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  • 1
    Online Resource
    Online Resource
    Glucose Excursions Between States of Glycemia With Progression to Type 1 Diabetes in the Diabetes Prevention Trial–Type 1 (DPT-1)
    American Diabetes Association ; 2010
    In:  Diabetes Vol. 59, No. 10 ( 2010-10-01), p. 2386-2389
    Details
    In: Diabetes, American Diabetes Association, Vol. 59, No. 10 ( 2010-10-01), p. 2386-2389
    Abstract: We characterized fluctuations between states of glycemia in progressors to type 1 diabetes and studied whether those fluctuations are related to the early C-peptide response to oral glucose. RESEARCH DESIGN AND METHODS Oral glucose tolerance tests (OGTTs) from differing states of glycemia were compared within individuals for glucose and C-peptide. Dysglycemic OGTTs (DYSOGTTs) were compared with normal OGTTs (NLOGTT), while transient diabetic OGTTs (TDOGTTs) were compared with subsequent nondiabetic OGTTs and with OGTTs performed at diagnosis. RESULTS Of 135 progressors with four or more OGTTs, 30 (22%) went from NLOGTTs to DYSOGTTs at least twice. Area under the curve (AUC) glucose values from the second NLOGTT were higher (P & lt; 0.001) than values from the first NLOGTT. Among 98 progressors whose DYSOGTTs and NLOGTTs were synchronized for the time before diagnosis, despite higher glucose levels (P & lt; 0.01 at all time points) in the DYSOGTTs, 30- to 0-min C-peptide difference values changed little. Likewise, 30- to 0-min C-peptide difference values did not differ between TDOGTTs and subsequent (within 3 months) nondiabetic OGTTs in 55 progressors. In contrast, as glucose levels increased overall from the first to last OGTTs before diagnosis (P & lt; 0.001 at every time point, n = 207), 30- to 0-min C-peptide difference values decreased (P & lt; 0.001). CONCLUSIONS Glucose levels fluctuate widely as they gradually increase overall with progression to type 1 diabetes. As glucose levels increase, the early C-peptide response declines. In contrast, glucose fluctuations are not related to the early C-peptide response. This suggests that changes in insulin sensitivity underlie the glucose fluctuations.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db10-0534
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2010
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    Patterns of Metabolic Progression to Type 1 Diabetes in the Diabetes Prevention Trial–Type 1
    American Diabetes Association ; 2006
    In:  Diabetes Care Vol. 29, No. 3 ( 2006-03-01), p. 643-649
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 29, No. 3 ( 2006-03-01), p. 643-649
    Abstract: OBJECTIVE—There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial–Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis. RESEARCH DESIGN AND METHODS—Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points. RESULTS—Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P & lt; 0.001 for all indexes). Area under the curve (AUC) C-peptide (P & lt; 0.05) and AUC C-peptide–to–AUC glucose ratio (P & lt; 0.001) values decreased in the oral group; peak C-peptide–to–2-h glucose ratio values decreased in both groups (P & lt; 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P & lt; 0.05) and peak C-peptide (oral group, P & lt; 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide–to–glucose ratio values decreased in both groups (P & lt; 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P & lt; 0.01). Fasting C-peptide–to–fasting glucose ratio values remained constant throughout the 30-month follow-up. CONCLUSIONS—These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.29.03.06.dc05-1006
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
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  • 3
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    Online Resource
    Role of Insulin Resistance in Predicting Progression to Type 1 Diabetes
    American Diabetes Association ; 2007
    In:  Diabetes Care Vol. 30, No. 9 ( 2007-09-01), p. 2314-2320
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 30, No. 9 ( 2007-09-01), p. 2314-2320
    Abstract: OBJECTIVE—The purpose of this study was to determine whether insulin resistance is a risk factor for the development of type 1 diabetes in autoantibody-positive first-degree relatives of diabetic family members. RESEARCH DESIGN AND METHODS—Subjects (n = 186) who had a projected 25–50% risk for diabetes and subjects (n = 170) who had a projected & gt;50% risk for type 1 diabetes in 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial–Type 1. We assessed insulin secretion with the first-phase insulin response (FPIR) and insulin resistance with homeostasis model assessment of insulin resistance (HOMA-IR) from an intravenous glucose tolerance test. The median follow-up was 4.3 years for moderate-risk subjects and 3.7 years for high-risk subjects. RESULTS—During the follow-up period, 53 subjects in the moderate-risk group and 70 subjects in the high-risk group developed type 1 diabetes. After adjustments for confounders using multivariate analysis, HOMA-IR and the FPIR–to–HOMA-IR ratio were significantly associated with type 1 diabetes in both risk groups. In the moderate-risk population, the hazard ratio (HR) of HOMA-IR was 2.70 (95% CI 1.45–5.06) and the HR of FPIR-to-HOMA-IR was 0.32 (95% CI 0.18–0.57). In the high-risk population, the HR of HOMA-IR was 1.83 (95% CI 1.19–2.82) and the HR of FPIR–to–HOMA-IR was 0.56 (95% CI 0.40–0.78). CONCLUSIONS—There is clear evidence of the association between insulin resistance and progression to type 1 diabetes. The combination of FPIR and HOMA-IR could be used as a better metabolic indicator for type 1 diabetes risk for prediction and suggests possible intervention strategies for diabetes prevention.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc06-2389
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 4
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    Online Resource
    Male Sex Increases the Risk of Autoimmunity but not Type 1 Diabetes
    American Diabetes Association ; 2004
    In:  Diabetes Care Vol. 27, No. 8 ( 2004-08-01), p. 1985-1990
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 27, No. 8 ( 2004-08-01), p. 1985-1990
    Abstract: OBJECTIVE—The goal of this study was to explore the role of sex on the prevalence of autoantibodies, protective genetic subtypes, β-cell function, and the incidence of type 1 diabetes in a population of first- and second-degree relatives of patients with type 1 diabetes (probands). We examined both the effect of the sex of the individual screened as well as the effect of the sex of the individual’s proband on diabetes risk variables tested. RESEARCH DESIGN AND METHODS—The Diabetes Prevention Trial-Type 1 has screened 93,188 relatives of type 1 diabetic patients from February 1994 to January 2002. After observing that more men than women were islet cell autoantibody (ICA) positive for the group as a whole, we further explored the role of sex by detailed analysis of variables in this population. RESULTS—Our data suggest only an influence of sex on the type 1 diabetes disease process. After adjustment for race, age, and relationship to proband, male sex was associated with the appearance of autoimmunity, i.e., the presence of ICA and having two or more antibodies. There was no effect of sex on the presence of other autoantibodies, insulin secretion, results of oral glucose tolerance test, or development of diabetes. CONCLUSIONS—Our finding that male sex conveys an independent increased risk for development of ICA and multiple antibodies, while at the same time finding no difference with respect to the development of diabetes, suggests that male relatives with the known risk factor of ICA are less likely than comparable female relatives to progress to overt disease, that the pathogenesis of type 1 diabetes among men is slower compared with women, or that women develop diabetes manifesting different antibody responses.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.27.8.1985
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
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  • 5
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    Online Resource
    A Risk Score for Type 1 Diabetes Derived From Autoantibody-Positive Participants in the Diabetes Prevention Trial–Type 1
    American Diabetes Association ; 2008
    In:  Diabetes Care Vol. 31, No. 3 ( 2008-03-01), p. 528-533
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 31, No. 3 ( 2008-03-01), p. 528-533
    Abstract: OBJECTIVE—The accurate prediction of type 1 diabetes is essential for appropriately identifying prevention trial participants. Thus, we have developed a risk score for the prediction of type 1 diabetes. RESEARCH DESIGN AND METHODS—Diabetes Prevention Trial–Type 1 (DPT-1) participants, islet cell autoantibody (ICA)-positive relatives of type 1 diabetic patients (n = 670), were randomly divided into development and validation samples. Risk score values were calculated for the validation sample from development sample model coefficients obtained through forward stepwise proportional hazards regression. RESULTS—A risk score based on a model including log-BMI, age, log-fasting C-peptide, and postchallenge glucose and C-peptide sums from 2-h oral glucose tolerance tests (OGTTs) was derived from the development sample. The baseline risk score strongly predicted type 1 diabetes in the validation sample (χ2 = 82.3, P & lt; 0.001). Its strength of prediction was almost the same (χ2 = 83.3) as a risk score additionally dependent on a decreased first-phase insulin response variable from intravenous glucose tolerance tests (IVGTTs). Biochemical autoantibodies did not contribute significantly to the risk score model. A final type 1 diabetes risk score was then derived from all participants with the same variables as those in the development sample model. The change in the type 1 diabetes risk score from baseline to 1 year was in itself also highly predictive of type 1 diabetes (P & lt; 0.001). CONCLUSIONS—A risk score based on age, BMI, and OGTT indexes, without dependence on IVGTTs or additional autoantibodies, appears to accurately predict type 1 diabetes in ICA-positive relatives.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc07-1459
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2008
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  • 6
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    Online Resource
    Pancreatic Islet Autoantibodies as Predictors of Type 1 Diabetes in the Diabetes Prevention Trial–Type 1
    American Diabetes Association ; 2009
    In:  Diabetes Care Vol. 32, No. 12 ( 2009-12-01), p. 2269-2274
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 32, No. 12 ( 2009-12-01), p. 2269-2274
    Abstract: There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA+). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA+). RESULTS In both cohorts autoantibody number was highly predictive of type 1 diabetes (P & lt; 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P & lt; 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P & lt; 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc09-0934
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2009
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  • 7
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    Online Resource
    Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes
    American Diabetes Association ; 2005
    In:  Diabetes Care Vol. 28, No. 5 ( 2005-05-01), p. 1068-1076
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 28, No. 5 ( 2005-05-01), p. 1068-1076
    Abstract: OBJECTIVE—This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes. RESEARCH DESIGN AND METHODS—We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26–50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes. RESULTS—Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) ≥80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). CONCLUSIONS—It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.28.5.1068
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2005
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  • 8
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    Incident Dysglycemia and Progression to Type 1 Diabetes Among Participants in the Diabetes Prevention Trial–Type 1
    American Diabetes Association ; 2009
    In:  Diabetes Care Vol. 32, No. 9 ( 2009-09-01), p. 1603-1607
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 32, No. 9 ( 2009-09-01), p. 1603-1607
    Abstract: We studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained. RESEARCH DESIGN AND METHODS Participants (n = 515) in the Diabetes Prevention Trial–Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction. RESULTS Of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of type 1 diabetes, both in those aged & lt;13 years (P & lt; 0.001) and those aged ≥13 years (P & lt; 0.01). Those aged & lt;13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis. CONCLUSIONS ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc08-2140
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2009
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  • 9
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    Increasing the Accuracy of Oral Glucose Tolerance Testing and Extending Its Application to Individuals With Normal Glucose Tolerance for the Prediction of Type 1 Diabetes
    American Diabetes Association ; 2007
    In:  Diabetes Care Vol. 30, No. 1 ( 2007-01-01), p. 38-42
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 30, No. 1 ( 2007-01-01), p. 38-42
    Abstract: OBJECTIVE—We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS—The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves. RESULTS—ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 ± 0.02) and an OGTT prediction index (0.78 ± 0.02) were higher (P & lt; 0.001) than those for the fasting (0.53 ± 0.02) and 2-h glucose (0.66 ± 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 ± 0.02 and 0.72 ± 0.02, respectively) were also higher (P & lt; 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P & lt; 0.001 for all). CONCLUSIONS—Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc06-1615
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 10
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    Online Resource
    Metabolic tests to determine risk for type 1 diabetes in clinical trials
    Wiley ; 2011
    In:  Diabetes/Metabolism Research and Reviews Vol. 27, No. 6 ( 2011-09), p. 584-589
    Details
    In: Diabetes/Metabolism Research and Reviews, Wiley, Vol. 27, No. 6 ( 2011-09), p. 584-589
    Type of Medium: Online Resource
    ISSN: 1520-7552
    URL: Issue
    URL: Article
    DOI: 10.1002/dmrr.v27.6
    DOI: 10.1002/dmrr.1205
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 2001565-3
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