Endocrine Abstracts

Objective: To examine the relationship between C-peptide levels and endogenous insulin secretion and to understand the effects of elevated C-peptide after dosing on evaluating study insulin and its analogs’ PK/PD values in euglycemic clamps.

Method: The study included 33 healthy male volunteers who underwent an 8-h euglycemic clamp with a subcutaneous injection of insulin aspart (0.2 U/kg). Blood glucose (BG), C-peptide, human insulin, and insulin aspart (IAsp) levels were tested at pre-defined time. They were divided into two groups according to C-peptide levels postdosing. Group A: at least one of C-peptide concentrations postdosing was higher than the baseline; group B: C-peptide concentrations postdosing were all below the baseline. The baseline of serum C-peptide was defined as the mean value of –30 min and 0 min pre-dosing. The time profiles of BG, human insulin and C-peptide were recorded, the relationship between human insulin and C-peptide was examined and the factors affect C-peptide were analyzed. IAsp’s PK/PD values were collected.

Results: There were 22 in group A and 11 in group B. Baseline BG and CVBG were comparable. The ‘clamped’ BG was 99.7% ± 7.1% (group A) and 94.9% ± 5.1% (group B) of baseline respectively. IAsp’s PK values were consistent in two groups while AUC_GIR,0–8h was higher in group A than B (1815 ± 551 mg/kg vs 1327 ± 306 mg/kg, P = 0.01). The C-peptide (308 pmol/l vs 299 pmol/l, P = 0.75) and human insulin (24.0 ± 7.4 pmol/l vs 29.5 ± 10.2 pmol/l, P = 0.09) were of no significant difference at baseline but group B had a much lower C-peptide (168 pmol/l vs 309 pmol/l, P < 0.01) and human insulin (17.3 pmol/l vs 26.0 pmol/l, P < 0.01) postdosing. The method using C-peptide to predict endogenous insulin secretion had a sensitivity of 85.19% (138/162) and a specificity of 79.20% (316/399). CVBG and the extent of postdosing C-peptide higher than baseline were positively correlated (r = 0.51, P = 0.01). The AUC of human insulin higher than baseline decreased with AUC of clamped BG higher than target declining.

Conclusion: Inappropriate elevated serum C-peptide concentrations after exogenous insulin administration indicate insufficient inhibition of endogenous insulin secretion. The BG levels during euglycemic clamp are preferably controlled below the baseline level to sufficiently inhibit endogenous insulin secretion of the subject. The estimated insulin PK values obtained from C-peptide correction method may not be very accurate if postdosing C-peptide level is higher than the baseline.