Studies of new therapies to preserve insulin secretion in early type 1 diabetes require several years to recruit eligible subjects and to see a treatment effect; thus, there is interest in ...alternative study designs to speed this process. Most people with longstanding type 1 diabetes no longer secrete insulin. However, studies from pancreata of those with longstanding T1D show that beta cells staining for insulin can persist for decades after diagnosis, and this is paralleled in work showing proinsulin secretion in individuals with longstanding disease; collectively this suggests that there is a reserve of alive but "sleeping" beta cells. Here, we designed a novel clinical trial platform to test whether a short course of therapy with an agent known to have effects in type 1 diabetes with residual endogenous insulin could transiently induce insulin secretion in those who no longer produce insulin. A therapy that transiently "wakes up" sleeping beta cells might be tested next in a fully powered trial in those with endogenous insulin secretion. In this three-arm non-randomized pilot study, we tested three therapies known to impact disease: two beta-cell supportive agents, liraglutide and verapamil, and an immunomodulatory agent, golimumab. The golimumab treated arm was not fully enrolled due to uncertainties about immunotherapy during the COVID-19 pandemic. Participants had mixed-meal tolerance test (MMTT)-stimulated C-peptide below the quantitation limit (<0.02 ng/mL) at enrollment and received 8 to 12 weeks of therapy. At the completion of therapy, none of the individuals achieved the primary outcome of MMTT-stimulated C-peptide ≥ 0.02 ng/mL. An exploratory outcome of the verapamil arm was MRI-assessed pancreas size, diffusion, and longitudinal relaxation time, which showed repeatability of these measures but no treatment effect. The liraglutide and golimumab arms were registered on clinicaltrials.gov under accession number NCT03632759 and the verapamil arm under accession number NCT05847413. Trail registration: Protocols are registered in ClinicalTrials.gov under accession numbers NCT03632759 and NCT05847413.
Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the ...polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.
Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or ...prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.
We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.
A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.
Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.
Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into ...progression to clinical stage 3 type 1 diabetes.
One hundred five relatives of individuals in type 1 diabetes probands (median age 16.8 years; 89% non-Hispanic White; 43.8% female) from the TrialNet Pathway to Prevention study underwent 7-day CGM assessments and oral glucose tolerance tests (OGTTs) at 6-month intervals. The baseline data are reported here. Three groups were evaluated: individuals with 1) stage 2 type 1 diabetes (n = 42) with two or more diabetes-related autoantibodies and abnormal OGTT; 2) stage 1 type 1 diabetes (n = 53) with two or more diabetes-related autoantibodies and normal OGTT; and 3) negative test for all diabetes-related autoantibodies and normal OGTT (n = 10).
Multiple CGM metrics were associated with progression to stage 3 type 1 diabetes. Specifically, spending ≥5% time with glucose levels ≥140 mg/dL (P = 0.01), ≥8% time with glucose levels ≥140 mg/dL (P = 0.02), ≥5% time with glucose levels ≥160 mg/dL (P = 0.0001), and ≥8% time with glucose levels ≥160 mg/dL (P = 0.02) were all associated with progression to stage 3 disease. Stage 2 participants and those who progressed to stage 3 also exhibited higher mean daytime glucose values; spent more time with glucose values over 120, 140, and 160 mg/dL; and had greater variability.
CGM could aid in the identification of individuals, including those with a normal OGTT, who are likely to rapidly progress to stage 3 type 1 diabetes.
SLC38A8 mutation spectrum in foveal hypoplasia Derar, Mohammed; Lord, Emma C.; Poulter, James A. ...
Acta ophthalmologica (Oxford, England),
January 2022, 2022-01-00, 20220101, Letnik:
100, Številka:
S267
Journal Article
Recenzirano
Purpose
Significant phenotypic overlap exists between ocular albinism and SLC38A8 related foveal hypoplasia (FH) which hinders differential diagnosis. To facilitate molecular testing, we catalogued ...the spectrum of known pathogenic variants in SLC38A8 responsible for FH.
Methods
The UK 100 000 genomes (100KG) datasets were analysed to detect pathogenic SLC38A8 variants compatible with recessive inheritance in cases with phenotypes reminiscent of FH. Published literature was accessed to capture deleterious variants reported in FH affected families. Additional variants identified locally were incorporated for bioinformatic analysis. Variant interpretation included in‐silico pathogenicity assessment, population data and protein modelling.
Results
In total, 41 pathogenic variants in SLC38A8 have been identified in 51 FH families; 17 missense, 4 splice site, 2 in‐frame deletions, 6 frameshift, 6 nonsense, 4 large deletions, a multiple exon inversion and a whole gene deletion. Nonsense variants are evenly distributed throughout the gene and protein, while missense variants are more likely to reside in transmembrane domains. 38 SLC38A8 variants were reported in the literature and we have identified 3 novel and 2 known variants in 4 families derived from the 100KG datasets and our local cohort. In one patient, a novel g.84049578_84060679inv (GRCh37) was detected in a homozygous state. Another harboured novel variant c.922_923insTG, p.(Thr308Metfs*14) and c.922A>G, p.(Thr308Ala). Other homozygous variants include c.848A>C, p.(Asp283Ala) and novel variant c.77C>T, p.(Ser26leu). Protein modelling of SLC38A8 predicted a destabilising effect by both p.(Ser26leu) and p.(Thr308Ala). Haplotype analysis of Pakistani, Bangladeshi and Indian patients harbouring c.264C>G, p.(Tyr88*) suggest a South Asian founder effect.
Conclusions
We reviewed and extended the spectrum of SLC38A8 variants causative for FH. The presence of multiple nonsense variants and in‐silico modelling of missense variants suggests a complete loss of function as the likely disease mechanism.
Background:
Under controlled conditions, the Dose Safety artificial pancreas (AP) system controller, which utilizes “fuzzy logic” (FL) methodology to calculate and deliver appropriate insulin dosages ...based on changes in blood glucose, successfully managed glycemic excursions. The aim of this study was to show whether stressing the system with pizza (high carbohydrate/high fat) meals and exercise would reveal deficits in the performance of the Dose Safety FL controller (FLC) and lead to improvements in the dosing matrix.
Methods:
Ten subjects with type 1 diabetes (T1D) were enrolled and participated in 30 studies (17 meal, 13 exercise) using 2 versions of the FLC. After conducting 13 studies with the first version (FLC v2.0), interim results were evaluated and the FLC insulin-dosing matrix was modified to create a new controller version (FLC v2.1) that was validated through regression testing using v2.0 CGM datasets prior to its use in clinical studies. The subsequent 17 studies were performed using FLC v2.1.
Results:
Use of FLC v2.1 vs FLC v2.0 in the pizza meal tests showed improvements in mean blood glucose (205 mg/dL vs 232 mg/dL, P = .04). FLC v2.1 versus FLC v2.0 in exercise tests showed improvements in mean blood glucose (146 mg/dL vs 201 mg/dL, P = .004), percentage time spent >180 mg/dL (19.3% vs 46.7%, P = .001), and percentage time spent 70-180 mg/dL (80.0% vs 53.3%, P = .002).
Conclusion:
Stress testing the AP system revealed deficits in the FLC performance, which led to adjustments to the dosing matrix followed by improved FLC performance when retested.
Identifying cases of diabetes caused by single gene mutations between the more common type 1 diabetes (T1D) and type 2 diabetes (T2D) is a difficult but important task. We report the diagnosis of ...ATP-binding cassette transporter sub-family C member 8 (ABCC8)-related monogenic diabetes in a 35-year-old woman with a protective human leukocyte antigen (HLA) allele who was originally diagnosed with T1D at 18 years of age.
Patient A presented with polyuria, polydipsia, and hypertension at the age of 18 years and was found to have a blood glucose > 500 mg/dL (70-199 mg/dL) and an HbA1C (hemoglobin A1C) >14% (4%-5.6%). She had an unmeasurable C-peptide but no urine ketones. She was diagnosed with T1D and started on insulin therapy. Antibody testing was negative. She required low doses of insulin and later had persistence of low but detectable C-peptide. At the age of 35 years, she was found to have a protective HLA allele, and genetic testing revealed a pathogenic mutation in the ABCC8 gene. The patient was then successfully transitioned to sulfonylurea therapy.
Monogenic diabetes diagnosed in adolescence typically presents with mild to moderate hyperglycemia, positive family history and, in some cases, other organ findings or dysfunction. The patient in this report presented with very high blood glucose, prompting the diagnosis of T1D. When she was found to have a protective HLA allele, further investigation revealed the mutation in the sulfonylurea receptor gene, ABCC8.
Patients suspected of having T1D but with atypical clinical characteristics such as negative autoantibodies, low insulin requirements, and persistence of C-peptide should undergo genetic testing for monogenic diabetes.
We conducted a phase II study in patients with HER2-positive locally advanced breast cancer or pathologic stage 3 breast cancer. Patients received epirubicin with cyclophosphamide followed by ...docetaxel. Targeted therapy with trastuzumab and bevacizumab were administered for 1 year. The pathologic complete response was comparable with other chemotherapy regimens and the high recurrence-free survival and overall survival are of interest in these high-risk populations.
The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC).
Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met.
A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval CI, 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively.
The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.
Abstract Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel following epirubicin plus cyclophosphamide (EC) ...in patients with HER2 positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Methods Patients received every three week treatment with 4 cycles of EC (90/600 mg/m2 ) followed by 4 cycles of docetaxel (100 mg/m2 ). Targeted therapy with standard dose trastuzumab plus bevacizumab 15 mg/kg was given for a total of one year. Co-primary endpoints were 1) rate of cardiac events (CE) in all patients defined as clinical CHF with a significant decrease in left ventricular ejection fraction (LVEF) or cardiac deaths and 2) pathological complete response (pCR) in both breast and nodes in the neoadjuvant cohort. An independent Cardiac Review Panel determined whether criteria for a cardiac event were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, four (4%; 95% CI, 1.1-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34-59). Five-year RFS and OS for all patients was 79.9% and 90.8%. Conclusions The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although pCR percentage is comparable to chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.
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