β-Cell Secretory Capacity Predicts Metabolic Outcomes over 6 Years following Human Islet Transplantation

Abstract

Transplanted islet functional β-cell mass is measured by the β-cell secretory capacity derived from the acute insulin response to glucose-potentiated arginine (AIRpot), however, data are limited beyond one-year post-transplant for individuals with type 1 diabetes. We evaluated changes in β-cell secretory capacity in a single-center longitudinal analysis and examined relationships with measures of islet cell hormone metabolism and clinical measures of graft function (mixed-meal tolerance test [MMTT] C-peptide, BETA-2 score, and continuous glucose monitoring [CGM]). Eleven individuals received purified human pancreatic islets over one or two intra-portal infusions to achieve insulin-independence and were followed over a median (IQR) 6 (5-7) years. β-cell secretory capacity remained stable over 3-years before declining. Fasting glucagon and proinsulin secretory ratios under glucose-potentiation were inversely correlated with AIRpot. A functional β-cell mass of 40% normal predicted insulin-independence and was strongly predicted by MMTT C-peptide-to-glucose and BETA-2 score. A functional β-cell mass of >20% predicted excellent glycemic outcomes including ≤1% time <60 mg/dL, ≤2% time >180 mg/dL and ≥90% time-inrange 70-180 mg/dL. β-cell replacement approaches should target a functional β-cell mass >40% to provide sufficient islet reserve for sustained insulin-independence. MMTT C-peptide-to-glucose and BETA-2 score can inform changes in functional β-cell mass in the clinical setting.