Search

OBJECTIVE Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. RESEARCH DESIGN AND METHODS Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. RESULTS GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30–0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs. CONCLUSIONS Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function.

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6–36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome—baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years—showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168–0.268) and 0.141 nmol/L (95% CI 0.071–0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

OBJECTIVE We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of β-cell function in recent-onset type 1 diabetes mellitus (T1DM) at 1 year. Subjects were followed further to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Eighty-seven subjects (aged 8–40 years) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome—baseline-adjusted mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 1 year—showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months. RESULTS The rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times with the placebo group means using a global test (P = 0.03). Odds ratio for loss of C-peptide to CONCLUSIONS Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide but does not appear to fundamentally alter the underlying pathophysiology of the disease.

OBJECTIVE—Compare the efficacy, safety, and patient satisfaction of continuous subcutaneous insulin infusion (CSII) therapy with multiple daily injection (MDI) therapy for patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 132 CSII-naive type 2 diabetic patients were randomly assigned (1:1) to CSII (using insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multicenter, open-label, randomized, parallel-group, 24-week study. Efficacy was assessed with HbA1c and eight-point blood glucose (BG) profiles. Treatment satisfaction was determined with a self-administered questionnaire. Safety assessments included adverse events, hypoglycemic episodes, laboratory values, and physical examination findings. RESULTS—HbA1c values decreased similarly for both groups from baseline (8.2 ± 1.37% for CSII, 8.0 ± 1.08% for MDI) to end of study (7.6 ± 1.22% for CSII, 7.5 ± 1.22% for MDI). The CSII group showed a trend toward lower eight-point BG values at most time points (only significant 90 min after breakfast; 167 ± 48 vs. 192 ± 65 mg/dl for CSII and MDI, respectively; P = 0.019). A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups. CONCLUSIONS—Insulin aspart in CSII therapy provided efficacy and safety comparable to MDI therapy for type 2 diabetes. Patients with type 2 diabetes can be trained as outpatients to use CSII and prefer CSII to injections, indicating that pump therapy should be considered when initiating intensive insulin therapy for type 2 diabetes.

OBJECTIVE Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes. RESULTS Compared with SBP 105–129 mmHg, the risk of ACR worsening increased significantly for SBP 130–139 mmHg (HR 1.88 [95% CI 1.28–2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66–3.78]; P < 0.0001). Compared with a PP range of 40–49 mmHg, PP CONCLUSIONS SBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to

Compare the efficacy, safety, and patient satisfaction of continuous subcutaneous insulin infusion (CSII) therapy with multiple daily injection (MDI) therapy for patients with type 2 diabetes.A total of 132 CSII-naive type 2 diabetic patients were randomly assigned (1:1) to CSII (using insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multicenter, open-label, randomized, parallel-group, 24-week study. Efficacy was assessed with HbA(1c) and eight-point blood glucose (BG) profiles. Treatment satisfaction was determined with a self-administered questionnaire. Safety assessments included adverse events, hypoglycemic episodes, laboratory values, and physical examination findings.HbA(1c) values decreased similarly for both groups from baseline (8.2 +/- 1.37% for CSII, 8.0 +/- 1.08% for MDI) to end of study (7.6 +/- 1.22% for CSII, 7.5 +/- 1.22% for MDI). The CSII group showed a trend toward lower eight-point BG values at most time points (only significant 90 min after breakfast; 167 +/- 48 vs. 192 +/- 65 mg/dl for CSII and MDI, respectively; P = 0.019). A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups.Insulin aspart in CSII therapy provided efficacy and safety comparable to MDI therapy for type 2 diabetes. Patients with type 2 diabetes can be trained as outpatients to use CSII and prefer CSII to injections, indicating that pump therapy should be considered when initiating intensive insulin therapy for type 2 diabetes.