Stroke incidence increases with diabetic retinopathy severity and macular edema in type 1 diabetes.

BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.

Bacterial infections as novel risk factors of severe diabetic retinopathy in individuals with type 1 diabetes.

BACKGROUND/AIMS: Diabetic retinopathy (DR) is associated and shares many risk factors with other diabetic complications, including inflammation. Bacterial infections, potent inducers of inflammation have been associated with the development of diabetic complications apart from DR. Our aim was to investigate the association between bacterial infections and DR. METHODS: Adult individuals with type 1 diabetes (n=1043) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. DR was defined as incident severe diabetic retinopathy (SDR), identified as first laser treatment. Data on DR were obtained through fundus photographs and medical records, data on bacterial infections from comprehensive national registries (1 January 1995 to 31 December 2015). Risk factors for DR and serum bacterial lipopolysaccharide (LPS) activity were determined at baseline. RESULTS: Individuals with incident SDR (n=413) had a higher mean number of antibiotic purchases/follow-up year compared with individuals without incident SDR (n=630) (0.92 [95% CI 0.82 to 1.02] vs 0.67 [0.62-0.73], p=0.02), as well as higher levels of LPS activity (0.61 [0.58-0.65] vs 0.56 [0.54-0.59] EU/mL, p=0.03). Individuals with on average ≥1 purchase per follow-up year (n=269) had 1.5 times higher cumulative incidence of SDR, compared with individuals with <1 purchase (n=774) per follow-up year (52% vs 35%, p<0.001). In multivariable Cox survival models, the mean number of antibiotic purchases per follow-up year as well as LPS activity were risk factors for SDR after adjusting for static confounders (HR 1.16 [1.05-1.27], p=0.002 and HR 2.77 [1.92-3.99], p<0.001, respectively). CONCLUSION: Bacterial infections are associated with an increased risk of incident SDR in type 1 diabetes.

Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes.

AIMS: The aim of this study was to investigate whether leisure-time physical activity (LTPA) is associated with the development of severe diabetic retinopathy in individuals with type 1 diabetes. METHODS: Prospective observational analysis as part of the Finnish diabetic nephropathy (FinnDiane) Study with a mean follow-up time of 10.7 years was performed. A total of 1612 individuals with type 1 diabetes were recruited, and LTPA was assessed at baseline using a validated self-report questionnaire. Severe diabetic retinopathy was defined as the initiation of laser treatment due to severe nonproliferative, proliferative retinopathy or diabetic maculopathy (identified from the Care Register for Health Care). RESULTS: A total of 261 patients received laser treatment during the follow-up. Higher frequency of LTPA was associated with a lower incidence of severe diabetic retinopathy (p = 0.024), a finding that remained significant after adjustment for gender, duration, age at onset of diabetes, kidney function, BMI, triglycerides and systolic blood pressure. However, when HbA1c and smoking were added to the Cox regression model the association was no more significant. CONCLUSIONS: Frequent LTPA is associated with a lower incidence of severe diabetic retinopathy during the follow-up. The total amount or the other components of LTPA (intensity or duration of a single session) were not associated with severe diabetic retinopathy.

CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes.

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 × 10-4 for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the ß2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.

Deep Learning Fundus Image Analysis for Diabetic Retinopathy and Macular Edema Grading.

Diabetes is a globally prevalent disease that can cause visible microvascular complications such as diabetic retinopathy and macular edema in the human eye retina, the images of which are today used for manual disease screening and diagnosis. This labor-intensive task could greatly benefit from automatic detection using deep learning technique. Here we present a deep learning system that identifies referable diabetic retinopathy comparably or better than presented in the previous studies, although we use only a small fraction of images (<1/4) in training but are aided with higher image resolutions. We also provide novel results for five different screening and clinical grading systems for diabetic retinopathy and macular edema classification, including state-of-the-art results for accurately classifying images according to clinical five-grade diabetic retinopathy and for the first time for the four-grade diabetic macular edema scales. These results suggest, that a deep learning system could increase the cost-effectiveness of screening and diagnosis, while attaining higher than recommended performance, and that the system could be applied in clinical examinations requiring finer grading.

Variation in SLC19A3 and Protection From Microvascular Damage in Type 1 Diabetes.

The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factors. Because thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesized that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy because they modify an individual's ability to achieve sufficiently high intracellular thiamine levels. We tested 134 single nucleotide polymorphisms (SNPs) in two thiamine transporters (SLC19A2/3) and their transcription factors (SP1/2) for an association with severe retinopathy or nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with a reduced rate of severe retinopathy and the combined phenotype of severe retinopathy and end-stage renal disease. The association for the combined phenotype reached genome-wide significance in a meta-analysis that included the WESDR cohort. These findings suggest that genetic variations in SLC19A3 play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy and may explain why some individuals with type 1 diabetes are less prone than others to develop microvascular complications.

[Update on Current Care Guideline: Diabetic retinopathy]. / Kaypa Hoite-Suosituksen Paivitystiivistelma. Diabeettinen retinopatia.

Good treatment of diabetes decreases the risk of diabetic retinopathy. The goals of the treatment are adequate glucose balance, blood pressure and prevention of metabolic syndrome. Every patient with diabetes should regularly be screened for diabetic retinopathy. Timely and efficient treatment of retinopathy significantly decreases the risk of visual impairment.

Higher age at onset of type 1 diabetes increases risk of macular oedema.

PURPOSE: To investigate whether age at onset of type 1 diabetes is a risk factor for clinically significant macular oedema (CSME). METHODS: A sample of 1354 patients with a mean duration of diabetes 24.6 ± 11.6 years was drawn from the FinnDiane Study population and divided into age at onset groups 0-4 (n = 184), 5-14 (n = 662) and 15-40 years (n = 508). Type 1 diabetes was defined as age at onset ≤40 years, C-peptide negativity and insulin treatment initiated within 1 year of diagnosis. Retinopathy status was assessed from fundus photographs and stereoscopic fundus examinations and graded with the ETDRS scale. RESULTS: After 30 years of diabetes, the estimated cumulative incidences of CSME were 17% (95% CI 11-26) in age at onset group 0-4 years, 27% (95% CI 23-32) in age at onset group 5-14 years and 34% (95% CI 27-41) in age at onset group 15-40 years (p = 0.002, Gray's test). In a competing risks regression model, adjusted for covariates selected with Bayesian information criteria, age at onset 5-14 years (HR 1.89 [95% CI 1.22-2.91], p = 0.004), and age at onset 15-40 years (HR 3.72 [95% CI 2.35-5.89], p < 0.0001), were significant overall risk factors for CSME (p < 0.0001). Higher ETDRS score (HR 1.04 ([95% CI 1.03-1.05], p < 0.0001), HbA1c (HR 1.12 [95% CI 1.02-1.23], p = 0.016), and total cholesterol (HR 1.19 [95% CI 1.04-1.37], p = 0.013) also increased the risk of CSME. CONCLUSIONS: Higher age at onset of type 1 diabetes is a significant risk factor for macular oedema. This suggests that ageing may modify the risk of retinopathy in type 1 diabetes.

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.

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.

Arterial stiffness and vascular complications in patients with type 1 diabetes: the Finnish Diabetic Nephropathy (FinnDiane) Study.

INTRODUCTION/AIMS: While patients with type 1 diabetes (T1D) are known to suffer from early cardiovascular disease (CVD), we examined associations between arterial stiffness and diabetic complications in a large patient group with T1D. METHODS: This study included 807 subjects (622 T1D and 185 healthy volunteers (age 40.6 ± 0.7 versus 41.6 ± 1.2 years; P = NS)). Arterial stiffness was measured by pulse wave analysis from each participant. Furthermore, information on diabetic retinopathy, nephropathy, and CVD was collected. The renal status was verified from at least two out of three urine collections. RESULTS: Patients with T1D without signs of diabetic nephropathy had stiffer arteries measured as the augmentation index (AIx) than age-matched control subjects (17.3% ± 0.6% versus 10.0% ± 1.2%; P < 0.001). Moreover, AIx (OR 1.08; 95% CI 1.03-1.13; P = 0.002) was associated with diabetic laser-treated retinopathy in patients with normoalbuminuria in a multivariate logistic regression analysis. The same was true for AIx and diabetic nephropathy (1.04 (1.01-1.08); P = 0.004) as well as AIx and CVD (1.06 (1.00-1.12); P = 0.01) in patients with T1D. CONCLUSIONS: Arterial stiffness was associated with microvascular and macrovascular complications in patients with T1D.

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.

Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe). METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods. RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively. CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

The cross-sectional associations between sense of coherence and diabetic microvascular complications, glycaemic control, and patients' conceptions of type 1 diabetes.

BACKGROUND: Sense of coherence (SOC) has been associated with various self-care behaviours in the general population. As the management of type 1 diabetes heavily relies on self-management, the SOC concept could also prove important in this population. This paper is a report of a study conducted among patients with type 1 diabetes to assess the associations between SOC and glycaemic control, microvascular complications, and patients' conceptions of their disease. METHODS: Altogether 1,264 adult patients (45% men, age range 18-82 years) with type 1 diabetes participated in this cross-sectional study. SOC was evaluated using a 13-item SOC questionnaire. Standardized assays were used to determine HbA1c. Nephropathy status was based on albumin excretion rate and retinal laser-treatment was used as an indication of severe retinopathy. Patients' subjective conceptions of diabetes were studied using a questionnaire. RESULTS: Higher SOC scores, reflecting stronger SOC, were associated with lower HbA1c values. Strong SOC was independently associated with reaching the HbA1c level <7.5%. Adjusting for diabetes duration, age at onset, socioeconomic status and HbA1c, weak SOC was associated with the presence of nephropathy among men, but not women. No associations were observed between SOC and severe retinopathy. Four dimensions describing patients' conceptions of HbA1c, complications, diabetes control and hypoglycaemia were formed from the diabetes questionnaire. Weak SOC was independently associated with worse subjective conceptions in the dimensions of HbA1c and hypoglycaemia. Furthermore among men, an association between weak SOC and the complications factor was observed. CONCLUSION: Interventions to improve patients' SOC, if available, could improve patients' metabolic control and therefore also reduce the incidence of diabetic complications.

Age at onset and the risk of proliferative retinopathy in type 1 diabetes.

OBJECTIVE: Age at onset of type 1 diabetes influences the risk of microvascular complications. However, the long-term risk of proliferative retinopathy within the wide spectrum of age at onset of type 1 diabetes is less well known. RESEARCH DESIGN AND METHODS: A sample of 1,117 consecutively recruited patients was drawn from the FinnDiane Study population (4,800 patients). Type 1 diabetes was defined as age at onset or=15 years (1.82 [1.40-2.36], P < 0.001). CONCLUSIONS: Age at onset significantly modifies the long-term risk of proliferative retinopathy. The highest risk is in age-at-onset group 5-14 years, whereas the lowest risk is in age-at-onset group 15-40 years.

Health-related quality of life in patients with type 1 diabetes--association with diabetic complications (the FinnDiane Study).

BACKGROUND: The daily treatment of type 1 diabetes with frequent monitoring of blood glucose levels and nuisance caused by insulin administration may affect patients' health-related quality of life (HRQoL). Type 1 diabetes is further burdened with an increased risk of complications which may additionally reduce a patient's HRQoL. We aimed to assess HRQoL and its association with diabetic complications in a large sample of patients with type 1 diabetes. METHODS: Altogether, 1070 patients with type 1 diabetes (46% men, mean age 46 +/- 12 years, diabetes duration 29 +/- 13 years) from the Finnish Diabetic Nephropathy Study (FinnDiane Study) participated in this cross-sectional study. Data on HRQoL were obtained from 1023 patients using the 15D instrument. When studying nephropathy, patients were divided into groups based on their albumin excretion rate. Laser-treated patients were classified as having proliferative retinopathy. RESULTS: The mean 15D score was 0.899 +/- 0.095 with no differences between men and women. HRQoL decreased with increasing age among patients with and without diabetic complications. In the Tobit regression model, macroalbuminuria (-0.036), dialysis (-0.082), renal transplant (-0.053), poor glycemic control (-0.006), ageing (-0.002) and longer diabetes duration (-0.001) explained the reduction in HRQoL. In a corresponding model, the presence of proliferative retinopathy did not have a significant negative influence on HRQoL. Of individual dimensions of the 15D instrument, nephropathy affected all but five dimensions, while retinopathy affected vision, mobility, eating and usual activities. CONCLUSIONS: The 15D scores decreased with increasing age. The presence of nephropathy, but not retinopathy, reduced the subjective HRQoL in patients with type 1 diabetes.

Adult stature and diabetes complications in patients with type 1 diabetes: the FinnDiane Study and the diabetes control and complications trial.

OBJECTIVE: Short adult stature has previously been associated with cardiovascular disease, but its relationship with the microvascular complications of diabetes is uncertain. Therefore, we evaluated the association between adult stature and prevalence and incidence of diabetic microvascular complications. RESEARCH DESIGN AND METHODS: This cross-sectional and longitudinal study comprises 3,968 adult patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and 1,246 adult patients from the Diabetes Control and Complications Trial (DCCT). In FinnDiane, diabetic nephropathy was defined as urinary albumin excretion > or = 300 mg/24 h, dialysis, or renal transplantation. Retinopathy was divided into background and proliferative (laser-treated) retinopathy. In the DCCT, original nephropathy (class 1-6) and retinopathy (Early Treatment of Diabetic Retinopathy Study) classifications were used. RESULTS: In the FinnDiane study, patients in the lowest quartile of adult height had increased risks of prevalent diabetic nephropathy (odds ratio [OR] 1.71, 95% CI 1.44-2.02) and prevalent laser-treated retinopathy (1.66, 1.43-1.93) compared with other patients. Similarly, in the DCCT, patients in the lowest quartile of adult height had increased risks of incident diabetic nephropathy class 4-6 (hazard ratio 2.70, 95% CI 1.59-4.59) and incident proliferative retinopathy (2.06, 1.15-3.71). In the FinnDiane study, the associations were largely explained by childhood exposure to diabetes. However, in the DCCT, where a greater proportion of patients had diabetes onset >18 years, the association with nephropathy was independent of childhood diabetes exposure. CONCLUSIONS: Short adult stature is associated with microvascular complications in patients with type 1 diabetes. These findings are compatible with either childhood diabetes exposure or "common soil" or both as potential explanations.

The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes.

OBJECTIVES: This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. RESULTS: During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2-4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5-1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. CONCLUSIONS: An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.

Metabolic syndrome as a risk factor for cardiovascular disease, mortality, and progression of diabetic nephropathy in type 1 diabetes.

OBJECTIVE: To assess the predictive value of the metabolic syndrome in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients were from the prospective Finnish Diabetic Nephropathy (FinnDiane) Study (n = 3,783): mean age 37 +/- 12 years and diabetes duration 23 +/- 12 years. Metabolic syndrome was defined according to World Health Organization (WHO), National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. Follow-up time was median 5.5 years (interquartile range 3.7-6.7). Mortality data were complete, whereas morbidity data were available in 69% of the patients. RESULTS: The WHO definition was associated with a 2.1-fold increased risk of cardiovascular events and a 2.5-fold increased risk of cardiovascular- and diabetes-related mortality, after adjustment for traditional risk factors and diabetic nephropathy. The NCEP definition did not predict outcomes when adjusted for nephropathy but markedly added to the risk associated with elevated albuminuria alone (P < 0.001). The IDF definition did not predict outcomes. CONCLUSIONS: The metabolic syndrome is a risk factor, beyond albuminuria, for cardiovascular morbidity and diabetes-related mortality in type 1 diabetes.

Effect of parental type 2 diabetes on offspring with type 1 diabetes.

OBJECTIVE: The purpose of this study was to study the association between a parental history of type 2 diabetes and the metabolic profile as well as the presence of the metabolic syndrome and diabetes complications in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a cross-sectional study design in 1,860 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study (620 patients with and 1,240 age-matched patients without a parental history of type 2 diabetes). Information on parental history was received from the type 1 diabetic offspring by a standardized questionnaire. RESULTS: Patients with type 1 diabetes and a positive parental history of type 2 diabetes had a higher prevalence of the metabolic syndrome (44 vs. 38%; P = 0.013) and a metabolic profile related to insulin resistance (higher BMI, larger waist circumference, and higher triglycerides, A1C, and insulin dose per kilogram) and also had a later onset of type 1 diabetes (17.2 +/- 9.2 vs. 16.1 +/- 8.9 years; P = 0.008), which was also confirmed in the publicly available Diabetes Control and Complications Trial data set. In contrast, no association was observed with blood pressure, diabetes complications, or HLA genotype distribution. Parental history of type 2 diabetes was independently associated with age at onset of type 1 diabetes (odds ratio 1.02 [95% CI 1.01-1.03]), BMI (1.07 [1.02-1.12]), triglycerides (1.18 [1.03-1.35]), and insulin dose per kilogram (1.63 [1.04-2.54]). CONCLUSIONS: Parental history of type 2 diabetes is associated with a later onset of type 1 diabetes, the metabolic syndrome, and a metabolic profile related to insulin resistance.