Gayle Lorenzi

Evaluating the Role of Epigenetic histone modifications in the Metabolic Memory of Type 1 Diabetes.

We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Advances and Contributions

The Diabetes Control and Complications Trial (DCCT) (1) and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (2), are celebrating the 30th anniversary since the start of the DCCT and 20th since the reporting of the DCCT primary results (3). During the past three decades, our understanding of the relationship between metabolic control and complications and the treatment of type 1 diabetes (T1D) has been transformed by the results of DCCT/EDIC. Most importantly, the long-term prospects for patients have dramatically improved with the adoption of intensive therapy designed to achieve near-normal glycemia as the standard of care of T1D. In this Perspective, we present an overview of the major scientific advances provided by the DCCT/EDIC Research Group, the resulting changes in therapy that have improved long-term outcomes in patients with T1D worldwide, and the challenges that remain. ### Background and rationale. After the introduction of insulin therapy in 1922, type 1 diabetes (T1D) was transformed from a uniformly fatal disease to a chronic degenerative one (4). During the 1930–1960s, the development of chronic complications affecting the eyes, kidneys, peripheral and autonomic nervous system, and a substantially increased risk of cardiovascular disease (CVD) were observed in patients who had survived >20 years with the disease (5). The origin of these newly discovered complications was debated vigorously, and theories to explain them abounded (4,6). The debate led to two opposing philosophies of diabetes treatment: one in which treatment to achieve glucose concentrations as low as possible was endorsed and another in which glycemic levels were thought to be inconsequential, at least with regard to the pathogenesis of long-term complications (7,8). Although the debate regarding the so-called glucose hypothesis was vigorous, it was largely academic, since objective means of measuring long-term glycemia and of achieving near-normal glycemia did not …

Delayed Gastric Emptying is Associated with Early and Long-Term Hyperglycemia in Type 1 Diabetes Mellitus

BACKGROUND & AIMS After the Diabetes Control and Complications Trial (DCCT), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to show persistent benefit of prior intensive therapy on neuropathy, retinopathy, and nephropathy in type 1 diabetes mellitus (DM). The relationship between control of glycemia and gastric emptying (GE) is unclear. METHODS We assessed GE with a (13)C-spirulina breath test and symptoms in 78 participants with type 1 diabetes at year 20 of EDIC. The relationship between delayed GE and glycated hemoglobin (HbA1c), complications of DM, and gastrointestinal symptoms were evaluated. RESULTS GE was normal (37 participants; 50%), delayed (35 participants; 47%), or rapid (2 participants; 3%). The latest mean HbA1c was 7.7%. In univariate analyses, delayed GE was associated with greater DCCT baseline HbA1c and duration of DM before DCCT (P ≤ .04), greater mean HbA1c over an average of 27 years of follow-up evaluation (during DCCT-EDIC, P = .01), lower R-R variability during deep breathing (P = .03) and severe nephropathy (P = .05), and a greater composite upper gastrointestinal symptom score (P < .05). In multivariate models, retinopathy was the only complication of DM associated with delayed GE. Separately, DCCT baseline HbA1c (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3) and duration of DM (OR, 1.2; 95% CI, 1.01-1.3) before DCCT entry and mean HbA1c during DCCT-EDIC (OR, 2.2; 95% CI, 1.04-4.5) were associated independently with delayed GE. CONCLUSIONS In the DCCT/EDIC study, delayed GE was remarkably common and associated with gastrointestinal symptoms and with measures of early and long-term hyperglycemia. ClinicalTrials.gov numbers NCT00360815 and NCT00360893.

Musculoskeletal Complications in Type 1 Diabetes

OBJECTIVE The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors, microvascular complications, and the effect of former DCCT therapy (intensive [INT] vs. conventional [CONV]) on its development. RESEARCH DESIGN AND METHODS This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy—defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytrens contracture, or a positive prayer sign—was assessed using a targeted medical history and standardized physical examination. A self-administered questionnaire (Disabilities of the Arm, Shoulder and Hand [DASH]) assessed functional disability. RESULTS Cheiroarthropathy was present in 66% of subjects (64% of the INT group and 68% of the CONV group; P = 0.1640) and was associated with age, sex, diabetes duration, skin intrinsic fluorescence, HbA1c, neuropathy, and retinopathy (P < 0.005 for each). DASH functional disability scores were worse among subjects with cheiroarthropathy (P < 0.0001). CONCLUSIONS Cheiroarthropathy is common in people with type 1 diabetes of long duration (∼30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability.

Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes.

BACKGROUND In patients who have had type 1 diabetes for 5 years, current recommendations regarding screening for diabetic retinopathy include annual dilated retinal examinations to detect proliferative retinopathy or clinically significant macular edema, both of which require timely intervention to preserve vision. During 30 years of the Diabetes Control and Complications Trial (DCCT) and its longitudinal follow‐up Epidemiology of Diabetes Interventions and Complications (EDIC) study, retinal photography was performed at intervals of 6 months to 4 years. METHODS We used retinal photographs from the DCCT/EDIC study to develop a rational screening frequency for retinopathy. Markov modeling was used to determine the likelihood of progression to proliferative diabetic retinopathy or clinically significant macular edema in patients with various initial retinopathy levels (no retinopathy or mild, moderate, or severe nonproliferative diabetic retinopathy). The models included recognized risk factors for progression of retinopathy. RESULTS Overall, the probability of progression to proliferative diabetic retinopathy or clinically significant macular edema was limited to approximately 5% between retinal screening examinations at 4 years among patients who had no retinopathy, 3 years among those with mild retinopathy, 6 months among those with moderate retinopathy, and 3 months among those with severe nonproliferative diabetic retinopathy. The risk of progression was also closely related to mean glycated hemoglobin levels. The risk of progression from no retinopathy to proliferative diabetic retinopathy or clinically significant macular edema was 1.0% over 5 years among patients with a glycated hemoglobin level of 6%, as compared with 4.3% over 3 years among patients with a glycated hemoglobin level of 10%. Over a 20‐year period, the frequency of eye examinations was 58% lower with our practical, evidence‐based schedule than with routine annual examinations, which resulted in substantial cost savings. CONCLUSIONS Our model for establishing an individualized schedule for retinopathy screening on the basis of the patients current state of retinopathy and glycated hemoglobin level reduced the frequency of eye examinations without delaying the diagnosis of clinically significant disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.)

Managing diabetes with integrated teams: maximizing your efforts with limited time.

Abstract The importance of glycemic control has been well established. In response, the American Diabetes Association has established goals for glycemic control and other cardiovascular parameters, including blood pressure and low–density and high–density lipoprotein cholesterol. However, the National Health and Nutrition Examination Survey has shown that only about half (57%) of patients with diabetes meet a glycated hemoglobin A1c (HbA1c) goal of < 7%, approximately 45% meet blood pressure and total cholesterol goals, and only 12% achieve all 3 treatment goals. While treating hyperglycemia remains the primary treatment goal, careful selection of pharmacotherapies that do not adversely affect cardiovascular risk factors or long–term glycemic control is an important consideration for patients with type 2 diabetes mellitus. During the past 5 years, the number of treatment options and the complexity of treatment guidelines for diabetes have increased markedly, which makes treatment decisions more complicated and time–consuming, and greatly impacts the workload of the primary care physicians who deliver care to the majority of this population. To provide optimal diabetes care when time and resources are limited, primary care physicians may want to enlist the support of other providers, such as nurse practitioners, physician assistants, diabetes educators, dietitians, and social and case workers. The use of team care, coupled with appropriately chosen pharmacologic therapy and patient education that fosters the development of critical thinking skills and the ability to make self–management decisions, have been shown to improve glycemic control and cardiovascular outcomes.

Participant characteristics and study features associated with high retention rates in a longitudinal investigation of type 1 diabetes mellitus.

Background 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. Purpose In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants. Methods 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. Results 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. Limitations 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. Conclusions 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.

Evolution of the study coordinator role : The 28-year experience in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)

Background The role of the study coordinator (SC) in multicenter studies of long duration has received limited attention. Purpose To describe the evolution of the SC’s role during the 28-year Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Methods The evolution of the SC’s position from the traditional role of protocol implementation to that of research collaborator and co-investigator, based on personal experience and observation, is described in detail. Findings from a survey regarding professional demographics and job satisfaction, completed by all 28 SCs in 2010, provided additional information. We used dimensions of the SC’s role specific to DCCT/EDIC to construct a classification schema of functions and responsibilities that describe the SC’s role. Results Among the 28 SCs, 24 were nurses, 12 held bachelor’s degrees, 11 had a master’s degree, 19 were certified diabetes educators (CDEs), 12 had worked with DCCT/EDIC for more than 20 years, and 5 had been with the study since its inception (>26 years). Responses confirmed a high degree of functional consistency across sites with data acquisition, performing study procedures, recruitment and consent for additional ancillary studies, regulatory management, scheduling, clinical consultation, and ongoing contact with study participants frequently reported. Study-wide leadership activities, a category not generally included in the usual SC role, were reported by approximately 30% of the SCs. The level of professional satisfaction was high with two-thirds being very satisfied, one-third moderately to quite satisfied, and none dissatisfied. Limitations The limitations include a relatively small sample size, self-reported data, and a single long-term multicenter trial and observational follow-up study on which we based our findings and conclusions. Conclusions By optimizing their organizational and scientific contributions to the overall research endeavor, SCs in DCCT/EDIC have made major contributions to the unprecedented success of the study and report high job satisfaction. The efforts of the SCs have been integral to the remarkably high participant retention and data completion rates. The DCCT/EDIC experience may serve as a model for the role of the SC in future diabetes and other multicenter clinical trials.

Hearing Impairment and Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort

OBJECTIVE To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia. RESEARCH DESIGN AND METHODS DCCT/EDIC participants (n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA >25 dB hearing loss. Logistic regression models were adjusted for age and sex. RESULTS DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA1c, there was a 32% (95% CI 1.15–1.50) and 19% (95% CI 1.07–1.33) increase in speech- and high-frequency hearing impairment, respectively. CONCLUSIONS We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA1c over time was associated with hearing impairment.