Kustaa Hietala

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.

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-β1) 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.

Heritability of proliferative diabetic retinopathy

OBJECTIVE—Diabetic nephropathy clusters in families, suggesting that genetic factors play a role in its pathogenesis. We investigated whether similar clustering exists for proliferative retinopathy in families with two or more siblings with type 1 diabetes. RESEARCH DESIGN AND METHODS—The FinnDiane Study has characterized 20% (4,800 patients) of adults with type 1 diabetes in Finland. In 188 families, there were at least two siblings with type 1 diabetes. Ophthalmic records were obtained for 369 of 396 (93%) and fundus photographs for 251 of 369 (68%) patients. Retinopathy was graded based on photographs and/or repeated ophthalmic examinations using the Early Treatment of Diabetic Retinopathy grading scale. RESULTS—Mean age at onset of diabetes was 14.3 ± 10.2 years, and mean duration was 25.9 ± 11.8 years. Proliferative retinopathy was found in 115 of 369 patients (31%). The familial risk of proliferative retinopathy was estimated in 168 of 188 sibships, adjusted for A1C, duration, and mean blood pressure. Proliferative retinopathy in the probands (48 of 168) was associated with an increased risk (odds ratio 2.76 [95% CI 1.25- 6.11], P = 0.01) of proliferative retinopathy in the siblings of probands (61 of 182). The heritability of proliferative retinopathy was h2 = 0.52 ± 0.31 (P < 0.05). CONCLUSIONS—We found a familial clustering of proliferative retinopathy in patients with type 1 diabetes. The observation cannot be accounted for by conventional risk factors, suggesting a genetic component in the pathogenesis of proliferative retinopathy in 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 HDL2 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 HDL2 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.

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.

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.

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.

Acute hyperglycaemia induces an inflammatory response in young patients with type 1 diabetes.

Background. Patients with type 1 diabetes (T1D) are at a substantially increased risk of cardiovascular disease. Stress-induced hyperglycaemia in turn is shown to worsen the prognosis of patients suffering from an acute myocardial infarction. However, the mechanisms behind these findings are incompletely known. Aim. To investigate whether markers of chronic inflammation, and oxidative stress respond to acute hyperglycaemia in patients with T1D. Methods. The plasma glucose concentration was rapidly raised from 5 to 15 mmol/L in 35 males (22 men with T1D and 13 age-matched non-diabetic volunteers) and maintained for 2 h. All participants were young non-smokers without any signs of diabetic or other complications. Markers of chronic inflammation, and oxidative stress were analysed in serum/plasma samples drawn at base-line and after 120 min of hyperglycaemia. Results. Compared to normoglycaemia, acute hyperglycaemia increased the interleukin (IL)-6 concentrations by 39% in patients with T1D (P<0.01) and 26% in healthy volunteers (P<0.05). During hyperglycaemia the superoxide dismutase concentration was increased by 17% in the healthy volunteers (P<0.01) and 5% in the patients with type 1 diabetes (P=NS). The increase in tumour necrosis factor (TNF)-α was larger in patients with type 1 diabetes than in non-diabetic volunteers (35% versus −10%, P<0.05). Conclusions. This study shows that acute hyperglycaemia induces an inflammatory response in patients with type 1 diabetes.

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.

Arterial stiffness and vascular complications in patients with type 1 diabetes: The finnish diabetic nephropathy (FinnDiane) study

Abstract 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.