To identify genetic predictors of diabetes-associated ED using genome
wide and candidate gene approaches in a cohort of men with type I
We examined 528 white men with T1D (125 with ED) from the DCCT and
its observational follow up EDIC Study. ED was defined from a single item of
the IIEF. An Illumina Human1M BeadChip was used for genotyping. 867,125
single nucleotide polymorphisms (SNPs) were subjected to analysis. Whole
genome and candidate gene approaches tested the hypothesis that genetic
polymorphisms may predispose men with T1D to ED. Univariate and multivariate
models were used controlling for age, HbA1c, diabetes duration, and prior
randomization to intensive or conventional insulin therapy during DCCT. A
stratified false discovery rate was used to perform the candidate gene
Two SNPs located on chromosome 3 in one genomic loci were associated
with ED with p < 1×10−6. rs9810233 had a
p-value of 7 × 10−7 and rs1920201 had a p-value
of 9×10−7 The nearest gene to these two SNPs is
ALCAM. The genetic association results at these loci were similar in
univariate and multivariate analysis. No candidate genes met criteria for
Two SNPs, rs9810233 and rs1920101, which are 25 kb apart, are both
associated with ED, albeit not meeting the standard GWAS significance
criteria of p < 5 × 10−8. Other studies with
larger sample sizes will be required to determine whether ALCAM represents a
novel gene in the pathogenesis of diabetes associated ED.
Erectile Dysfunction; Diabetes; Genetics
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study has sustained an extraordinarily high level of participant involvement for over two decades.
In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants.
Confidential questionnaires were completed during EDIC Years 15–17. Participants were classified as Completely Adherent (completed all visits), Partly Adherent (missed >1 visit or major portion of a visit), or Inactive (did not participate for >5 years). Questionnaire items addressed specific aspects of clinic visits, evaluation procedures, staff–participant relationships, and medical/health-care support provided by EDIC.
The most commonly cited reasons for continuing participation were Cutting Edge Tests to assess diabetes complications (79.3%), Annual Evaluations (67.7%), a desire to Help Others (65.2%), and Better Care for Diabetes (61.6%). Women chose Cutting Edge Tests as their first or second most important reason significantly more often than men, whereas men chose Better Care for Diabetes more frequently. Individuals with at least three diabetes-related complications were more likely than those with fewer complications to choose Annual Evaluations as their first or second reason for continued involvement.
The small proportion of individuals who discontinued participation restricted our ability to identify factors associated with suspended involvement. In addition, our analysis is limited to a cohort with type 1 diabetes followed in an observational study after an average participation time of 6.5 years in a randomized trial.
The primary reasons identified by respondents for their long-term commitment are consistent with shorter-term studies and underscore the importance of expert medical care, supportive staff–participant relationships, and involvement with clinically and scientifically meaningful research.
Haptoglobin (Hp) is an abundant serum protein which binds extracorpuscular hemoglobin (Hb). Two alleles exist in humans for the Hp gene, denoted 1 and 2. Diabetic individuals with the Hp 2-2 genotype are at increased risk of developing vascular complications including heart attack, stroke, and kidney disease. Recent evidence shows that treatment with vitamin E can reduce the risk of diabetic vascular complications by as much as 50% in Hp 2-2 individuals. We sought to develop a rapid and accurate test for Hp phenotype (which is 100% concordant with the three major Hp genotypes) to facilitate widespread diagnostic testing as well as prospective clinical trials.
A monoclonal antibody raised against human Hp was shown to distinguish between the three Hp phenotypes in an enzyme linked immunosorbent assay (ELISA). Hp phenotypes obtained in over 8000 patient samples using this ELISA method were compared with those obtained by polyacrylamide gel electrophoresis or the TaqMan PCR method.
Our analysis showed that the sensitivity and specificity of the ELISA test for Hp 2-2 phenotype is 99.0% and 98.1%, respectively. The positive predictive value and the negative predictive value for Hp 2-2 phenotype is 97.5% and 99.3%, respectively. Similar results were obtained for Hp 2-1 and Hp 1-1 phenotypes. In addition, the ELISA was determined to be more sensitive and specific than the TaqMan method.
The Hp ELISA represents a user-friendly, rapid and highly accurate diagnostic tool for determining Hp phenotypes. This test will greatly facilitate the typing of thousands of samples in ongoing clinical studies.
diabetes; ELISA; haptoglobin phenotype; pharmacogenomics; vitamin E
The DCCT/EDIC (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications) provides a comprehensive characterization of the natural history of diabetic neuropathy in patients with type 1 diabetes and provides insight into the impact of intensive insulin therapy in disease progression. The lessons learned about the natural history of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy and the impact of glycemic control on neuropathy are discussed in this review.
Distal symmetrical polyneuropathy; Cardiovascular autonomic neuropathy; Nerve conduction studies; Heart rate variability studies; Glycemic control
We report relationships of cardiovascular disease (CVD) risk factors with myocardial structure, function and scar in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.
METHODS and RESULTS
Cardiac magnetic resonance (CMR) was obtained in 1017 patients with type 1 diabetes. Gadolinium CMR was also obtained in 741 patients. The mean age was 49 ± 7 years, 52% were men, and mean diabetes duration was 28± 5 years. Associations of CVD risk factors with CMR parameters were examined using linear and logistic regression models. History of macroalbuminuria was positively associated with LV mass (by +14.8 g) leading to a significantly higher LV mass/EDV ratio (by 8%). Mean hemoglobin A1c (HbA1c) levels over the preceding 22 years were inversely associated with end-diastolic volume (−3.0 ml per unit mean HbA1c %) and stroke volume (−2.3 ml per unit mean HbA1c %) and positively related to elevated LV mass/EDV ratio (0.02 g/ml per unit). The overall prevalence of myocardial scar was 4.3% by CMR and 1.4% by clinical adjudication of myocardial infarction. Both mean HbA1c (Odds ratio (O.R.) 1.5 [1.0–2.2] per unit) and macroalbuminuria (OR 3.5 [1.2–9.9]) were significantly associated with myocardial scar as well as traditional CVD risk factors.
In addition to traditional CVD risk factors, elevated mean HbA1c and macroalbuminuria were significantly associated with alterations in LV structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function.
Myocardial function; myocardial scar; type 1 diabetes; delayed enhancement; CMR
Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes. Long-term outcomes after the development of microalbuminuria are variable.
We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the DCCT/EDIC Study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed during the observational EDIC Study. During DCCT/EDIC, 325 participants developed incident persistent microalbuminuria (albumin excretion rate [AER] ≥ 30 mg/24hr on two consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (AER ≥ 300 mg/24hr x2), impaired glomerular filtration rate (estimated GFR < 60 mL/min/1.73m2 x2), and end stage renal disease (ESRD), and regression to normoalbuminuria (AER < 30 mg/24hr x2).
Median follow-up after persistent microalbuminuria diagnosis was 13 years (maximum 23 years). 10-year cumulative incidences of progression to macroalbuminuria, impaired GFR, and ESRD and regression to normoalbuminuria were 28%, 15%, 3%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower hemoglobin A1c, lack of retinopathy, female gender, lower blood pressure, and lower concentrations of LDL cholesterol and triglyceride. Lower hemoglobin A1c, lack of retinopathy, and lower blood pressure were also associated with decreased risk of impaired GFR.
After the development of persistent microalbuminuria, progression and regression of kidney disease each occur commonly. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.
This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT).
RESEARCH DESIGN AND METHODS
A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device.
Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 mm less (P = 0.048); but change from years 6 to 12 was similar (intensive − conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression.
Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6–12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis.
To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy.
RESEARCH DESIGN AND METHODS
VPT was determined in 1,177 adults with type 1 diabetes 13–14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction).
Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71–0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy.
VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest.
To determine whether intensive glycemic therapy reduces the risk of erectile dysfunction (ED) in men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT).
MATERIALS AND METHODS
DCCT randomized 761 males with type 1 diabetes to intensive or conventional glycemic therapy in 28 sites between 1983–1989, of whom 366 had diabetes for 1–5 years and no microvascular complications (primary prevention cohort) and 395 for 1–15 years with non-proliferative retinopathy or microablbuminuria (secondary intervention cohort). Subjects were treated until 1993 and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In 2003, we conducted an ancillary study using a validated assessment of ED in 571 men (80% participation rate); 291 in the primary cohort and 280 in the secondary cohort.
Twenty-three percent of participants reported ED. The prevalence was significantly lower in the intensive versus conventional treatment group in the secondary cohort (12.8% versus 30.8%, p=0.001); but not the primary cohort (17% versus 20.3%, p=0.49). The risk of ED in both primary and secondary cohorts was directly associated with mean HbA1c during DCCT and EDIC combined. Age, peripheral neuropathy, and lower urinary tract symptoms were other risk factors.
A period of intensive therapy significantly reduced the prevalence of ED ten years later among those in the secondary intervention cohort, but not the primary prevention cohort; higher HbA1c was significantly associated with risk in both cohorts. These findings provide further support for early implementation of intensive insulin therapy in young men with type 1 diabetes.
Glycemic Control; Diabetes; Erectile Dysfunction; Risk
This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).
RESEARCH DESIGN AND METHODS
Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.
A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.
Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.
The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT).
RESEARCH DESIGN AND METHODS
During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents.
During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).
Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.
To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13–14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels.
RESEARCH DESIGN AND METHODS
Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves.
The prevalence of neuropathy increased 13–14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84–1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy.
The benefits of former intensive insulin treatment persisted for 13–14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.
Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.
RESEARCH DESIGN AND METHODS
We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.
We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 × 10−10), which was also associated with mean glucose (P = 2 × 10−5). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.
A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive (INT) and conventional (CONV) therapy subjects13-to-14 (13/14) years after DCCT closeout.
Methods and Results
DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1,226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjusting for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in former INT group vs. former CONV group (28.9 vs. 35.2%; P = 0.018). Adjusted R-R variation was significantly greater in former DCCT INT vs. former CONV group (29.9 vs.25.9, P < 0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% [odds ratio(95% CI) 0.69 (0.51–0.93)] and of incident abnormal R-R variation by 30% [odds ratio(95%CI) 0.70 (0.51–0.96)] in EDIC year 13/14.
Although CAN prevalence increased in both groups, the incidence was significantly lower in former INT group compared to former CONV group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.
type 1 diabetes mellitus; cardiac autonomic neuropathy; nervous system autonomic; intensive glucose control; metabolic memory
To determine risk factors for and long-term effects of glycemic control on urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
The Diabetes Control and Complications Trial (1982 to 1993) cohort follow-up, EDIC, began in 1994. In 2004, women participants (N=550), completed a self-administered questionnaire on incontinence. Our primary outcome was ≥ weekly incontinence, overall and by type. Multivariable regression models were used to determine independent predictors of weekly UI, both overall and by type.
Overall, 38% of women reported any incontinence and 17% reported ≥ weekly incontinence. Increasing body mass index (Odds Ratio (OR) 1.1 per kg/m2, 95% Confidence Interval (CI) 1.1−1.2) was significantly associated with weekly incontinence, overall and by type. Advancing age and two or more urinary tract infections in the prior year were associated with weekly urge incontinence (OR 1.4, 95% CI 1.0−2.0 per 5 years; OR 4.9, 95% CI 1.8−13.5, respectively). There was weaker evidence for increased risk with age for overall weekly incontinence (22% per 5 years, p=0.06) and stress incontinence (21 % per 5 years, p=0.08)
Urinary incontinence is common among women with type 1 diabetes and risk factors including advancing age, increased weight, and prior urinary tract infection are important. Weight reduction and treatment of urinary tract infections may have the additional benefit of preventing incontinence or reducing its severity.
Risk Factors; Urinary Incontinence; Type 1 Diabetes
Levels of lipoprotein (a) [Lp(a)], apolipoprotein (apo) B, and lipoprotein cholesterol distribution using density-gradient ultracentrifugation were measured as part of a cross-sectional study at the final follow-up examination (mean 6.2 years) in the Diabetes Control and Complications Trial. Compared with the subjects in the conventionally treated group (n = 680), those subjects receiving intensive diabetes therapy (n = 667) had a lower level of Lp(a) (Caucasian subjects only, median 10.7 vs. 12.5 mg/dl, respectively; P = 0.03), lower apo B (mean 83 vs. 86 mg/dl, respectively; P = 0.01), and a more favorable distribution of cholesterol in the lipoprotein fractions as measured by density-gradient ultracentrifugation with less cholesterol in the very-low-density lipoprotein and the dense low-density lipoprotein fractions and greater cholesterol content of the more buoyant low-density lipoprotein. Compared with a nondiabetic Caucasian control group (n = 2,158), Lp(a) levels were not different in the intensive treatment group (median 9.6 vs. 10.7 mg/dl, respectively; NS) and higher in the conventional treatment group (9.6 vs. 12.5 mg/dl, respectively; P less than 0.01). No effect of renal dysfunction as measured by increasing albuminuria or reduced creatinine clearance on Lp(a) levels could be demonstrated in the diabetic subjects. Prospective follow-up of these subjects will determine whether these favorable lipoprotein differences in the intensive treatment group persist and whether they influence the onset of atherosclerosis in insulin-dependent diabetes.
Adolescent; Adult; African Continental Ancestry Group; Apolipoproteins B; Blood Glucose; Cholesterol; Cholesterol; LDL; Diabetes Mellitus; Type 1; Diabetes Mellitus; Type 1; European Continental Ancestry Group; Female; Follow-Up Studies; Hemoglobin A; Glycosylated; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Probability; Reference Values; Sex Characteristics; Triglycerides
Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM.
An analysis of the cumulative incidence of long-term complications was performed. The DCCT (1983-1993) assigned patients to conventional or intensive therapy. Since 1993, the DCCT has been observational, and intensive therapy was recommended for all patients. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study is an observational study of patients with T1DM from Allegheny County, Pennsylvania. The study population comprised the DCCT T1DM cohort (N=1441) and a subset of the EDC cohort (n=161) selected to match DCCT entry criteria. In the DCCT, intensive therapy aimed for a near-normal glycemic level with 3 or more daily insulin injections or an insulin pump. Conventional therapy, with 1 to 2 daily insulin injections, was not designed to achieve specific glycemic targets. Main outcome measures included the incidences of proliferative retinopathy, nephropathy (albumin excretion rate >300 mg/24 h, creatinine level ≥2 mg/dL [to convert to micromoles per liter, multiply by 88.4], or renal replacement), and cardiovascular disease.
After 30 years of diabetes, the cumulative incidences of proliferative retinopathy, nephropathy, and cardiovascular disease were 50%, 25%, and 14%, respectively, in the DCCT conventional treatment group, and 47%, 17%, and 14%, respectively, in the EDC cohort. The DCCT intensive therapy group had substantially lower cumulative incidences (21%, 9%, and 9%) and fewer than 1% became blind, required kidney replacement, or had an amputation because of diabetes during that time.
The frequencies of serious complications in patients with T1DM, especially when treated intensively, are lower than that reported historically.
To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GFR was measured as the renal clearance of (125I)iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation (CV)) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (>90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (<13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (intertest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median intertest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice. The usefulness of GFR measurements in practice depends, in part, on the results of these and other ongoing clinical trials investigating therapeutic interventions to prevent the onset or retard the progression of renal disease.
Renal function; GFR; diabetes; chronic renal disease; clinical trial
The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N∊-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30–32% lower furosine, 9% lower pentosidine, 9–13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0 .006–0.001) and also of the secondary intervention cohort (P < 0.015–0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c).
This study aimed to investigate the prevalence and risk factors associated with sexual dysfunction in a well-characterized cohort of women with type 1 diabetes.
RESEARCH DESIGN AND METHODS
The study was conducted in women enrolled in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study, a North American study of men and women with type 1 diabetes. At year 10 of the EDIC study, 652 female participants were invited to complete a validated self-report measure of sexual function, standardized history and physical examinations, laboratory testing, and mood assessment.
Of the sexually active women with type 1 diabetes in the EDIC study, 35% met criteria for female sexual dysfunction (FSD). Women with FSD reported loss of libido (57%); problems with orgasm (51%), lubrication (47%), and arousal (38%); and pain (21%). Univariate analyses revealed a positive association between FSD and age (P = 0.0041), marital status (P = 0.0016), menopausal status (P = 0.0019), microvasculopathy (P = 0.0092), and depression (P = 0.0022). However, in a multivariate analysis, only depression (P = 0.004) and marital status (P = 0.003) were significant predictors of FSD.
FSD is common in women with type 1 diabetes and affects all aspects of sexual function and satisfaction. Depression is the major predictor of sexual dysfunction in women with type 1 diabetes. These findings suggest that women with type 1 diabetes should be routinely queried about the presence of sexual dysfunction and possible co-association with depression.
Male sexual dysfunction is a common complication of diabetes (DM), but the relative impact of erectile dysfunction (ED), orgasmic dysfunction (OD), and/or decreased libido (DL) on global sexual bother has not been assessed.
To assess the relationship between ED, OD, and DL and overall sexual satisfaction in men with type 1 DM, and determine which form of dysfunction causes the most bother.
The study cohort consisted of 713 men with type 1 DM who completed the Diabetes Control and Complication Trial and then participated in the follow-up Epidemiology of Diabetes Interventions and Complications Study. In year 10 of EDIC, 583 (83%) completed a validated instrument assessing ED, OD, and DL and the bother these conditions cause. Statistical tests determined the concordance of function and bother in each domain, and the impact of each domain on overall sexual satisfaction.
Main Outcome Measures
Patient-reported outcomes using responses to individual items of the International Index of Erectile Function (IIEF).
ED was present in 34%, OD in 20%, and DL in 55%. When correlated with overall sexual satisfaction, ED had the highest weighted kappa (0.84, 95% confidence interval [CI] = 0.80–0.87), while OD (0.57, 95% CI = 0.51–0.63) and DL (0.55, 95%CI = 0.48–0.62) were considerably lower. Furthermore, the single item assessing confidence in getting and keeping an erection had the strongest correlation with overall sexual bother as well as specific erectile bother.
ED, OD, and DL are highly prevalent in men with long-standing type I diabetes. All three sexual dysfunctions cause bother in men with DM, but ED causes more general sexual bother and likely has a greater overall impact on quality of life. Our data underscore the importance of asking men with DM about their sexual function and point to the need for further research to investigate disorders of orgasm and desire.
Male Sexual Dysfunction; Diabetes; Erectile Dysfunction; Questionnaire
Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants.
RESEARCH DESIGN AND METHODS
Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression.
Of the 591 men who completed the AUASI questions, nearly 20% (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score ≥8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 EDIC (UroEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS.
These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort.
The Genetics of Kidneys in Diabetes (GoKinD) study is an initiative that aims to identify genes that are involved in diabetic nephropathy. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents also were enrolled to form family trios. As of November 2005, GoKinD included 3075 participants who comprise 671 case singletons, 623 control singletons, 272 case trios, and 323 control trios. Interested investigators may request the DNA collection and corresponding clinical data for GoKinD participants using the instructions and application form that are available at http://www.gokind.org/access. Participating scientists will have access to three data sets, each with distinct advantages. The set of 1294 singletons has adequate power to detect a wide range of genetic effects, even those of modest size. The set of case trios, which has adequate power to detect effects of moderate size, is not susceptible to false-positive results because of population substructure. The set of control trios is critical for excluding certain false-positive results that can occur in case trios and may be particularly useful for testing gene—environment interactions. Integration of the evidence from these three components into a single, unified analysis presents a challenge. This overview of the GoKinD study examines in detail the power of each study component and discusses analytic challenges that investigators will face in using this resource.
OBJECTIVE—The purpose of this study was to evaluate whether severe hypoglycemia or intensive therapy affects cognitive performance over time in a subgroup of patients who were aged 13–19 years at entry in the Diabetes Control and Complications Trial (DCCT).
RESEARCH DESIGN AND METHODS—This was a longitudinal study involving 249 patients with type 1 diabetes who were between 13 and 19 years old when they were randomly assigned in the DCCT. Scores on a comprehensive battery of cognitive tests obtained during the Epidemiology of Diabetes Interventions and Complications follow-up study, ∼18 years later, were compared with baseline performance. We assessed the effects of the original DCCT treatment group assignment, mean A1C values, and frequency of severe hypoglycemic events on eight domains of cognition.
RESULTS—There were a total of 294 reported episodes of coma or seizure. Neither frequency of hypoglycemia nor previous treatment group was associated with decline on any cognitive domain. As in a previous analysis of the entire study cohort, higher A1C values were associated with declines in the psychomotor and mental efficiency domain (P < 0.01); however, the previous finding of improved motor speed with lower A1C values was not replicated in this subgroup analysis.
CONCLUSIONS—Despite relatively high rates of severe hypoglycemia, cognitive function did not decline over an extended period of time in the youngest cohort of patients with type 1 diabetes.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ~7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT.