New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ß1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Health coaching by telephony to support self-care in chronic diseases: clinical outcomes from The TERVA randomized controlled trial.

BACKGROUND: The aim was to evaluate the effect of a 12-month individualized health coaching intervention by telephony on clinical outcomes. METHODS: An open-label cluster-randomized parallel groups trial. Pre- and post-intervention anthropometric and blood pressure measurements by trained nurses, laboratory measures from electronic medical records (EMR). A total of 2594 patients filling inclusion criteria (age 45 years or older, with type 2 diabetes, coronary artery disease or congestive heart failure, and unmet treatment goals) were identified from EMRs, and 1535 patients (59%) gave consent and were randomized into intervention or control arm. Final analysis included 1221 (80%) participants with data on primary end-points both at entry and at end. Primary outcomes were systolic and diastolic blood pressure, serum total and LDL cholesterol concentration, waist circumference for all patients, glycated hemoglobin (HbA1c) for diabetics and NYHA class in patients with congestive heart failure. The target effect was defined as a 10-percentage point increase in the proportion of patients reaching the treatment goal in the intervention arm. RESULTS: The proportion of patients with diastolic blood pressure initially above the target level decreasing to 85 mmHg or lower was 48% in the intervention arm and 37% in the control arm (difference 10.8%, 95% confidence interval 1.5-19.7%). No significant differences emerged between the arms in the other primary end-points. However, the target levels of systolic blood pressure and waist circumference were reached non-significantly more frequently in the intervention arm. CONCLUSIONS: Individualized health coaching by telephony, as implemented in the trial was unable to achieve majority of the disease management clinical measures. To provide substantial benefits, interventions may need to be more intensive, target specific sub-groups, and/or to be fully integrated into local health care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00552903.

Change in retinal blood flow and retinal arterial diameter after intraocular pressure reduction in glaucomatous eyes.

PURPOSE: To study retinal blood flow and vessel diameter after intra-ocular pressure (IOP) reduction in high- and low-pressure glaucomas, that is, exfoliation glaucoma (ExG) and normal-tension glaucoma (NTG). METHODS: The study included 17 eyes with ExG and 20 with NTG. A minimum of 25% IOP reduction was achieved by deep sclerectomy. Blood flow in the temporal peripapillary retina was measured with scanning laser Doppler flowmetry (Heidelberg Retina Flowmeter, HRF), and retinal vessel diameters were evaluated with the retinal vessel analyser (RVA). Examinations were carried out before and 3 months after the operation. RESULTS: Pre-operative IOP was significantly higher in ExG than in NTG (median 26 mmHg, range 20-33 mmHg versus 15 mmHg, 12-20; p < 0.001). Surgery reduced IOP significantly both in ExG eyes (postoperative IOP 13 mmHg, 5-17; p < 0.001) and NTG eyes (9 mmHg, 3-13; p < 0.001). After the operation, systolic retinal flow was significantly reduced in ExG eyes, whereas in NTG, HRF parameters remained unchanged. Pre-operatively, the central retinal artery equivalent (CRAE) and arteriovenous ratio (AVR) were higher in ExG than in NTG eyes. After IOP reduction, both CRAE and AVR were reduced in ExG eyes, but remained unchanged in NTG. CONCLUSION: The study showed that before IOP reduction, arterial diameter was larger in ExG eyes than in NTG eyes. IOP reduction resulted in vasoconstriction and reduction of flow in ExG, whereas in NTG, both vessel diameter and retinal flow remained unchanged.

Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes.

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5-6 short periods of hypoxia each day over 1-3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies.

Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy.

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Decline in the cumulative incidence of severe diabetic retinopathy in patients with type 1 diabetes.

OBJECTIVE: To determine if the cumulative incidence of severe retinopathy in patients with type 1 diabetes has changed. RESEARCH DESIGN AND METHODS: The study looked at 3,781 patients diagnosed with type 1 diabetes (1939-2005), median age at onset 13 (interquartile range [IQR] 9-21) years, and duration of diabetes 19 (IQR 13-27) years. The severe retinopathy was based on a history of laser treatment. Patients were divided into <1975, 1975-1979, 1980-1984, and ≥1985 cohorts according to the diagnosis of diabetes. RESULTS: The cumulative incidence of severe retinopathy has declined (P < 0.0001). After 20 years of duration, the cumulative incidence was 23% (95% CI 21-25) and 33 (30-35) in the earliest cohorts, 18 (15-21) in the next cohort, and 6 (4-9) in the recent cohort. After 30 years, the cumulative incidence was 52 and 48% in the earliest cohorts, while it was 62% after 40 years in the earliest cohort. CONCLUSIONS: The cumulative incidence of severe retinopathy has declined in patients with type 1 diabetes.

Metabolic phenotypes, vascular complications, and premature deaths in a population of 4,197 patients with type 1 diabetes.

OBJECTIVE: Poor glycemic control, elevated triglycerides, and albuminuria are associated with vascular complications in diabetes. However, few studies have investigated combined associations between metabolic markers, diabetic kidney disease, retinopathy, hypertension, obesity, and mortality. Here, the goal was to reveal previously undetected association patterns between clinical diagnoses and biochemistry in the FinnDiane dataset. RESEARCH DESIGN AND METHODS: At baseline, clinical records, serum, and 24-h urine samples of 2,173 men and 2,024 women with type 1 diabetes were collected. The data were analyzed by the self-organizing map, which is an unsupervised pattern recognition algorithm that produces a two-dimensional layout of the patients based on their multivariate biochemical profiles. At follow-up, the results were compared against all-cause mortality during 6.5 years (295 deaths). RESULTS: The highest mortality was associated with advanced kidney disease. Other risk factors included 1) a profile of insulin resistance, abdominal obesity, high cholesterol, triglycerides, and low HDL(2) cholesterol, and 2) high adiponectin and high LDL cholesterol for older patients. The highest population-adjusted risk of death was 10.1-fold (95% CI 7.3-13.1) for men and 10.7-fold (7.9-13.7) for women. Nonsignificant risk was observed for a profile with good glycemic control and high HDL(2) cholesterol and for a low cholesterol profile with a short diabetes duration. CONCLUSIONS: The self-organizing map analysis enabled detailed risk estimates, described the associations between known risk factors and complications, and uncovered statistical patterns difficult to detect by classical methods. The results also suggest that diabetes per se, without an adverse metabolic phenotype, does not contribute to increased mortality.

Intravitreal triamcinolone acetonide as an adjuvant therapy to panretinal photocoagulation for proliferative retinopathy with high risk characteristics in type 1 diabetes: case report with 22 weeks follow-up.

PURPOSE: To describe a new treatment protocol to deliver panretinal photocoagulation that may avoid further deterioration of vision in patients with type 1 diabetes mellitus with proliferative retinopathy with high risk characteristics for severe visual loss and cystoid macular oedema. METHODS: Fundus photography, measurement of foveal thickness with optical coherence tomography and best corrected visual acuity (BCVA) determined by Snellen and ETDRS charts were measured before and after treatment in a 28-year-old man. RESULTS: Over 9 weeks, BCVA improved from 0.05 to 0.25 and the number of letters read at 2 metres from four to 39 after panretinal photocoagulation and adjuvant intravitreal triamcinolone injection under intraconal anaesthesia. Foveal thickness decreased from 691 microm to 239 microm and cysts disappeared by 15 weeks. By 22 weeks, foveal thickness had increased to 282 microm and small cysts had reappeared, but BCVA remained at 0.2 and the number of letters read at 30. CONCLUSION: Proliferative retinopathy regressed, cystoid macular oedema disappeared and vision improved after panretinal photocoagulation and adjuvant intravitreal triamcinolone acetonide injection under intraconal anaesthesia. This represents a feasible option in cases where pain during laser treatment and impairment of vision afterwards due to cystoid macular oedema result in poor compliance with standard laser treatment under topical anaesthesia.