Predictive Value of C-peptide Measures for Clinical Outcomes of Beta Cell Replacement Therapy in Type 1 Diabetes: Report from the Collaborative Islet Transplant Registry (CITR)

OBJECTIVE
To determine C-peptide measures and levels associated with positive glycemic control outcomes following islet transplantation (ITx) in type 1 diabetes.

RESEARCH DESIGN AND METHODS
We evaluated Collaborative Islet Transplant Registry (CITR) Islet-Alone recipients with pre-transplant C-peptide <0.1 nmol/L and mean follow up of 4.6±1.1 years (n=677). Area under the curve of receiver-operator characteristics (ROC-AUC) were used to evaluate predictive value of fasting and stimulated glucose and C-peptide measures for 7 primary outcomes: a) absence of severe hypoglycemic events (ASHE); b) HbA1c<7.0%; c) HbA1c<7.0% & ASHE; d) HbA1c≤6.5%; e) HbA1c≤6.5% & ASHE; f) insulin independence; and g) ASHE, HbA1c≤6.5% & insulin independence (the optimal outcome). Measures with the highest ROC-AUC were selected for determination of optimal cut points.

RESULTS
Fasting C-peptide was highly predictive for ASHE (ROC-AUC=0.906; optimal cut point=0.070 nmol/L), and the optimal outcome (ROC-AUC=0.845; optimal cut point=0.33 nmol/L). Mixed-meal tolerance test (MMTT) stimulated C-peptide to Glucose ratio (CPGR) outperformed both fasting and stimulated C-peptide for all outcomes except ASHE. Optimal cut point for the optimal outcome was 0.12 nmol/mmol for MMTT stimulated CPGR, and 0.97 nmol/L for MMTT stimulated C-peptide.

CONCLUSION
Fasting C-peptide reliably predicts ITx primary outcomes. MMTT stimulated CPGR provides marginally better prediction for composite ITx outcomes, including insulin independence.  In the absence of a MMTT, a fasting C-peptide ≥0.33 nmol/L is a reassuring measure of optimal islet graft function. C-peptide targets represent excellent and easily determinable means to predict glycemic control outcomes after ITx and should be considered as potential goals of beta cell replacement.