Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia.
ABSTRACT: BACKGROUNDWe investigated residual β cell function in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study participants with an average 35-year duration of type 1 diabetes mellitus (T1DM).METHODSSerum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among nonresponders (all C-peptide values after meal <0.003 nmol/L) and 3 categories of responders, classified by peak C-peptide concentration (nmol/L) as high (>0.2), intermediate (>0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).RESULTSOf the 944 participants, 117 (12.4%) were classified as responders. Residual C-peptide concentrations were associated with higher DCCT baseline concentrations of stimulated C-peptide (P value for trend = 0.0001). Residual C-peptide secretion was not associated with current or mean HbA1c, HLA high-risk haplotypes for T1DM, or the current presence of T1DM autoantibodies. The proportion of subjects with a history of severe hypoglycemia was lower with high (27%) and intermediate (48%) residual C-peptide concentrations than with low (74%) and no (70%) residual C-peptide concentrations (P value for trend = 0.0001). Responders and nonresponders demonstrated similar rates of advanced microvascular complications.CONCLUSIONβ Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of >0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.TRIAL REGISTRATIONClinicalTrials.gov NCT00360815 and NCT00360893.FUNDINGDivision of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157).
Project description: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.
Project description:Type 1 diabetes mellitus (T1DM) results from immune mediated destruction of pancreatic beta cells. However, clinical and immunologic phenotypes of T1DM are variable. Several auto-antibodies including GADA, IA-2A, and ZnT8A, were identified in T1DM, but the prevalence of these auto-antibodies varied for a broad spectrum of T1DM. Here, we systemically profiled auto-antibodies from serum samples of 16 T1DM, 16 type 2 diabetes (T2DM) patients, and 27 healthy controls with normal glucose tolerance (NGT) using protein microarrays containing 9,480 proteins. Among 9,480 different proteins on the array, we identified novel auto-antibody candidates (EEF1A1-AAb and UBE2L3-AAb) by M-test coupled with PLS-DA. These auto-antibodies were highly present in T1DM than controls and detected in 40% of T1DM without GADA. Furthermore, these auto-antibodies might help to differentiate subtype of T1DM when combined with GADA. These novel auto-antibodies provide new diagnostic information of T1DM, as well as new insights into the pathogenesis of T1DM. Auto-antibodies from serum samples were profiled using a high-density, fluorescence-based protein microarray containing duplicate spots of 9,480 human proteins derived from the Ultimate ORF collection The cohort of patients and controls consisted of 16 T1DM, 16 T2DM patients, and 27 healthy controls with NGT. This cohort was used to screen candidate auto-antibodies using protein microarrays (ProtoArray platform version 5.0, Invitrogen Corp., Carlsbad, CA). Serum samples were drawn from T1DM patients who have 1) fasting C-peptide level <0.3 nmol/L or serum C-peptide <0.6 nmol/L after glucagon loading, 2) initiation of insulin treatment within six months after diagnosis, and 3) duration of diabetes ≤12 months. Mean age of T1DM in the first cohort was 42 ± 16 years. The control serum samples were obtained from T2DM patients who were treated only with oral anti-diabetic drug at least 5 years and from NGTs who had no history of diabetes, no first-degree relatives with diabetes, a fasting plasma glucose concentration of <6.1 mmol/l, and a HbA1c value of <5.8%.
Project description:BACKGROUND:Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM. METHODS:We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A1c (HbA1c) ?9.0% (n=83) and ?7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7-9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4-6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA1c ?9.0% (n=70) and ?7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51). RESULTS:Apart from HbA1c levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA1c ?9.0% group showed markedly higher cardiac AAb levels than the HbA1c ?7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively ( P<0.001). In the HbA1c ?9.0% group, 46%, 22%, and 11% tested positive for ?1, ?2, and ?3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA1c ?7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ?2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0-88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4-410.0). Patients with ?2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ?1 AAbs; P=0.003). CONCLUSIONS:Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.
Project description:Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves ?-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ? baseline), "super responders" (24-month C-peptide ? baseline), and "nonresponders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24 months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG+G-CSF demonstrated reduced CD4+ T cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ effector memory T cells (Tem), CD4+PD-1+ central memory T cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24 months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.
Project description:OBJECTIVE The Diabetes Control and Complications Trial (DCCT) was designed to test the glucose hypothesis and determine whether the complications of type 1 diabetes (T1DM) could be prevented or delayed. The Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up determined the durability of the DCCT effects on the more-advanced stages of diabetes complications including cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS The DCCT (1982-1993) was a controlled clinical trial in 1,441 subjects with T1DM comparing intensive therapy (INT), aimed at achieving levels of glycemia as close to the nondiabetic range as safely possible, with conventional therapy (CON), which aimed to maintain safe asymptomatic glucose control. INT utilized three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. EDIC (1994-present) is an observational study of the DCCT cohort. RESULTS The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a 35-76% reduction in the early stages of microvascular disease with INT, with a median HbA1c of 7%, compared with CONV, with a median HbA1c of 9%. The major adverse effect of INT was a threefold increased risk of hypoglycemia, which was not associated with a decline in cognitive function or quality of life. EDIC showed a durable effect of initial assigned therapies despite a loss of the glycemic separation (metabolic memory) and demonstrated that the reduction in early-stage complications during the DCCT translated into substantial reductions in severe complications and CVD. CONCLUSIONS DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span.
Project description:Type 1 diabetes (T1DM) is associated with increased risk of macrovascular complications. We examined longitudinal associations of serum conventional lipids and nuclear magnetic resonance (NMR)-determined lipoprotein subclasses with carotid intima-media thickness (IMT) in adults with T1DM (n=455) enrolled in the Diabetes Control and Complications Trial (DCCT). Data on serum lipids and lipoproteins were collected at DCCT baseline (1983-89) and were correlated with common and internal carotid IMT determined by ultrasonography during the observational follow-up of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at EDIC 'Year 1' (199-1996) and EDIC 'Year 6' (1998-2000). This article contains data on the associations of DCCT baseline lipoprotein profiles (NMR-based VLDL & chylomicrons, IDL/LDL and HDL subclasses and 'conventional' total, LDL-, HDL-, non-HDL-cholesterol and triglycerides) with carotid IMT at EDIC Years 1 and 6, stratified by gender. The data are supplemental to our original research article describing detailed associations of DCCT baseline lipids and lipoprotein profiles with EDIC Year 12 carotid IMT (Basu et al. in press) .
Project description:Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis and the risk of cardiovascular disease (CVD) events in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared with conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years of additional follow-up in EDIC, left ventricular (LV) indices were measured by cardiac magnetic resonance (CMR) imaging in 1,017 of the 1,371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume (EDV), end systolic volume, stroke volume (SV), cardiac output (CO), LV mass, ejection fraction, LV mass/EDV, or aortic distensibility (AD). Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LV mass, LV mass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
Project description:Type 1 diabetes mellitus (T1DM) results from immune mediated destruction of pancreatic beta cells. However, clinical and immunologic phenotypes of T1DM are variable. Several auto-antibodies including GADA, IA-2A, and ZnT8A, were identified in T1DM, but the prevalence of these auto-antibodies varied for a broad spectrum of T1DM. Here, we systemically profiled auto-antibodies from serum samples of 16 T1DM, 16 type 2 diabetes (T2DM) patients, and 27 healthy controls with normal glucose tolerance (NGT) using protein microarrays containing 9,480 proteins. Among 9,480 different proteins on the array, we identified novel auto-antibody candidates (EEF1A1-AAb and UBE2L3-AAb) by M-test coupled with PLS-DA. These auto-antibodies were highly present in T1DM than controls and detected in 40% of T1DM without GADA. Furthermore, these auto-antibodies might help to differentiate subtype of T1DM when combined with GADA. These novel auto-antibodies provide new diagnostic information of T1DM, as well as new insights into the pathogenesis of T1DM. Auto-antibodies from serum samples were profiled using a high-density, fluorescence-based protein microarray containing duplicate spots of 9,480 human proteins derived from the Ultimate ORF collection The cohort of patients and controls consisted of 16 T1DM, 16 T2DM patients, and 27 healthy controls with NGT. This cohort was used to screen candidate auto-antibodies using protein microarrays (ProtoArray platform version 5.0, Invitrogen Corp., Carlsbad, CA). Serum samples were drawn from T1DM patients who have 1) fasting C-peptide level <0.3 nmol/L or serum C-peptide <0.6 nmol/L after glucagon loading, 2) initiation of insulin treatment within six months after diagnosis, and 3) duration of diabetes M-bM-^IM-$12 months. Mean age of T1DM in the first cohort was 42 M-BM-1 16 years. The control serum samples were obtained from T2DM patients who were treated only with oral anti-diabetic drug at least 5 years and from NGTs who had no history of diabetes, no first-degree relatives with diabetes, a fasting plasma glucose concentration of <6.1 mmol/l, and a HbA1c value of <5.8%.
Project description:OBJECTIVE:This study evaluated associations among cardiovascular autonomic neuropathy (CAN), female sexual dysfunction (FSD), and urinary incontinence (UI) in women with type I diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS:We studied 580 women with T1DM in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). CAN was defined as: 1) R-R variation <15 with deep breathing or 2) R-R variation of 15-19.9 plus Valsalva ratio ?1.5 or a supine-to-standing drop of 10 mmHg in diastolic blood pressure. A Sandvik Severity Index of 3-12 defined UI, and a Female Sexual Function Index (FSFI-R) score ?22.75 defined FSD. Multivariable models estimated associations among CAN, FSD, and UI. RESULTS:At EDIC year 17, FSD was observed in 41% of women and UI in 30%. No statistically significant associations were observed between measures of CAN at DCCT closeout and subsequent report of FSD or UI. At EDIC year 16/17, there was a 53% increased odds of having UI with a Valsalva ratio ?1.5. At both EDIC year 13/14 and EDIC year 16/17, a 5-unit increase in R-R variation was associated with a 1.11 greater odds of having FSD. CONCLUSIONS:In women with T1DM in the DCCT/EDIC, we found significant increased odds of FSD and UI with specific measures of CAN. In long-standing T1DM, CAN may predict development of FSD and may be a useful surrogate for generalized diabetic autonomic neuropathy.
Project description:OBJECTIVE:To simulate the cost-effectiveness of historical and modern treatment scenarios that achieve excellent vs. poor glycemic control in type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS:We describe and compare the costs of intensive and conventional therapies for T1DM as performed during DCCT, and modern intensive and basic therapy scenarios using insulin analogs, pens, pumps, and continuous glucose monitoring (CGM) to achieve excellent or poor glycemic control. We then assess the differences in treatment costs and the costs of outcomes over 30?years and report incremental cost-effectiveness ratios. RESULTS:Over 30?years, DCCT intensive therapy cost $127,500 to $181,600 more per participant than DCCT conventional therapy, and modern intensive therapy cost $87,700 to $409,000 more per individual than modern basic therapy. Excellent glycemic control averted as much as $90,900 in costs from complications and added ~1.62 quality-adjusted life-years (QALYs) per participant over 30?years. When costs and QALYs were discounted at 3% annually, DCCT intensive therapy and modern intensive therapies that use multiple daily injections (MDI) or pumps are cost-saving or cost-effective (<$100,000/QALY-gained). If applied to all patients with T1DM, modern intensive therapy using pumps and CGM is not cost-effective (>$250,000/QALY-gained) but would be more cost-effective if associated with less hypoglycemia, better glycemic control, fewer complications, or improved health-related quality-of-life. CONCLUSIONS:Use of the least expensive intensive therapy needed to safely achieve treatment goals for patients with T1DM represents a good value for money. TRIAL REGISTRATION:clinicaltrials.govNCT00360815 and NCT00360893.