Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.

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. (ClinicalTrials.gov number, NCT00279305.)

Gender differences in vascular function and insulin sensitivity in young adults.

To examine influence of insulin resistance and other clinical risk factors for the MetS (metabolic syndrome) on vascular structure and function in young adults. This cross-sectional study was conducted in a cohort of young adults (mean age 22 years) and their siblings participating in a longitudinal study of cardiovascular risk (n=370). Insulin sensitivity was determined by euglycaemic insulin clamp. EDD (endothelium-dependent dilation) was determined by flow-mediated dilation using high-resolution ultrasound imaging of the brachial artery. EID (endothelium-independent dilation) was determined by NTG (nitroglycerine)-mediated dilation. The diameter and cIMT (intima-media thickness) of the carotid artery were also measured. There was no significant difference between males and females for age or body mass index. However, males had significantly higher glucose and triacylglycerol (triglyceride) levels, while the females had significantly higher HDL-C (high-density lipoprotein-cholesterol) and insulin sensitivity (13.00 ± 0.33 compared with 10.71 ± 0.31 mg·kg-1 of lean body mass·min-1, P<0.0001). Although peak EDD was significantly lower (6.28 ± 0.26 compared with 8.50 ± 0.28%, P<0.0001) in males than females, this difference was largely explained by adjustment for brachial artery diameter (P=0.15). Peak EID also was significantly lower in males than females (20.26 ± 0.44 compared with 28.64 ± 0.47%, P<0.0001), a difference that remained significantly lower after adjustment for brachial artery diameter. Males had a significantly greater cIMT compared with females (females 0.420 ± 0.004 compared with males 0.444 ± 0.004 mm, P=0.01), but when adjusted for carotid diameter, there was no significant difference (P=0.163). Although there were gender differences in vascular function and structure in the young adult population examined in this study, many of the differences were eliminated simply by adjusting for artery diameter. However, the lower EID observed in males could not be explained by artery diameter. Future studies need to continue to examine influence of gender on EID and other measures of vascular function.

Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 diabetes.

OBJECTIVE: This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing beta-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS: One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS: Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.

Influence of waist on adiponectin and insulin sensitivity in adolescence.

It has been hypothesized that abdominal obesity leads to insulin resistance partly through decreased adiponectin. However, the cross-sectional and longitudinal associations among waist, adiponectin, and insulin sensitivity have not been examined in older adolescents. Non-Hispanic white and black children were recruited from the Minneapolis school district and underwent three examinations at mean ages 13, 15, and 19. Insulin sensitivity (measured using the gold-standard euglycemic clamp) and waist circumference were measured at all exams. Adiponectin was measured at mean ages 15 and 19. Partial correlations were used to examine associations among waist, adiponectin, and insulin sensitivity at mean age 15 (n = 308) and mean age 19 (n = 218). Longitudinal correlations and a longitudinal regression model were used to predict adiponectin and insulin sensitivity measured at ages 15 and 19, from age 13 waist and change in waist. At age 15, waist and adiponectin were significantly correlated (r = -0.32). At age 19, waist and adiponectin were significantly correlated (r = -0.36), as were waist and insulin sensitivity (r = -0.16). Both baseline waist and change in waist were significantly inversely associated with age 19 adiponectin but with age 19 insulin sensitivity only in men. In conclusion, in adolescents, the association between waist and adiponectin appears to develop several years before the association between waist and insulin sensitivity and there is a longitudinal association between waist and adiponectin. These results support the hypothesis that adiponectin may contribute to the association of waist and insulin sensitivity.