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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 (1986-1988), 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., Conclusions/interpretation: These data confirm the importance of RD, including persistent microalbuminuria, as a marker of mortality risk and suggest that type 1 diabetes patients without renal disease achieve long-term survival comparable to the general population.

Aims/hypothesis: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria., Methods: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study)., Results: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively)., Conclusions/interpretation: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.

Aims/hypothesis: To complete a comparative analysis of studies that have examined the relationship between glycaemia and cardiovascular disease (CVD)/coronary artery disease (CAD) and perform a prospective analysis of the effect of change in glycosylated Hb level on CAD risk in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of childhood-onset type 1 diabetes mellitus (n = 469) over 16 years of two yearly follow-up., Methods: Measured values for HbA(1) and HbA(1c) from the EDC were converted to the DCCT-standard HbA(1c) for change analyses and the change in HbA(1c) was calculated (final HbA(1c) minus baseline HbA(1c)). CAD was defined as EDC-diagnosed angina, myocardial infarction, ischaemia, revascularisation or fatal CAD after medical record review., Results: The comparative analysis suggested that glycaemia may have a stronger effect on CAD in patients without, than in those with, albuminuria. In EDC, the change in HbA(1c) differed significantly between CAD cases (+0.62 +/- 1.8%) and non-cases (-0.09 +/- 1.9%) and was an independent predictor of CAD., Conclusions/interpretation: Discrepant study results regarding the relationship of glycaemia with CVD/CAD may, in part, be related to the prevalence of renal disease. Measures of HbA(1c) change over time show a stronger association with CAD than baseline values.

Aims/hypothesis: We determined whether oxidative damage in collagen is increased in (1) patients with diabetes; (2) patients with diabetic complications; and (3) subjects from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, with comparison of subjects from the former standard vs intensive treatment groups 4 years after DCCT completion., Subjects, Materials and Methods: We quantified the early glycation product fructose-lysine, the two AGEs N (epsilon)-(carboxymethyl)lysine (CML) and pentosidine, and the oxidised amino acid methionine sulphoxide (MetSO) in skin collagen from 96 patients with type 1 diabetes (taken from three groups: DCCT/EDIC patients and clinic patients from South Carolina and Scotland) and from 78 healthy subjects., Results: Fructose-lysine was increased in diabetic patients (p<0.0001), both with or without complications (p<0.0001). Controlling for HbA(1c), rates of accumulation of AGEs were higher in diabetic patients than control subjects, regardless of whether the former had complications (CML and pentosidine given as log(e)[pentosidine]) or not (CML only) (all p<0.0001). MetSO (log(e)[MetSO]) also accumulated more rapidly in diabetic patients with complications than in controls (p<0.0001), but rates were similar in patients without complications and controls. For all three products, rates of accumulation with age were significantly higher in diabetic patients with complications than in those without (all p<0.0001). At 4 years after the end of the DCCT, no differences were found between the previous DCCT management groups for fructose-lysine, AGEs or MetSO., Conclusions/interpretation: The findings suggest that in type 1 diabetic patients enhanced oxidative damage to collagen is associated with the presence of vascular complications.

Aims/hypothesis: Recent findings suggest the potential involvement of adiponectin in obesity, diabetes and cardiovascular disease. We assessed the prospective association between adiponectin concentration and coronary artery disease in individuals with type 1 diabetes., Methods: Participants were identified from the Pittsburgh Epidemiology of Diabetes Complications cohort, a prospective follow-up study of childhood-onset type 1 diabetes. At baseline, subjects had a mean age of 28 years, and a mean diabetes duration of 19 years. Cases (determined by physician-diagnosed angina, confirmed myocardial infraction, stenosis >or=50%, ischemic ECG or revascularization) were matched to the control subjects with respect to sex, age and diabetes duration. Samples and risk factors for analyses were identified from the earliest exam prior to incidence in cases. Sera and information on all covariates were available for 28 cases and 34 control subjects. Proportional hazards models were constructed including matching variables., Results: Compared with those in men, adiponectin concentrations were elevated in females (p=0.009) and among individuals with macroalbuminuria (p=0.04). In multivariable analyses (adjusting for standard risk factors as well as lipoprotein measurements determined by nuclear magnetic resonance spectroscopy, E-selectin or antioxidants), adiponectin inversely predicted the incidence of coronary artery disease (hazard ratio=0.37 per 1 SD increase, 95% CI 0.19-0.73, p=0.004)., Conclusions/interpretation: The results suggest that increased adiponectin concentration is prospectively associated with a lower risk of coronary artery disease type 1 diabetes. The potential of adiponectin determination as a useful marker of, and potential therapeutic target for, coronary artery disease prevention in type 1 diabetes should be further explored.

Aims/hypothesis: Mild cognitive dysfunction is not uncommon in adults with Type 1 diabetes, but its pathogenesis remains unclear. Previous cross-sectional studies had suggested that microangiopathy might affect brain integrity and lead to "central neuropathy." To assess the relationship between changes in cognitive performance and the incidence of new micro- and macrovascular complications, 103 young and middle-aged adults (mean age: 40 yrs) with childhood-onset Type 1 diabetes were followed over a 7-year period, and were compared to 57 demographically-similar adults without diabetes., Methods: All subjects completed a comprehensive battery of neurocognitive tests on two occasions. Diabetic subjects also received repeated medical assessments to diagnose the onset of clinically significant complications., Results: Relative to control subjects, diabetic adults showed significant declines on measures of psychomotor efficiency; no between-group differences were evident on learning, memory, or problem-solving tasks. The development of proliferative retinopathy and autonomic neuropathy during the follow-up period predicted decline in psychomotor speed (p<0.01), as did incident macrovascular complications (p<0.05), systolic blood pressure at follow-up (p<0.01), and duration of diabetes (p<0.01)., Conclusion/interpretation: This study shows that cognitive efficiency may decline over time in diabetic adults, and that this neurocognitive change may be linked, at least in part, to the occurrence of complications like proliferative retinopathy and elevated blood pressure. Therapeutic interventions that reduce the risk of vascular complications may have a similarly beneficial effect on the brain and reduce the risk of neurocognitive dysfunction in diabetic patients.

Aim/hypothesis: To examine whether nuclear magnetic resonance lipoprotein spectroscopy improves the prediction of coronary artery disease in patients with Type 1 diabetes, independently of conventional lipid and other risk factors., Methods: A prospective nested case-control design of subjects with childhood onset Type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study was used. 59 controls were age-, sex- and duration-matched to 59 incident cases of coronary artery disease (fatal or non-fatal myocardial infarction, angina, coronary stenosis >50%) occurring during 10 years of follow-up. Lipid mass and particle concentrations of VLDL, LDL, and HDL subclasses, grouped into three size categories (large, medium, and small), were assessed prior to event with nuclear magnetic resonance spectroscopy., Results: Univariate analyses showed that both lipid mass and particle concentrations of all three VLDL subclasses, small LDL, medium LDL, and medium HDL were increased in CAD cases compared to controls, while large HDL was decreased. Mean LDL and HDL particle sizes were lower in cases. In multivariate models using conventional lipid and non-lipid risk factors, triglycerides and overt nephropathy were the strongest predictors of CAD. Nuclear magnetic resonance measures further improved the prediction, i.e. large HDL particle concentration (OR=0.43, p=0.030), medium HDL mass (OR=3.79, p=0.026) and total VLDL particle concentration (OR=2.33, p=0.033)., Conclusion/interpretation: While these results underscore the importance of triglycerides and overt nephropathy in CAD risk in Type 1 diabetic patients, they also suggest that nuclear magnetic resonance lipoprotein spectroscopy could further refine its prediction and show novel findings concerning HDL subclasses.

The aim of this study was to evaluate factors related to the markedly increased risk of dying from diabetic renal disease in Japanese insulin-dependent diabetic patients compared to those in the USA. The study was based on two population-based cohorts consisting of 1374 cases from Japan and 995 cases from Allegheny County, Pennsylvania, USA, who were diagnosed between 1 January 1965 and 31 December 1979. The living status and dialysis experience were determined as of 1 January 1990. The duration-adjusted renal-failure-related mortality rates in the Japanese cohort and the USA cohort were 277.2 and 130.9 per 100,000 person-years, and the duration-adjusted incidence rates of dialysis were 564.9 and 295.6 per 100,000 person-year, respectively. After adjustment for sex, age at onset, calendar year of onset, and duration of diabetes, individuals with insulin-dependent diabetes in the Japanese cohort were still 2.4-fold more likely to receive dialysis compared to those in the USA cohort. Ten of the 36 renal-failure-related deaths in the Japanese cohort had never been treated by dialysis, while all renal-failure-related deaths in the USA cohort had been treated by dialysis. Survival after initiation of dialysis in the Japanese cohort was virtually the same as the USA cohort. These data suggest that a greater frequency of diabetic end-stage renal disease and reduced access to acceptance at dialysis underlie much of the excess of diabetic renal deaths in Japan.

To examine the long-term effects of recurrent severe hypoglycaemia and other biomedical complications on mental efficiency, a battery of cognitive tests was administered to 142 Type 1 (insulin-dependent) diabetic adult patients (age 33.5 +/- 5.6 years; mean +/- SD) and 100 demographically similar non-diabetic control subjects. All diabetic subjects had been diagnosed before the age of 17 years. Diabetic subjects with one or more complications (distal symmetrical polyneuropathy; advanced background or proliferative retinopathy; overt nephropathy; one or more episodes of severe hypoglycaemia) performed significantly (p < 0.001) more poorly than non-diabetic control subjects on tests requiring sustained attention, rapid analysis of visuospatial detail, and hand eye co-ordination. Regression analyses indicated that the best biomedical predictor of cognitive test performance was a diagnosis of polyneuropathy. Although severe recurrent hypoglycaemia was not associated with performance on any test, the neuropathy x recurrent hypoglycaemia interaction term was significant. These results suggest that in adults with Type 1 diabetes of long duration, recurrent hypoglycaemia does not appear to influence cognitive performance directly, but may interact with neuropathy to exaggerate or otherwise magnify the extent of neurobehavioural dysfunction.

Genetic, immunological and viral factors have been implicated in pathogenesis of Type 1 diabetes mellitus. The development of Type 1 diabetes in two siblings of patients with Type 1 diabetes studied as part of a large epidemiological study, is described. One case, a 13-year-old male not sharing either HLA haplotype with his diabetic sister, had virtually normal glucose tolerance 80 days before symptomatic presentation. He showed serological evidence of infection by Coxsackie CB4 (at diagnosis) and influenza A virus (soon after diagnosis). The other case, a 15-year-old male, had impaired glucose tolerance for over 500 days (i.e., since the diagnosis of diabetes in his HLA-identical brother) before symptomatic presentation which was not associated with serological evidence of acute viral infection. The former case was negative for islet cell antibody (cytoplasmic) when first seen though positive at diagnosis, while the latter was positive throughout. These two cases suggest contrasting interactions of the main pathogenetic factors associated with Type 1 diabetes.

In this report, we present an analysis of glucose and insulin responses during oral glucose tolerance tests in 369 siblings of Type 1 diabetic patients. All have been HLA typed at the A, B and C loci. Though most had normal glucose tolerance by National Diabetes Data Group criteria (92% of the males and 95% of the females), siblings who shared both HLA haplotypes with the diabetic patient in the family had higher mean 3-hour glucose areas than those who shared one or neither HLA haplotype (p less than 0.01). This difference was more marked in males and older siblings. Insulin concentrations did not differ significantly between the two groups except that, for those aged less than 16 years, the group sharing both haplotypes had lower fasting insulin concentrations (p = 0.05); for 16-29 year olds, the corresponding group had marginally higher 3-hour insulin areas than the remainder of siblings (p = 0.17). Little association with specific haplotypes (A1B8 or A2B15) was seen. Multivariate analyses, adjusting for age and obesity, eliminated the 3-h glucose difference in females by HLA sharing status (p = 0.37) although in males it remained significant (p less than 0.001). Failure to account for age, sex and obesity may explain some of the conflicts in the reported literature. The glucose tolerance differences seen by HLA haplotype sharing status did not correlate with the presence of anti-islet cell antibodies. These results are consistent with the hypothesis that the HLA identical siblings, particularly males, have different (i.e. worse) glucose tolerance than their haploidentical and non-HLA identical siblings.

A series of patients having onset of Type I (insulin-dependent) diabetes mellitus before age 17 years was identified from consecutive admissions to the Children's Hospital of Pittsburgh. Family history data were obtained yielding 1006 families (1085 cases) with complete information. The prevalence of diabetes among the children differed by birth order, with a greater number than expected among first born. There was also an increased prevalence among children born to mothers older than 35 years, as well as an increased prevalence among children of very young mothers. The increased prevalence of diabetes among offspring of older mothers was apparent even after life table age corrections were made. However, both the increased prevalence among first born children and the increased prevalence among children of very young mothers could be attributed to an older attained age of these children in this particular population. This indicated that the maternal age effect was present but a birth order effect was absent when age was taken into account.