32 research outputs found
Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented
Anti-Müllerian hormone and its relationships with subclinical cardiovascular disease and renal disease in a longitudinal cohort study of women with type 1 diabetes
Abstract
Background
Reproductive age may be a risk factor for vascular disease. Anti-Müllerian hormone (AMH) is produced by viable ovarian follicles and reflects reproductive age. We examined whether AMH concentrations were associated with markers of subclinical cardiovascular disease (CVD) and kidney disease among women with type 1 diabetes.
Methods
We performed a cross-sectional analysis of the Epidemiology of Diabetes Interventions and Complications Study. Participants included women with type 1 diabetes and ≥1 AMH measurement (n = 390). In multivariable regression models which adjusted for repeated measures, we examined the associations between AMH with CVD risk factors, estimated glomerular filtration rate, and albumin excretion ratio. We also examined whether initial AMH concentrations were associated with the presence of any coronary artery calcification (CAC) or carotid intima media thickness (cIMT).
Results
After adjustment for age, AMH was not associated with waist circumference, blood pressure, lipid profiles, or renal function. Higher initial AMH concentrations had borderline but non-significant associations with the presence of CAC after adjustment for age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.00, 1.16) which were minimally altered by addition of other CVD risk factors, although women in the 3rd quartile of AMH had lower odds of CAC than women in the lowest quartile (OR 0.40, 95% CI 0.17, 0.94). After adjustment for age, higher AMH was associated with statistically significant but only slightly higher cIMT (0.005 mm, p = 0.0087) which was minimally altered by addition of other CVD risk factors.
Conclusions
Among midlife women with type 1 diabetes, AMH has slight but significant associations with subclinical measures of atherosclerosis. Future studies should examine whether these associations are clinically significant.
Trial registration
NCT00360815
and
NCT00360893
Study Start Date April 1994.https://deepblue.lib.umich.edu/bitstream/2027.42/138004/1/40695_2017_Article_23.pd
Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.
The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland
A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability
43 p.-5 fig.Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This unprecedented mechanism of action resulted in highly potent and selective pathway inhibition, in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this novel mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders.C.T. thanks the CMVM of the University of Edinburgh (Principal's scholarship). D.L.
acknowledges support from the Spanish Ministry of Science, Innovation and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R.W., J.C.D. and K.G.M. are funded by CRUK. J.R.L.O. acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T.V. is funded by H2020-MSCA-IF-2016-749299. RCM thanks the support from the Vice Rectorate for Research of the University of Granada. X.-F.L. and B.-Z.Q. are funded by a CRUK Career Development Fellowship (C49791/A17367). B.-Z.Q. also acknowledges support from an ERC Starting Grant (716379). C.S, M.C.F. and V.G.B are funded by CRUK Programme Grant C157/A15703. N.O.C. and A.U.B are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3).Peer reviewe
Assessment of Circulating Insulin Using Mass Spectrometry During Insulin Glargine Treatment in Type 2 Diabetes: Implications for Estimating Insulin Sensitivity and β-cell Function
AIMS: Given the potential effect of cross-reactivity of insulin glargine U-100 and its metabolites in the insulin immunoassay, we determined the impact on insulin sensitivity and β-cell measures in GRADE participants with type 2 diabetes receiving the analog. MATERIALS AND METHODS: Using liquid chromatography mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine, and its two metabolites (M1 and M2) in fasting and OGTT-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 pm the night before. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (HOMA2-S%; QUIKI index, PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] / iAUC glucose). RESULTS: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analog and its metabolites cross-reacted \u3c100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting based measures. In contrast, as M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin. CONCLUSIONS: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased. This article is protected by copyright. All rights reserved
Testosterone and cardiac mass and function in men with type 1 diabetes in the Epidemiology of Diabetes Interventions and Complications Study (EDIC)
Objective Low testosterone concentrations have been reported to be associated with increased risk of congestive heart failure, but the mechanisms are unclear. Our objective was to examine the relationship between endogenous testosterone and measures of cardiac mass and function among men with type 1 diabetes. Design Secondary analysis of a prospective observational study. Participants Men (n = 508) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT). Measurements Testosterone assessed by liquid chromatography mass spectrometry at EDIC year 10 and cardiac magnetic resonance imaging (CMR) measures at EDIC years 14/15. Linear regression models were used to assess the relationship between testosterone, sex hormone binding globulin (SHBG) and left ventricular (LV) mass, volume, ejection fraction and cardiac index before and after adjustment for age, randomization arm, alcohol and cigarette use, macroalbuminuria, haemoglobin A1c, insulin dose, body mass index, lipids, blood pressure, use of antihypertensive medications and microvascular complications. Results In fully adjusted models, total testosterone concentrations were significantly associated with LV mass (P = 0·014), end-diastolic volume (P = 0·002), end-systolic volume (P = 0·012) and stroke volume (P = 0·022), but not measures of LV function after adjustment for cardiac risk factors. Bioavailable testosterone was associated with LV mass, but not volume or function, while SHBG was associated with volume, but not mass or function. Conclusions Among men with type 1 diabetes, higher total testosterone was associated with higher LV mass and volume, but not with function. The clinical significance of this association remains to be established
Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented
Biochemical Markers of Bone Turnover in Older Adults with Type 1 Diabetes
CONTEXT: Type 1 diabetes (T1D) is characterized by high fracture risk, yet little is known regarding diabetes-related mechanisms or risk factors. OBJECTIVE: Determine if glycemic control, advanced glycation end products (AGEs), and microvascular complications are associated with bone turnover markers among older T1D adults. DESIGN: Cross-sectional. SETTING: Epidemiology of Diabetes Interventions and Complications study (6 of 27 clinical centers). PARTICIPANTS: 232 T1D participants followed for \u3e30 years. EXPOSURES: Glycemic control ascertained as concurrent and cumulative HbA1c; kidney function by estimated glomerular filtration rates (eGFR); AGEs by skin intrinsic fluorescence. MAIN OUTCOME MEASURES: Serum procollagen 1 intact N-terminal propeptide (PINP), bone specific alkaline phosphatase (Bone ALP), serum C-telopeptide (sCTX), tartrate-resistant acid phosphatase 5b (TRACP5b), sclerostin. RESULTS: Mean age was 59.6 ± 6.8 years, and 48% were female. In models with HbA1c, eGFR and AGEs, adjusted for age and sex, higher concurrent HbA1c was associated with lower PINP (β: -3.4 pg/ml (95% CI: -6.1, -0.7), p=0.015 for each 1% higher HbA1c). Lower eGFR was associated with higher PINP (6.9 pg/ml (3.8, 10.0), p\u3c0.0001 for each -20 mL/min/1.73 m 2 eGFR), Bone ALP (1.0 U/L (0.2, 1.9), p =0.011), sCTX (53.6 pg/mL (32.6, 74.6), p\u3c0.0001), and TRACP5b (0.3 U/L (0.1, 0.4), p=0.002). However, AGEs were not associated with any bone turnover markers in adjusted models. HbA1c, eGFR and AGEs were not associated with sclerostin levels. CONCLUSIONS: Among older adults with T1D, poor glycemic control is a risk factor for reduced bone formation, while reduced kidney function is a risk factor for increased bone resorption and formation
Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia.
BACKGROUND: We 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).
METHODS: Serum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among non-responders (all C-peptide values after meal0.2), intermediate (\u3e0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).
RESULTS: Of 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 non-responders demonstrated similar rates of advanced microvascular complications.
CONCLUSION: β Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of \u3e0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00360815 and NCT00360893.
FUNDING: Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157)