Prevention versus intervention of type 1 diabetes.

Type 1 diabetes (T1D) is a cell-mediated autoimmune disease. New cases of T1D are on the increase and exogenous insulin therapy is the only intervention regularly initiated for T1D patients. Though tremendous strides have been made in prediction of T1D, prevention and intervention strategies have not experienced the same success. In this review, we will discuss some possible reasons why new intervention therapies for T1D have not been implemented into the mainstream treatment regimen for T1D patients. We will also discuss potential caveats for why prevention and intervention trials in T1D may not have experienced the same success as prediction trials.

A comparison of the baseline metabolic profiles between Diabetes Prevention Trial-Type 1 and TrialNet Natural History Study participants.

OBJECTIVE: We assessed whether differing autoantibody screening criteria for type 1 diabetes (T1D) prevention trials result in different baseline metabolic profiles of those who screen positive. METHODS: Diabetes Prevention Trial-Type 1 (DPT-1) participants were screened for islet cell autoantibodies, whereas TrialNet Natural History Study (TNNHS) participants were screened for biochemical autoantibodies. In both studies, those determined to be autoantibody positive underwent baseline oral glucose tolerance tests (OGTTs) in which glucose and C-peptide were measured. RESULTS: The percentage of those with an OGTT in the diabetic range was higher among the DPT-1 participants (10.0% of 956 vs. 6.4% of 645, p < 0.01). In a logistic regression analysis with adjustments for age and gender, the difference persisted (p < 0.01). Among those in the non-diabetic range (n = 860 for DPT-1 and n = 604 for the TNNHS), glucose levels were similar at all time points, except for higher fasting glucose levels in the TNNHS participants (p < 0.001). There was a higher percentage of impaired fasting glucose (IFG) in the TNNHS participants (10.9 vs. 6.7%, p < 0.01); however, with adjustments for age and gender, there was no longer a significant difference. There was no significant difference in the percentages with impaired glucose tolerance. C-peptide levels were much lower in the DPT-1 cohort at all OGTT time points (p < 0.001 for all). DISCUSSION: Differing criteria for autoantibody screening can result in marked differences in the baseline metabolic profiles of prospective participants of T1D prevention trials.

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

OBJECTIVE: In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity. RESEARCH DESIGN AND METHODS: For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS: In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS: In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results.

OBJECTIVES: TrialNet's goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials. RESEARCH DESIGN AND METHODS: The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset. RESULTS: Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), > or =25% (n = 36), and > or =50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, > or =25%; 3 or more, > or =50%) and/or an abnormal OGTT (> or =50%). CONCLUSIONS: The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers.

Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients.

Insulin resistance is a primary component in the pathophysiology of type 2 diabetes. In latent autoimmune diabetes in adults (LADA), insulin resistance has been reported to be significantly lower than in autoantibody-negative type 2 diabetes (T2DM), but whether this might be related to differences in body mass index (BMI) has not been excluded. Furthermore, previous studies have used limiting inclusive criteria for LADA, requiring only the presence of GADA or IA-2A. To apply more inclusive criteria for LADA, consistent with recent recommendations, we defined LADA by clinical manifestations characteristic of T2DM, but with the presence of any combination of GADA, IA-2A, ICA, or IAA. We recruited 43 LADA patients, 70 T2DM patients, and 150 non-diabetic controls. Insulin resistance was assessed by both the homeostasis model assessment and the quantitative insulin sensitivity check index, and BMI was calculated. We found that insulin resistance in LADA is equivalent to that of T2DM. When insulin resistance is assessed as a function of BMI, both diabetic populations demonstrated an insulin resistance equally greater than normal controls. The interaction between insulin resistance and BMI in the two diabetic groups was significantly different from that demonstrated in non-diabetic controls. In summary, LADA demonstrates insulin resistance of similar magnitude to T2DM, but with the concurrent component of an immune attack against the pancreatic beta-cells. LADA patients may be at significant risk for metabolic consequences of insulin resistance other than glucose metabolism, such as those described in the metabolic syndrome. As complications and treatment regimens specific to LADA are realized, improved means of identification of LADA will become increasingly important.

Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes.

The objective of this study was to determine the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had two or more immunologic markers from the group consisting of islet cell antibodies (ICA), micro insulin autoantibodies (MIAA), GAD65 autoantibodies (GAA), and ICA512 autoantibodies (ICA512AA). Relatives of subjects with type 1 diabetes were screened for ICA as part of the Diabetes Prevention Trial-Type 1. A total of 71,148 samples were also tested for GAA and ICA512AA. IAA results were available on 17,207 of these samples using a protein A/protein G MIAA assay as well. The study population was defined to be those in which all four antibodies were tested. There were 1010 (5.9%) relatives with a single autoantibody on initial screening and 394 (2.3%) with two or more autoantibodies. GAA was more sensitive than ICA [GAA, 91% (357 of 394); ICA, 82% (324 of 394)] in the detection of multiple antibody-positive individuals. The addition of ICA512AA to GAA as a screening test increased sensitivity to 97% (381 of 394), whereas adding ICA512AA to ICA as a screening test increased sensitivity to 93% (367 of 394). GAA and ICA identified somewhat nonoverlapping subgroups of multiple antibody-positive subjects. Thus, the substitution of GAA or ICA for the other failed to detect 8-17% of multiple antibody subjects. Higher ICA titers were associated with increased percentages of multiple antibody-positive subjects; 86% of subjects having Juvenile Diabetes Foundation titers of at least 160 were positive for two or more antibodies. A screening strategy combining GAA and ICA512AA resulted in a higher sensitivity than using any marker individually, although statistically it was not significantly higher than using GAA alone. Screening for any three antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for two antibodies at one time and testing for the remaining antibodies among those who are positive for one resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with one biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. Further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort.