Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes

Carla J Greenbaum, Thomas Mandrup-Poulsen, Paula Friedenberg McGee, Tadej Battelino, Burkhard Haastert, Johnny Ludvigsson, Paolo Pozzilli, John M Lachin, Hubert Kolb, Type 1 Diabetes Trial Net Research Group, European C-Peptide Trial Study Group, Carla J Greenbaum, Paula F McGee, John M Lachin, Thomas Mandrup-Poulsen, Tadej Battelino, Burkhard Haastert, Johnny Ludvigsson, Paolo Pozzilli, Hubert Kolb, Carla J Greenbaum, Thomas Mandrup-Poulsen, Paula Friedenberg McGee, Tadej Battelino, Burkhard Haastert, Johnny Ludvigsson, Paolo Pozzilli, John M Lachin, Hubert Kolb, Type 1 Diabetes Trial Net Research Group, European C-Peptide Trial Study Group, Carla J Greenbaum, Paula F McGee, John M Lachin, Thomas Mandrup-Poulsen, Tadej Battelino, Burkhard Haastert, Johnny Ludvigsson, Paolo Pozzilli, Hubert Kolb

Abstract

Objective: Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures.

Research design and methods: In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs.

Results: Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R(2) = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group.

Conclusions: The MMTT is preferred for the assessment of beta-cell function in therapeutic trials in type 1 diabetes.

Trial registration: ClinicalTrials.gov NCT00105352.

Figures

Figure 1
Figure 1
TrialNet mean peak C-peptide (solid lines) and 95% CI bands (dotted lines), from an MMTT (upper solid lines) and a GST (lower solid lines) with respect to the age of onset in subjects with duration of type 1 diabetes A), 1–2 years (B), and 2–3 years (C) obtained from separate models within each duration category with an interaction between test (MMTT versus GST) and age at onset of type 1 diabetes, adjusted for fasting C-peptide, fasting glucose, weight, visit number, and randomization group.
Figure 2
Figure 2
Relationship between the duplicate measurements of the peak (A) and AUC mean C-peptide values (B) (pmol/ml) from the MMTT and the GST. The 6-min European GST values are presented in lieu of the peak values.

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