Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.
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ABSTRACT:
SUBMITTER: Sims EK
PROVIDER: S-EPMC8610022 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS:We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS:A total of 76 participants (55 [72%] of whom were ?18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P?=?0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS:Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).
| S-EPMC6776880 | biostudies-literature
Project description:End points that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic end points can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-h oral glucose tolerance tests on a two-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic end points that indicate GCRC changes, the within-quadrant end point and the ordinal directional end point, were consistent with visual impressions of an appreciable treatment effect at the 3- and 6-month time points. In conclusion, an analytic approach combining visual evidence with novel end points demonstrated that teplizumab delays rapid metabolic decline and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.
| S-EPMC8660991 | biostudies-literature
Project description:ObjectiveIn November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10.Research design and methodsTo provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted.ResultsThe primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted.ConclusionsThese data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment.
| S-EPMC10545553 | biostudies-literature
Project description:Alterations in mitochondrial function have been implicated in the etiology of schizophrenia. Most studies have investigated alterations in mitochondrial function in patients in which the disorder is already established; however, whether mitochondrial dysfunction predates the onset of psychosis remains unknown. We measured peripheral mitochondrial complex (I-V) function and lactate/pyruvate levels in 27 antipsychotic-naïve individuals at clinical high risk for psychosis (CHR) and 16 healthy controls. We also explored the association between mitochondrial function and brain microglial activation and glutathione levels using a translocator protein 18 kDa [18F]FEPPA PET scan and 1H-MRS scan, respectively. There were no significant differences in mitochondrial complex function and lactate/pyruvate levels between CHR and healthy controls. In the CHR group, mitochondrial complex III function (r = -0.51, p = 0.008) and lactate levels (r = 0.61, p = 0.004) were associated with prodromal negative symptoms. As previously reported, there were no significant differences in microglial activation and glutathione levels between groups, however, mitochondrial complex IV function was inversely related to microglial activation in the hippocampus in CHR (r = -0.42, p = 0.04), but not in healthy controls. In conclusion, alterations in mitochondrial function are not yet evident in CHR, but may relate to the severity of prodromal symptoms, particularly negative symptoms.
| S-EPMC5906614 | biostudies-literature
Project description:Introduction: Alterations in autonomic functioning in individuals diagnosed with schizophrenia are well-documented. Yet, it is currently unclear whether these dysfunctions extend into the clinical high-risk state. Thus, we investigated resting heart rate (RHR) and heart rate variability (HRV) indices in individuals at clinical high-risk for psychosis (CHR-P). Methods: We recruited 117 CHR-P participants, 38 participants with affective disorders and substance abuse (CHR-N) as well as a group of 49 healthy controls. CHR-P status was assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). We obtained 5 min, eyes-open resting-state MEG data, which was used for the extraction of cardiac field-related inter-beat-interval data and from which heart-rate and heart-rate variability measures were computed. Results: Compared to both CHR-N and healthy controls, CHR-P participants were characterized by an increased RHR, which was not explained by differences in psychopathological comorbidity and medication status. Increased RHR correlated with the presence of subthreshold psychotic symptoms and associated distress. No differences between groups were found for heart-rate variability measures, however. Furthermore, there was an association between motor-performance and psychophysiological measures. Conclusion: The current study provides evidence of alterations in autonomic functioning as disclosed by increased RHR in CHR-P participants. Future studies are needed to further evaluate this characteristic feature of CHR-P individuals and its potential predictive value for psychosis development.
| S-EPMC7677235 | biostudies-literature
Project description:Background and purposeGlycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi-s) are glucose lowering agents that cause the accumulation of glucose in the liver as glycogen. Glycogen metabolism has implications in beta cell function. Glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in beta cells by GPi-s affects the function of these cells.Experimental approachThe effects of structurally different GPi-s were investigated on MIN6 insulinoma cells and in a mouse model of diabetes.Key resultsGPi treatment increased glycogen content and, consequently, the surface area of glycogen in MIN6 cells. Furthermore, GPi treatment induced insulin receptor β (InsRβ), Akt and p70S6K phosphorylation, as well as pancreatic and duodenal homeobox 1(PDX1) and insulin expression. In line with these findings, GPi-s enhanced non-stimulated and glucose-stimulated insulin secretion in MIN6 cells. The InsRβ was shown to co-localize with glycogen particles as confirmed by in silico screening, where components of InsR signalling were identified as glycogen-bound proteins. GPi-s also activated the pathway of insulin secretion, indicated by enhanced glycolysis, mitochondrial oxidation and calcium signalling. Finally, GPi-s increased the size of islets of Langerhans and improved glucose-induced insulin release in mice.Conclusion and implicationsThese data suggest that GPi-s also target beta cells and can be repurposed as agents to preserve beta cell function or even ameliorate beta cell dysfunction in different forms of diabetes.Linked articlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
| S-EPMC5758390 | biostudies-literature
Project description:PURPOSE:Epstein-Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families. EXPERIMENTAL DESIGN:We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated. RESULTS:A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4-16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5-61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker. CONCLUSIONS:Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity.
| S-EPMC3268357 | biostudies-literature
Project description:Breakthrough COVID-19 may occur in fully vaccinated persons. In this cohort of 1395 persons (mean age, 54.3 years; 60% female; median body mass index, 30.7) who developed breakthrough COVID-19, there were 107 (7.7%) who required hospitalization by day 28. Hospitalization was significantly associated with the number of medical comorbidities. Anti-spike monoclonal antibody treatment was significantly associated with a lower risk of hospitalization (Odds Ratio: 0.227; 95% confidence interval, 0.128 - 0.403; p<0.001). The number needed to treat (NNT) to prevent one hospitalization was 225 among the lowest-risk patient group compared to NNT of 4 among those with highest numbers of medical comorbidity.
| S-EPMC8767864 | biostudies-literature
Project description:Studies comparing linear and radial EUS for the detection of pancreatic lesions in an asymptomatic population with increased risk for pancreatic cancer are lacking.To compare pancreatic lesion detection rates between radial and linear EUS and to determine the incremental diagnostic yield of a second EUS examination.Randomized controlled tandem study.Five academic centers in the United States.Asymptomatic high-risk individuals (HRIs) for pancreatic cancer undergoing screening EUS.Linear and radial EUS performed in randomized order.Pancreatic lesion detection rate by type of EUS, miss rate of 1 EUS examination, and incremental diagnostic yield of a second EUS examination (second-pass effect).Two hundred seventy-eight HRIs were enrolled, mean age 56 years (43.2%), and 90% were familial pancreatic cancer relatives. Two hundred twenty-four HRIs underwent tandem radial and linear EUS. When we used per-patient analysis, the overall prevalence of any pancreatic lesion was 45%. Overall, 16 of 224 HRIs (7.1%) had lesions missed during the initial EUS that were detected by the second EUS examination. The per-patient lesion miss rate was significantly greater for radial followed by linear EUS (9.8%) than for linear followed by radial EUS (4.5%) (P = .03). When we used per-lesion analysis, 73 of 109 lesions (67%) were detected by radial EUS and 99 of 120 lesions (82%) were detected by linear EUS (P < .001) during the first examination. The overall miss rate for a pancreatic lesion after 1 EUS examination was 47 of 229 (25%). The miss rate was significantly lower for linear EUS compared with radial EUS (17.5% vs 33.0%, P = .007).Most detected pancreatic lesions were not confirmed by pathology.Linear EUS detects more pancreatic lesions than radial EUS. There was a "second-pass effect" with additional lesions detected with a second EUS examination. This effect was significantly greater when linear EUS was used after an initial radial EUS examination.
| S-EPMC4609234 | biostudies-literature
Project description:BackgroundAnti-nuclear antibodies (ANA) assessed by immunofluorescence (IF) microscopy are associated with systemic autoimmune rheumatic diseases (SARD) and can be detected years before onset of clinical symptoms. Recent data indicate dysregulation of the immune system with increased levels of proinflammatory cytokines, including type I interferons (IFN), in ANA-positive versus ANA-negative individuals. Herein, the aims were to investigate IF-ANA, ANA fine specificities, and IFN-α protein levels in relation to self-reported symptoms, as well as clinical signs, of SARD in a large group of healthy blood donors (HBD).MethodsSera from 825 HBD (48.8% females) were included. IF-ANA was assessed, using HEp-2 cells, according to the routine at the accredited laboratory of Clinical Immunology, Linköping University Hospital. All samples were analyzed for IgG-ANA fine specificities using addressable laser bead assay (ALBIA) at the same laboratory. IFN-α was determined using ELISA. Antibody-positive individuals, and their sex- and age-matched antibody-negative controls, were asked to fill a questionnaire regarding symptoms associated with SARD.ResultsIn total, 130 HBD (15.8%) were positive with IF-ANA and/or ALBIA. Anti-U1RNP was significantly more common among women. Generally, self-reported symptoms correlated poorly with IF-ANA and/or ALBIA results. Two females with high levels of Ro60/SSA, Ro52/SSA and IFN-α reported mild sicca symptoms and were diagnosed with Sjögren's disease after clinical evaluation.ConclusionA considerable proportion of apparently HBD are autoantibody positive, but without clear association to self-reported symptoms. Nevertheless, the combination of autoantibodies, relevant symptoms and high IFN-α levels identified the small proportion of individuals with SARD in the study population.
| S-EPMC11368755 | biostudies-literature