Rachel G. Miller

Modern-Day Clinical Course of Type 1 Diabetes Mellitus After 30 Years’ Duration: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005)

BACKGROUND 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. METHODS 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 >or=2 mg/dL [to convert to micromoles per liter, multiply by 88.4], or renal replacement), and cardiovascular disease. RESULTS 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. CONCLUSION The frequencies of serious complications in patients with T1DM, especially when treated intensively, are lower than that reported historically.

Translating the Diabetes Prevention Program: A Comprehensive Model for Prevention Training and Program Delivery

BACKGROUND The Diabetes Prevention Program (DPP) demonstrated that lifestyle intervention reduces risk for type 2 diabetes and the metabolic syndrome. A universal framework for translation of multiple aspects of the DPP intervention, including training, support, and evaluation is needed to enhance treatment fidelity in a variety of settings. PURPOSE This study aims to develop a comprehensive model for diabetes prevention translation using a modified DPP lifestyle intervention. METHODS The DPP lifestyle intervention was adapted to a 12-session group-based program called Group Lifestyle Balance for implementation in the community setting. A model for training and support mirroring that of the DPP was developed for prevention professionals administering the program. The process of training/support and program implementation was evaluated for feasibility and effectiveness using a nonrandomized prospective design in two phases (N=51, Phase 1: 2005-2006; N=42, Phase 2: 2007-2009; data analysis completed 2008-2009). A total of 93 nondiabetic individuals with BMI >or=25 kg/m(2) and the metabolic syndrome or prediabetes participated. Measures were collected at baseline and post-intervention for all and 6 and 12 months post-intervention for Phase 2. RESULTS Significant decreases in weight, waist circumference, and BMI were noted in both phases from baseline. Participants in Phase 2 also demonstrated decreases in total cholesterol, non-HDL cholesterol, and systolic and diastolic blood pressure that were maintained at 12 months. Average combined weight loss for both groups over the course of the 3-month intervention was 7.4 pounds (3.5% relative loss, p<0.001); 23.8% and 52.2% of those who completed the program reached 7% and 5% weight loss, respectively. More than 80% of those achieving 7% weight loss in the Phase-2 group maintained their weight loss at 6 months. CONCLUSIONS A comprehensive diabetes prevention model for training, intervention delivery, and support was shown to be successful and was effective in reducing diabetes and cardiovascular disease risk factors in this group of high-risk individuals.

Temporal patterns in overweight and obesity in Type 1 diabetes.

Diabet. Med. 27, 398–404 (2010)

Improvements in the life expectancy of type 1 diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study cohort

Survival in type 1 diabetes has improved, but the impact on life expectancy in the U.S. type 1 diabetes population is not well established. Our objective was to estimate the life expectancy of the Pittsburgh Epidemiology of Diabetes Complications (EDC) study cohort and quantify improvements by comparing two subcohorts based on year of diabetes diagnosis (1950–1964 [n = 390] vs. 1965–1980 [n = 543]). The EDC study is a prospective cohort study of 933 participants with childhood-onset (aged <17 years) type 1 diabetes diagnosed at Children’s Hospital of Pittsburgh from 1950 to 1980. Mortality ascertainment was censored 31 December 2009. Abridged cohort life tables were constructed to calculate life expectancy. Death occurred in 237 (60.8%) of the 1950–1964 subcohort compared with 88 (16.2%) of the 1965–1980 subcohort. The life expectancy at birth for those diagnosed 1965–1980 was ∼15 years greater than participants diagnosed 1950–1964 (68.8 [95% CI 64.7–72.8] vs. 53.4 [50.8–56.0] years, respectively) (P < 0.0001); this difference persisted regardless of sex or pubertal status at diagnosis. This improvement in life expectancy emphasizes the need for insurance companies to update analysis of the life expectancy of those with childhood-onset type 1 diabetes because weighting of insurance premiums is based on outdated estimates.

Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study

BACKGROUND— Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes. RESEARCH DESIGN AND METHODS— We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery rate q values were calculated separately for each outcome. RESULTS— We observed association between rs17880135 in the 3′ region of superoxide dismutase 1 (SOD1) and the incidence of both severe nephropathy (hazard ratio [HR] 2.62 [95% CI 1.64–4.18], P = 5.6 × 10−5, q = 0.06) and persistent microalbuminuria (1.82 [1.29–2.57], P = 6.4 × 10−4, q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which were also associated (P < 10−3) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results. We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression in lymphoblastoid cell lines. CONCLUSIONS— Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.

Multiple SOD1/SFRS15 variants are associated with the development and progression of diabetic nephropathy: The DCCT/EDIC Genetics study

BACKGROUND— Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes. RESEARCH DESIGN AND METHODS— We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery rate q values were calculated separately for each outcome. RESULTS— We observed association between rs17880135 in the 3′ region of superoxide dismutase 1 (SOD1) and the incidence of both severe nephropathy (hazard ratio [HR] 2.62 [95% CI 1.64–4.18], P = 5.6 × 10−5, q = 0.06) and persistent microalbuminuria (1.82 [1.29–2.57], P = 6.4 × 10−4, q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which were also associated (P < 10−3) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results. We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression in lymphoblastoid cell lines. CONCLUSIONS— Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.

Children's binge eating and development of metabolic syndrome

Background:Binge eating predisposes children to excessive weight gain. However, it is unknown if pediatric binge eating predicts other obesity-associated adverse health outcomes.Objective:The objective of this study was to investigate the relationship between binge eating and metabolic syndrome (MetS) in children.Method:Children aged 5–12 years at high risk for adult obesity, either because they were overweight/obese when first examined or because their parents were overweight/obese, were recruited from Washington, DC and its suburbs. Children completed a questionnaire assessment of binge eating at baseline and underwent measurements of MetS components at baseline and at a follow-up visit approximately 5 years later. Magnetic resonance imaging was used to measure the visceral adipose tissue (VAT) in a subset.Results:In all, 180 children were studied between July 1996 and August 2010. Baseline self-reported binge eating presence was associated with a 5.33 greater odds of having MetS at follow-up (95% confidence interval (CI): 1.47, 19.27, P=0.01). The association between binge eating and body mass index (BMI) only partially explained changes in MetS components: baseline binge eating predicted higher follow-up triglycerides, even after accounting for baseline triglycerides, baseline BMI, BMI change, sex, race, baseline age and time in study (P=0.05). Also, adjusting for baseline VAT and demographics, baseline binge eating predicted greater follow-up L2−3 VAT (P=0.01).Discussion:Childrens reports of binge eating predicted development of MetS, worsening triglycerides and increased VAT. The excessive weight gain associated with childrens binge eating partly explained its adverse metabolic health outcomes. Reported binge eating may represent an early behavioral marker upon which to focus interventions for obesity and MetS.

A novel approach to diabetes prevention: Evaluation of the Group Lifestyle Balance program delivered via DVD

This pilot project evaluated the Group Lifestyle Balance program (GLB), an adaptation of the DPP lifestyle intervention, delivered via DVD with remote participant support provided by the University of Pittsburgh Diabetes Prevention Support Center. Results suggest that GLB-DVD with remote support may provide an effective alternative for GLB delivery.

Adiposity and mortality in type 1 diabetes.

Background:In the general population, adiposity exhibits a J- or U-shaped relationship with mortality; however, in catabolic states this relationship is often inversely linear. We have recently documented an age-independent increase in overweight/obesity in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of type 1 diabetes (T1D). As intensified insulin therapy (IIT) may promote weight gain, the impact of weight gain in T1D is of importance. We therefore assessed the association of adiposity with mortality in 655 EDC participants during 20 years of follow-up.Methods:Individuals were categorized as underweight (body mass index (BMI)<20), normal (20⩽ BMI <25), overweight (25⩽ BMI <30), or obese (BMI ⩾30). Cox models were constructed using BMI and covariates at baseline, updated means during follow-up, time variation (reflecting most recent status), and change during adulthood as predictors of mortality.Results:The prevalence of IIT (3+ insulin shots daily and/or pump) increased from 7 to 82%. Overweight increased by 47% and obesity increased sevenfold. There were 146 deaths. In unadjusted models, BMI (modeled continuously) showed a quadratic relationship with mortality (P=0.002, <0.0001 <0.0001 for baseline, updated mean and time-varying models, respectively). However, only in the time-varying model were the obese significantly different from the normal weight, whereas the baseline model showed no differences by BMI category. In both the updated mean and time-varying models, the underweight were at greater risk than were the normal weight (P<0.0001 both models). The nonlinear relationship of adiposity with mortality remained after adjustment for diabetes complications and for biological or socioeconomic/lifestyle risk factors, with the exception of baseline socioeconomic/lifestyle risk factors, in which a linear association emerged. Adjustment for waist circumference eliminated risk in the obese. Finally, weight gain during follow-up was protective.Conclusion:The relationship of adiposity with mortality in T1D now seems to resemble that of the general population, albeit with a marked increased risk in those who are underweight.

Longitudinal Study of Depressive Symptoms and Progression of Insulin Resistance in Youth at Risk for Adult Obesity

OBJECTIVE The purpose of this study was to determine whether having childhood depressive symptoms is a risk factor that prospectively predicts impairment in glucose homeostasis. RESEARCH DESIGN AND METHODS A non–treatment-seeking sample of 115 children (aged 5–13 years), oversampled for being at risk for adult obesity, was assessed at baseline and again ~6 years later. Children self-reported depressive symptoms using the Children’s Depression Inventory at baseline. Insulin resistance was assessed at baseline and follow-up with the homeostasis model assessment of insulin resistance index (HOMA-IR). RESULTS Children’s depressive symptoms were a significant predictor of follow-up HOMA-IR, fasting insulin, and fasting glucose in models accounting for baseline HOMA-IR, insulin, or glucose values; sex; race; baseline age; baseline BMI; change in BMI at follow-up; family history of type 2 diabetes; and time in the study (P < 0.01). CONCLUSIONS In this study, depressive symptomatology at baseline predicted the progression of insulin resistance during child and adolescent development independent of changes in BMI. Research is needed to determine whether early intervention to decrease elevated depressive symptoms in youth ameliorates later development of insulin resistance and lessens the risk of type 2 diabetes.