8-42.9) for ESRD. Excluding those (n=64) with NA who later progressed to RD, no significant excess mortality was observed in the remaining NA group (1.2, 0.5-1.9), whose deaths were largely unrelated to diabetes.

BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Background Time trends in overweight and obesity in the general population have been well documented; however, temporal patterns in type 1 diabetes (T1D) have not been thoroughly investigated. We therefore assessed temporal patterns in overweight and obesity and predictors of weight change in 589 individuals from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, a cohort of childhood onset T1D. Methods Participants were first seen in 1986–1988, when mean age and diabetes duration were 29 and 20 years, respectively, and biennially thereafter for 18 years. Overweight was defined as 25≤BMI<30 kg/m2. Obese was defined as a BMI≥30 kg/m2. Results At baseline, the prevalence of overweight and obesity were 28.6% and 3.4%, respectively. After 18 years of follow-up, the prevalence of overweight increased by 47% while the prevalence of obesity increased 7-fold. Seven percent were on intensive insulin therapy (≥3 insulin injections per day or on insulin pump) at baseline; by 2004–2007, this was 82%. Predictors of weight change were a higher baseline HbA1c, symptomatic autonomic neuropathy (inversely), overt nephropathy (inversely), and going onto intensive insulin therapy during follow-up. Conclusion These data demonstrate dramatic weight gain in T1D and underscore the complexity of weight change in this disease.

Significant safety culture variation exists across ICUs of a single hospital. ICU nursing directors tend to overestimate their personnel's attitudes, particularly for teamwork. Culture assessments based on institutional level analysis or director opinion may be flawed.