Background/Rationale: Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes ...and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies.
Methods: Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8–493 World Health Organization (WHO) units/ml and IA-2A 2–235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using 35S-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays.
Results: The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001).
Conclusion: Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements.
Improved concordance of measurement of islet autoantibodies among international laboratories is achieved by the establishment of harmonized, sensitive, and specific reference immunoassays.
Aim
This study compared the 5‐year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the ...Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model.
Research Design and Methods
This study was a 5‐year SURPASS‐2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1‐year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low‐density lipoprotein and body weights were obtained from the SUSTAIN‐4 and SURPASS‐2 trials. We used the BRAVO model to predict 5‐year complications for each study arm under two scenarios: the 1‐year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative).
Results
When compared with insulin glargine, we projected a 5‐year risk reduction in cardiovascular adverse events rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61‐0.67 and microvascular composite (RR 0.67, 95% CI 0.64‐0.70) with 15 mg tirzepatide, and 5‐year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72‐0.79) and microvascular composite (RR 0.79, 95% CI 0.76‐0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5‐year risk reduction in diabetes‐related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%‐33% when a conservative scenario was assumed.
Conclusion
With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5‐year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long‐term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.
The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 ...diabetes and the presentation of an innovative model describing the disorder's natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal-a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network. Hence, the National Institutes of Health formed the landmark Diabetes Prevention Trial-Type 1 (DPT-1) in the mid-1990s, an effort that led to Type 1 Diabetes TrialNet. TrialNet studies have helped identify novel biomarkers; delineate type 1 diabetes progression, resulting in identification of highly predictable stages defined by the accumulation of autoantibodies (stage 1), dysglycemia (stage 2), and disease meeting clinical criteria for diagnosis (stage 3); and oversee numerous clinical trials aimed at preventing disease progression. Such efforts pave the way for stage-specific intervention trials with improved hope that a means to effectively disrupt the disorder's development will be identified.
Summary Background The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main ...antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. Methods In this multicentre, double-blind, randomised controlled trial, patients aged 6–45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov , NCT00505375. Findings 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1–112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47–15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 22% patients on abatacept and 11 reactions in six 17% on placebo). There was no increase in infections (32 42% patients on abatacept vs 15 43% on placebo) or neutropenia (seven 9% vs five 14%). Interpretation Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding US National Institutes of Health.
Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type ...1 diabetes in a population of homogenous HLA class II genotypes.
High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland.
Study site-specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location.
The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects.
Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and ...before disease onset. We hypothesized that three pancreas enzymes (amylase, lipase, and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody-positive (1AAb
) and multiple-AAb
(≥2AAb
) subjects, individuals with recent-onset or established type 1 diabetes, their AAb-negative (AAb
) first-degree relatives, and AAb
control subjects. Lipase and trypsinogen were significantly reduced in ≥2AAb
, recent-onset, and established type 1 diabetes subjects versus control subjects and 1AAb
, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (area under the receiver operating characteristic curve AUROC = 81.4%) performed equivalently to all three enzymes (AUROC = 81.4%) in categorizing ≥2AAb
versus 1AAb
subjects. For cohort 2 (
= 246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPV
,
< 0.001), previously measured by MRI. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPV
and may improve disease staging in pretype 1 diabetes.
Objectives To investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and ...across diverse subgroups. Methods We conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF. Results Of the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67–9.99) and 11.70 (95% CI: 10.9–12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease. Conclusion Compared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.
Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example, insulin as a marker of ...β-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here, we demonstrate the use of cell type-specific DNA methylation markers for determining the fraction of specific cell types in human islet and pancreas specimens. We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition. In islet preparations, normalization of insulin secretion to β-cell DNA revealed similar β-cell function in pre-type 1 diabetes (T1D), T1D, and type 2 diabetes (T2D), which was significantly lower than in donors without diabetes. In histological pancreas specimens from recent-onset T1D, this assay showed β-cell fraction within the normal range, suggesting a significant contribution of β-cell dysfunction. In T2D pancreata, we observed increased α-cell fraction and normal β-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease.
Functional Defects and the Influence of Age on the Frequency of CD4 + CD25 + T-Cells in Type 1 Diabetes
Todd M. Brusko 1 ,
Clive H. Wasserfall 1 ,
Michael J. Clare-Salzler 1 ,
Desmond A. Schatz 2 and
...Mark A. Atkinson 1
1 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida
2 Department of Pediatrics, University of Florida, Gainesville, Florida
Address correspondence and reprint requests to Mark A. Atkinson, PhD, Department of Pathology, College of Medicine, University
of Florida, ARB-R3-128, 1600 SW Archer Rd., Gainesville, FL 32610-0275. E-mail: atkinson{at}ufl.edu
Abstract
CD4 + CD25 + T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency
and function of CD4 + CD25 + T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between
increasing age and CD4 + CD25 + T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients,
similar frequencies of CD4 + CD25 + and CD4 + CD25 +Bright T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between
type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD4 + CD25 + or CD4 + CD25 +Bright T-cell frequency. However, type 1 diabetic patients were markedly defective in their ability to suppress the proliferation
of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced
production of interleukin (IL)-2, γ-interferon, and transforming growth factor-β, whereas other cytokines including those
of adaptive and innate immunity (IL-10, IL-1β, IL-6, IL-8, IL-12p70, and tumor necrosis factor-α) were similar in control
subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD4 + CD25 + T-cells and that function, rather than frequency, may represent the means by which these cells associate with type 1 diabetes
in humans.
APC, allophycocyanin
GM-CSF, granulocyte-macrophage colony-stimulating factor
IFN-γ, γ-interferon
IL, interleukin
PE, phycoerythrin
Teff, CD4+CD25− effector T-cell
TGF, transforming growth factor
TNF, tumor necrosis factor
Treg, CD4+CD25+ regulatory T-cell
Footnotes
Accepted February 9, 2005.
Received October 20, 2004.
DIABETES
Emerging data suggest that type 1 diabetes affects not only the β-cell–containing islets of Langerhans, but also the surrounding exocrine compartment. Using digital pathology, machine learning ...algorithms were applied to high-resolution, whole-slide images of human pancreata to determine whether the tissue composition in individuals with or at risk for type 1 diabetes differs from those without diabetes. Transplant-grade pancreata from organ donors were evaluated from 16 nondiabetic autoantibody-negative controls, 8 nondiabetic autoantibody-positive subjects with increased type 1 diabetes risk, and 19 persons with type 1 diabetes (0 to 12 years’ duration). HALO image analysis algorithms were implemented to compare architecture of the main pancreatic duct as well as cell size, density, and area of acinar, endocrine, ductal, and other nonendocrine, nonexocrine tissues. Type 1 diabetes was found to affect exocrine area, acinar cell density, and size, whereas the type of difference correlated with the presence or absence of insulin-positive cells remaining in the pancreas. These changes were not observed before disease onset, as indicated by modeling cross-sectional data from pancreata of autoantibody-positive subjects and those diagnosed with type 1 diabetes. These data provide novel insights into anatomic differences in type 1 diabetes pancreata and demonstrate that machine learning can be adapted for the evaluation of disease processes from cross-sectional data sets.
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