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

Abstract

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

Research design and methods: We evaluated Collaborative Islet Transplant Registry (CITR) islet-alone recipients with pretransplant C-peptide <0.1 nmol/L and mean follow-up of 4.6 ± 1.1 years (n = 677). Receiver operating characteristic area under the curve (ROC-AUC) was used to evaluate the predictive value of fasting and stimulated glucose and C-peptide measures for seven primary outcomes: 1) absence of severe hypoglycemic events (ASHEs); 2) HbA1c <7.0%; 3) HbA1c <7.0% and ASHEs; 4) HbA1c ≤6.5%; 5) HbA1c ≤6.5% and ASHEs; 6) insulin independence; and 7) ASHEs, HbA1c ≤6.5%, and 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. The 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.

Conclusions: 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 an 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 β-cell replacement.

Graphical abstract

Figure 1

Predictive value of concurrent fasting C-peptide ranges/thresholds (nmol/L) on outcomes of clinical ITx. A: ASHEs. B: HbA_1c <7.0%. C: HbA_1c ≤6.5%. D: HbA_1c <7.0% and ASHEs. E: HbA_1c ≤6.5% and ASHEs. F: Insulin independence. G: ASHEs, HbA_1c ≤6.5%, and insulin independence.

Figure 2

Predictive value of concurrent stimulated C-peptide on outcomes of clinical ITx. A: ASHEs. B: HbA_1c <7.0%. C: HbA_1c ≤6.5%. D: HbA_1c <7.0% and ASHEs. E: HbA_1c ≤6.5% and ASHEs. F: Insulin independence. G: ASHEs, HbA_1c ≤6.5%, and insulin independence.

Figure 3

Comparison of predictive value (ROC-AUC) of fasting C-peptide vs. other predictors for each primary outcome of clinical ITx. A: ASHEs (P ns). B: HbA_1c <7.0% (P < 0.0001). C: HbA_1c ≤6.5% (P < 0.0001). D: HbA_1c <7.0% and ASHEs (P < 0.0001). E: HbA_1c ≤6.5% and ASHEs (P < 0.0001). F: Insulin independence (P < 0.0001). G: ASHEs, HbA_1c ≤6.5%, and insulin independence (P < 0.0001).