Browsing by Author "Marks, Jennifer B."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose
    (Portland Press, 2012-02) Perlstein, Todd S.; Henry, Robert R.; Mather, Kieren J.; Rickels, Michael R.; Abate, Nicola I.; Grundy, Scott M.; Mai, Yabing; Albu, Jeanine B.; Marks, Jennifer B.; Pool, James L.; Creager, Mark A.; Department of Endodontics, IU School of Dentistry
    AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic β-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic β-cell function.
  • Thumbnail Image
    Item
    Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials
    (Elsevier, 2013) Moran, Antoinette; Bundy, Brian; Becker, Dorothy J.; DiMeglio, Linda A.; Gitelman, Stephen E.; Goland, Robin; Greenbaum, Carla J.; Herold, Kevan C.; Marks, Jennifer B.; Raskin, Philip; Sanda, Srinath; Schatz, Desmond; Wherrett, Diane K.; Wilson, Darrell M.; Krischer, Jeffrey P.; Skyler, Jay S.; Pickersgill, Linda; de Koning, Eelco; Ziegler, Anette-G; Böehm, Bernhard; Badenhoop, Klaus; Schloot, Nanette; Bak, Jens Friis; Pozzilli, Paolo; Mauricio, Didac; Donath, Marc Y.; Castaño, Luis; Wägner, Ana; Lervang, Hans Henrik; Perrild, Hans; Poulsen, Thomas Mandrup; Pediatrics, School of Medicine
    Background: Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. Methods: We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Findings: Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Interpretation: Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders.
  • Thumbnail Image
    Item
    Oral Glucose Tolerance Test Measures of First-phase Insulin Response and Their Predictive Ability for Type 1 Diabetes
    (Oxford University Press, 2022) Baidal, David A.; Warnock, Megan; Xu, Ping; Geyer, Susan; Marks, Jennifer B.; Moran, Antoinette; Sosenko, Jay; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Context: Decreased first-phase insulin response (FPIR) during intravenous glucose tolerance testing (IVGTT) is an early indicator of β-cell dysfunction and predictor of type 1 diabetes (T1D). Objective: Assess whether oral glucose tolerance test (OGTT) measures could serve as FPIR alternatives in their ability to predict T1D in autoantibody positive (Aab+) subjects. Design: OGTT and IVGTT were performed within 30 days of each other. Eleven OGTT variables were evaluated for (1) correlation with FPIR and (2) T1D prediction. Setting: Type 1 Diabetes TrialNet "Oral Insulin for Prevention of Diabetes in Relatives at Risk for T1D" (TN-07) and Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) studies clinical sites. Patients: TN-07 (n = 292; age 9.4 ± 6.1 years) and DPT-1 (n = 194; age 15.1 ± 10.0 years) Aab + relatives of T1D individuals. Main outcome measures: (1) Correlation coefficients of OGTT measures with FPIR and (2) T1D prediction at 2 years using area under receiver operating characteristic (ROCAUC) curves. Results: Index60 showed the strongest correlation in DPT-1 (r = -0.562) but was weaker in TN-07 (r = -0.378). C-peptide index consistently showed good correlation with FPIR across studies (TN-07, r = 0.583; DPT-1, r = 0.544; P < 0.0001). Index60 and C-peptide index had the highest ROCAUCs for T1D prediction (0.778 vs 0.717 in TN-07 and 0.763 vs 0.721 in DPT-1, respectively; P = NS), followed by FPIR (0.707 in TN-07; 0.628 in DPT-1). Conclusions: C-peptide index was the strongest measure to correlate with FPIR in both studies. Index60 and C-peptide index had the highest predictive accuracy for T1D and were comparable. OGTTs could be considered instead of IVGTTs for subject stratification in T1D prevention trials.
  • Thumbnail Image
    Item
    Rituximab, B-lymphocyte depletion, and preservation of beta-cell function
    (Massachusetts Medical Society, 2009-11-26) Pescovitz, Mark D.; Greenbaum, Carla J.; Krause-Steinrauf, Heidi; Becker, Dorothy J.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Marks, Jennifer B.; McGee, Paula F.; Moran, Antoinette M.; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond A.; Wherrett, Diane; Wilson, Darrell M.; Lachin, John M.; Skyler, Jay S.; Type 1 Diabetes TrialNet Anti-CD20 Study Group; Medicine, School of Medicine
    BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition.