Background: There is mounting evidence for residual β-cell mass in a significant portion of patients with long-standing type 1 diabetes (T1D). Residual β-cell function is associated with improved glycemic control including a lower risk of hypoglycemia and microvascular complications. It is unknown whether these β-cells function normally. Here we aim to determine the β-cell response to various physiological and other β-cell secretagogues.

Methods: Male patients with auto-antibody positive T1D and diabetes duration ≥5 years were included. On day one, a mixed meal test (MMT) was performed, followed by an arginine bolus. On day two, a three-phase clamp was performed: 1. euglycemia (5 mmol/L), 2. hyperglycemia (14 mmol/L) and 3. hyperglycemia+GLP-1 (1.5 pmol/kg/min) infusion. Arginine boluses were given at the end of every phase. An ultra-sensitive C-peptide essay was used.

Results: Fifteen patients were included (age: 34.9±9.3 years, diabetes duration: 18.7±9.4 years). C-peptide was detected at all time points in 2/15 participants. In 3/15 participants, C-peptide only became detectable after varying stimuli. Age, diabetes duration, age at diagnosis and BMI were not statistically different in the 5 C-peptide positive patients as compared to the C-peptide negative patients. On day 2, C-peptide did not show a first phase response to glucose, but C-peptide did increase eventually 2.9 fold [95% CI 1.2;7.1] during the hyperglycemic phase and 3.5 fold [95% CI 2.4;5.2] during the hyperglycemia+GLP-1 infusion. During all phases arginine further stimulated C-peptide. On day 1, the MMT increased C-peptide 6.7 fold [95% CI 1.1;42.4]. The subsequent arginine bolus further stimulated C-peptide 2.2 fold [95% CI 1.2;4.1]. C-peptide was detectable in the same 5 patients during the two study days.

Conclusion: In patients with T1D and detectable C-peptide, different secretagogues (glucose, GLP1, arginine) can stimulate β-cells, but a first-phase response to glucose was absent. An MMT followed by an arginine bolus is sufficient to uncover residual β-cell function in T1D.