Determining a threshold for Residual C-peptide associated with clinical and physiologic measures in type 1 diabetes (T1D)

Background: Cross-sectional data from the Type 1 Diabetes Exchange (T1DX) has shown that 1/3 of individuals with longstanding T1D maintain detectable C-peptide. Yet, no clear relationship between clinical or physiologic outcomes and level of C-peptide was identified. Therefore, the present study was designed to use a systematic approach to investigate the significance of residual C-peptide and to determine if there is a minimum threshold of C-peptide that is physiologically important.

Methods: Adults with T1D underwent a mixed-meal tolerance test (MMTT), glucose-potentiated arginine (GPA) studies, continuous glucose monitoring (CGM) placement, and a hyperinsulinemic euglycemic-hypoglycemic clamp. These studies evaluated β-cell secretory capacity, α-cell function, glycemic control, counter-regulatory hormone response to hypoglycemia, insulin sensitivity and endogenous glucose production. Participants were classified by the peak C-peptide achieved during the MMTT [Negative n=15: 0.200-0.400; high n=18: >0.400 nmol/L].

Results: The group with highest C-peptide (>0.4 nmol/L) had lower fasting glucose (111±26 mg/dl), lower HbA1c (6.6%), increased CGM measured time in range (72%), greater glucagon secretion during hypoglycemia, and was the only group who demonstrated measurable glucose-dependent C-peptide and proinsulin secretion during GPA test. No clear differences were found between groups for other measures. Our results support the concept that classification of residual C-peptide by peak MMTT response is consistent with the underlying β-cell secretory capacity derived from GPA. Indeed, peak C-peptide of >0.4 nmol/L may indicate a minimum threshold of physiologic importance that warrants further consideration as a potential treatment target for interventions aimed at preserving or restoring β-cell function in T1D. Additional analysis evaluating C-peptide as a continuous variable are underway.