Objective: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody positive (Ab+) relatives of people with type 1 diabetes. Methods: We examined 2-hour OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (Mean±SD age: 13.84±9.53 years; BMI-Z-Score: 0.33±1.07; 56.1% male) and 3,720 PTP participants (age: 16.01±12.33 Years, BMI-Z-Score 0.66±1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-Score, HOMA-IR and peak Glucose/C-peptide levels, respectively) were performed. Results: In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (p<0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: X2 = 25.76 vs. X2 = 8.62 and PTP: X2 = 149.19 vs. X2 = 79.98; all p<0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. Conclusions: In two independent at risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.

C-peptide

10.2337/figshare.14974563

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Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

The Lancet (2011)

Diane K. Wherrett Brian N. Bundy Dorothy J. Becker Linda A. DiMeglio Stephen E. Gitelman

10.1016/s0140-6736(11)60895-7

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Citations (351)

Successful Prospective Prediction of Type 1 Diabetes in Schoolchildren Through Multiple Defined Autoantibodies

Diabetes Care (2002)

James M. LaGasse Michael S. Brantley Nicola Leech Rachel Rowe Stephanie A. Monks

OBJECTIVE—Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population. RESEARCH DESIGN AND METHODS—Autoantibodies to pancreatic islets (islet cell antibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test >99th percentile. RESULTS—Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25–75%) and 100% sensitivity (58–100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86–99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers. CONCLUSIONS—Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years.

10.2337/diacare.25.3.505

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Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans

Diabetes (1989)

Jerry P. Palmer S. Helqvist G. A. Spinas J. Molvig T. Mandrup-Poulsen

BETA (programming language)

10.2337/diabetes.38.10.1211

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Citations (17)

Evaluation of a novel radioimmunoassay using125I-labelled human recombinant GAD65 for the determination of glutamic acid decarboxylase (GAD65) autoantibodies

International Journal of Clinical & Laboratory Research (2000)

S Marcovina Mona Landin‐Olsson A. Essen-Möller Jerry P. Palmer Åke Lernmark

10.1007/s005990070029

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Citations (14)

Comparison of two insulin assays for first-phase insulin release in type 1 diabetes prediction and prevention studies

Clinica Chimica Acta (2011)

Jeffrey L. Mahon Craig A. Beam Santica M. Marcovina David Boulware Jerry P. Palmer

10.1016/j.cca.2011.07.019

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Citations (16)

Latent autoimmune diabetes in adults (LADA).

Reviews in Endocrine and Metabolic Disorders (2003)

Ramachandra G. Naik Jerry P. Palmer

Autoimmune diabetes

10.1023/a:1025148211587

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Citations (98)

Insulin Autoantibodies

E&M. Endocrinology and metabolism (1990)

Jerry P. Palmer

10.1007/978-1-4612-3218-6_7

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Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes

Diabetes Care (2014)

Barbara Brooks‐Worrell Edward J. Boyko Jerry P. Palmer

Cross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.Twenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits.Of the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab-T-), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses.These pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline.

10.2337/dc14-0961

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Citations (43)