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Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients

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Abstract
Context and Objective: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D). Design: The design is a registry-based study. Setting: Functional tests were performed in a hospital setting. Participants: Persistently autoAb(+) first-degree relatives of patients with T1D (n = 81; age 5-39 years). Main Outcome Measures: We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC(5-10min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150min); min 120-150) in those aged 12-39 years (n = 62). Results: Overall, the predictive ability of AUC(5-10min) was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95%CI]: 0.89 [0.80-0.98] vs 0.81 [0.70-0.93]). Fasting blood glucose (FBG) and AUC(5-10min) provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC[95%CI]: 0.92 [0.84-1.00]). In multivariate Cox regression analysis, AUC(5-10min) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10min) below percentile 10 of controls was associated with 50-70% progression to T1D regardless of age. Similar results were obtained for AUC(120-150min). Conclusions: Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb(+) offspring and siblings of T1D patients to predict impending diabetes.
Keywords
HIGH-RISK, C-PEPTIDE, INSULIN, PROGRESSION, RELATIVES, MELLITUS, PREVENTION, PROINSULIN LEVELS, ZINC TRANSPORTER 8, MAJOR AUTOANTIGEN

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Citation

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Chicago
Balti, Eric V, Evy Vandemeulebroucke, Ilse Weets, Ursule Van De Velde, Annelien Van Dalem, Simke Demeester, Katrijn Verhaeghen, et al. 2015. “Hyperglycemic Clamp and Oral Glucose Tolerance Test for 3-year Prediction of Clinical Onset in Persistently Autoantibody-positive Offspring and Siblings of Type 1 Diabetic Patients.” Journal of Clinical Endocrinology & Metabolism 100 (2): 551–560.
APA
Balti, E. V., Vandemeulebroucke, E., Weets, I., Van De Velde, U., Van Dalem, A., Demeester, S., Verhaeghen, K., et al. (2015). Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 100(2), 551–560.
Vancouver
1.
Balti EV, Vandemeulebroucke E, Weets I, Van De Velde U, Van Dalem A, Demeester S, et al. Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM. 2015;100(2):551–60.
MLA
Balti, Eric V, Evy Vandemeulebroucke, Ilse Weets, et al. “Hyperglycemic Clamp and Oral Glucose Tolerance Test for 3-year Prediction of Clinical Onset in Persistently Autoantibody-positive Offspring and Siblings of Type 1 Diabetic Patients.” JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 100.2 (2015): 551–560. Print.
@article{8022754,
  abstract     = {Context and Objective: In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D). 
Design: The design is a registry-based study. 
Setting: Functional tests were performed in a hospital setting. 
Participants: Persistently autoAb(+) first-degree relatives of patients with T1D (n = 81; age 5-39 years). 
Main Outcome Measures: We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC(5-10min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150min); min 120-150) in those aged 12-39 years (n = 62). 
Results: Overall, the predictive ability of AUC(5-10min) was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95\%CI]: 0.89 [0.80-0.98] vs 0.81 [0.70-0.93]). Fasting blood glucose (FBG) and AUC(5-10min) provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC[95\%CI]: 0.92 [0.84-1.00]). In multivariate Cox regression analysis, AUC(5-10min) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10min) below percentile 10 of controls was associated with 50-70\% progression to T1D regardless of age. Similar results were obtained for AUC(120-150min). 
Conclusions: Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb(+) offspring and siblings of T1D patients to predict impending diabetes.},
  author       = {Balti, Eric V and Vandemeulebroucke, Evy and Weets, Ilse and Van De Velde, Ursule and Van Dalem, Annelien and Demeester, Simke and Verhaeghen, Katrijn and Gillard, Pieter and De Block, Christophe and Ruige, Johannes and Keymeulen, Bart and Pipeleers, Daniel G and Decochez, Katelijn and Gorus, Frans K},
  issn         = {0021-972X},
  journal      = {JOURNAL OF CLINICAL ENDOCRINOLOGY \& METABOLISM},
  keyword      = {HIGH-RISK,C-PEPTIDE,INSULIN,PROGRESSION,RELATIVES,MELLITUS,PREVENTION,PROINSULIN LEVELS,ZINC TRANSPORTER 8,MAJOR AUTOANTIGEN},
  language     = {eng},
  number       = {2},
  pages        = {551--560},
  title        = {Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients},
  url          = {http://dx.doi.org/10.1210/jc.2014-2035},
  volume       = {100},
  year         = {2015},
}

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