Rose Gubitosi-Klug

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 …

5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy

OBJECTIVE—Lipoxygenases are regulators of chronic inflamation and oxidative stress generation. We evaluated the role of 5- and 12-lipoxygenases in the development of diabetic retinopathy. RESEARCH DESIGN AND METHODS—Wild-type mice, 5-lipoxygenase–deficient mice, and 12/15-lipoxygenase–deficient mice were assessed 1) after 9 months of diabetes for retinal histopathology and leukotriene receptor expression and 2) after 3 months of diabetes for leukostasis and retinal superoxide generation. RESULTS—Diabetic wild-type mice developed the expected degeneration of retinal capillaries and pericytes and increases in both leukostasis and superoxide production (P < 0.006). We found no evidence of diabetes-induced degeneration of retinal ganglion cells in these animals. The vascular histopathology was significantly inhibited in 5-lipoxygenase–deficient mice, but not in 12/15-lipoxygenase–deficient mice. Retinas from diabetic 5-lipoxygenase–deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-κB (NF-κB) expression (all P < 0.006), whereas retinas from diabetic 12/15-lipoxygenase–deficient mice had significantly less leukostasis (P < 0.005) but not superoxide production or NF- κB expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B4. Diabetes-induced histological and biochemical alterations were significantly reduced in 5-lipoxygenase–deficient mice, but not 12/15-lipoxygenase–deficient mice. CONCLUSIONS—5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.

The Long-Term Effects of Type 1 Diabetes Treatment and Complications on Health-Related Quality of Life: A 23-year follow-up of the Diabetes Control and Complications/Epidemiology of Diabetes Interventions and Complications cohort

OBJECTIVE To examine the long-term effects of type 1 diabetes treatment, metabolic control, and complications on health-related quality of life (HRQOL). RESEARCH DESIGN AND METHODS A total of 1,441 participants, initially 13–39 years of age, were followed for an average of 23.5 years as part of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. The Diabetes Quality-of-Life questionnaire (DQOL) was administered annually during DCCT and every other year during EDIC. Biomedical data, including HbA1c levels, exposure to severe hypoglycemia, intercurrent psychiatric events, and development of diabetes complications were collected at regular intervals throughout the follow-up. RESULTS Mean total DQOL scores were not significantly different between the former DCCT intensive and conventional treatment groups (DCCT baseline, 78 ± 8 vs. 78 ± 9; EDIC year 17, 75 ± 11 vs. 74 ± 11). Over the course of the study, a drop of ≥5 points in DQOL score from DCCT baseline maintained on two successive visits occurred in 755 individuals and was associated with increased HbA1c, albumin excretion rate, mean blood pressure, BMI, and occurrence of hypoglycemic events requiring assistance. Lower DQOL scores after 23.5 years of follow-up were associated with prior development of retinopathy (P = 0.0196), nephropathy (P = 0.0019), and neuropathy (P < 0.0001) as well as self-reported chest pain (P = 0.0004), decreased vision in both eyes (P = 0.0005), painful paresthesias (P < 0.0001), recurrent urinary incontinence (P = 0.0001), erectile dysfunction (P < 0.0001), and history of psychiatric events (P < 0.0001). CONCLUSIONS Among DCCT/EDIC participants, worsening metabolic control, serious diabetes complications and their associated symptoms, and development of psychiatric conditions led to decreased HRQOL.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Summary and Future Directions

OBJECTIVE The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study continues to address knowledge gaps in our understanding of type 1 diabetes and the effects of intensive therapy on its long-term complications. RESEARCH DESIGN AND METHODS During the DCCT (1982–1993), a controlled clinical trial of 1,441 subjects with type 1 diabetes, and the EDIC (1994–present), an observational study of the DCCT cohort, core data collection has included medical history questionnaires, surveillance health exams, and frequent laboratory and other evaluations for microvascular and macrovascular disease. Numerous collaborations have expanded the outcome data with more detailed investigations of cardiovascular disease, cognitive function, neuropathy, genetics, and potential biological pathways involved in the development of complications. RESULTS The longitudinal follow-up of the DCCT/EDIC cohort provides the opportunity to continue monitoring the durability of intensive treatment as well as to address lingering questions in type 1 diabetes research. Future planned analyses will address the onset and progression of microvascular triopathy, evidence-based screening for retinopathy and nephropathy, effects of glycemic variability and nonglycemic risk factors on outcomes, long-term impact of intensive therapy on cognitive decline, and health economics. Three new proposed investigations include an examination of residual C-peptide secretion and its impact, prevalence of hearing impairment, and evaluation of gastrointestinal dysfunction. CONCLUSIONS With the comprehensive data collection and the remarkable participant retention over 30 years, the DCCT/EDIC continues as an irreplaceable resource for understanding type 1 diabetes and its long-term complications.

Marrow-Derived Cells Regulate the Development of Early Diabetic Retinopathy and Tactile Allodynia in Mice

The hypothesis that marrow-derived cells, and specifically proinflammatory proteins in those cells, play a critical role in the development of diabetes-induced retinopathy and tactile allodynia was investigated. Abnormalities characteristic of the early stages of retinopathy and allodynia were measured in chimeric mice lacking inducible nitric oxide synthase (iNOS) or poly(ADP-ribosyl) polymerase (PARP1) in only their marrow-derived cells. Diabetes-induced capillary degeneration, proinflammatory changes, and superoxide production in the retina and allodynia were inhibited in diabetic animals in which iNOS or PARP1 was deleted from bone marrow cells only. Of the various marrow cells, neutrophils (and monocytes) play a major role in retinopathy development, because retinal capillary degeneration likewise was significantly inhibited in diabetic mice lacking the receptor for granulocyte colony-stimulating factor in their marrow-derived cells. Immunodepletion of neutrophils or monocytes inhibited the endothelial death otherwise observed when coculturing leukocytes from wild-type diabetic animals with retinal endothelium. iNOS and PARP1 are known to play a role in inflammatory processes, and we conclude that proinflammatory processes within marrow-derived cells play a central role in the development of diabetes complications in the retina and nerve.

Increased Synthesis of Leukotrienes in the Mouse Model of Diabetic Retinopathy

PURPOSE Evidence suggests that capillary degeneration in early diabetic retinopathy results from chronic inflammation, and leukotrienes have been implicated in this process. The authors investigated the cellular sources of leukotriene biosynthesis in diabetic retinas and the effects of hyperglycemia on leukotriene production. METHODS Retinas and bone marrow cells were collected from diabetic and nondiabetic mice. Mouse retinal glial cells and retinal endothelial cells (mRECs) were cultured under nondiabetic and diabetic conditions. Production of leukotriene metabolites was assessed by mass spectrometry, and Western blot analysis was used to quantitate the expression of enzymes and receptors involved in leukotriene synthesis and signaling. RESULTS Bone marrow cells from nondiabetic mice expressed 5-lipoxygenase, the enzyme required for the initiation of leukotriene synthesis, and produced leukotriene B(4) (LTB(4)) when stimulated with the calcium ionophore A23187. Notably, LTB(4) synthesis was increased threefold over normal (P < 0.03) in bone marrow cells from diabetic mice. In contrast, retinas from nondiabetic or diabetic mice produced neither leukotrienes nor 5-lipoxygenase mRNA. Despite an inability to initiate leukotriene biosynthesis, the addition of exogenous leukotriene A(4) (LTA(4); the precursor of LTB(4)) to retinas resulted in robust production of LTB(4). Similarly, retinal glial cells synthesized LTB(4) from LTA(4), whereas mRECs produced both LTB(4) and the cysteinyl leukotrienes. Culturing the retinal cells in high-glucose concentrations enhanced leukotriene synthesis and selectively increased expression of the LTB(4) receptor BLT1. Antagonism of the BLT1 receptor inhibited LTB(4)-induced mREC cell death. CONCLUSIONS Transcellular delivery of LTA(4) from marrow-derived cells to retinal cells results in the generation of LTB(4) and the death of endothelial cells and, thus, might contribute to chronic inflammation and retinopathy in diabetes.

Factors Associated With Microalbuminuria in 7,549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry

OBJECTIVE To examine factors associated with clinical microalbuminuria (MA) diagnosis in children and adolescents in the T1D Exchange clinic registry. RESEARCH DESIGN AND METHODS T1D Exchange participants <20 years of age with type 1 diabetes ≥1 year and urinary albumin-to-creatinine ratio (ACR) measured within the prior 2 years were included in the analysis. MA diagnosis required all of the following: 1) a clinical diagnosis of sustained MA or macroalbuminuria, 2) confirmation of MA diagnosis by either the most recent ACR being ≥30 mg/g or current treatment with an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 3) no known cause for nephropathy other than diabetes. Logistic regression was used to assess factors associated with MA. RESULTS MA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI (P ≤ 0.01 for each in multivariate analysis). Older age was most strongly associated with MA among participants with HbA1c ≥9.5% (≥80 mmol/mol). MA was uncommon (<2%) among participants with HbA1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment. CONCLUSIONS Our results emphasize the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy. Since age and diabetes duration are important nonmodifiable factors associated with MA, the importance of routine screening is underscored to ensure early diagnosis and timely treatment of MA.

Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes

Understanding the early pathogenesis of DR may uncover new therapeutic targets to prevent or slow the progression of this sight‐threatening disorder. We investigated the role of leukocyte‐mediated generation of LTs in regulation of retinal capillary degeneration and inflammation in the diabetic mouse. We generated (1) chimeric mice that lacked the ability to generate LTs by transplanting 5LO−/− bone marrow cells into ND.WT mice and into SD.WT mice and (2) “control” chimeric mice by transplanting WT bone marrow cells into 5LO−/− mice or into WT mice. Retinas from diabetic chimeric mice with WT marrow demonstrated capillary degeneration to the same extent as retinas from diabetic, nonchimeric WT mice. In contrast, retinas from diabetic chimeric mice with 5LO−/− marrow developed significantly less capillary degeneration and pericyte loss (P<0.05). In the retinas from chimeric mice with WT marrow, diabetes induced a rise in leukocyte adherence to the microvasculature, expression of the NF‐κB p65 subunit, and ICAM1, superoxide generation, and retinal microvascular permeability, yet these characteristic responses were blunted by >50% in diabetic chimeras containing 5LO−/− leukocytes (P<0.05). Our data suggest the critical involvement of leukocytes and LTs in the regulation of inflammation and capillary degeneration in DR.

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.)

The Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study

OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.