Islet Autotransplant Recipients Have Elevated Proinsulin-to-C-Peptide Ratios Supporting Metabolic Stress as a Cause of Islet Attrition.

Attrition of islet function is observed over time following total pancreatectomy with islet autotransplantation (TPIAT). Metabolic stress on a suboptimal islet mass is a suspected, but unconfirmed, contributor. We measured proinsulin-to-C-peptide (PI:C) ratios as an indicator of β-cell stress in TPIAT recipients >5 years post-TPIAT. Individuals ≥16 years old with TPIAT 5-20 years prior underwent 4-h mixed-meal tolerance testing (MMTT) and assessment of ambulatory glycemia by continuous glucose monitoring (CGM). Insulin use and HbA1c were obtained. PI:C was measured from fasting and +90 min MMTT samples. PI:C ratios were compared with healthy control individuals (n = 24) and were associated with MMTT and CGM measures. PI:C ratios from 132 TPIAT (median age 48 [interquartile range 33, 55] years, 33% male, 9.4 [6.7, 11.8] years post-TPIAT, islet mass transplanted 4,022 [2,777, 5,390]) were high compared with healthy control individuals (P < 0.0001; mean PI:C two- to threefold higher). Within the TPIAT recipients, higher PI:C ratios were associated with lower islet equivalents per kilogram transplanted, partial or failed islet function, higher HbA1c, higher BMI, reduced time in range on CGM, and more time in hyperglycemia by MMTT. Overweight/obesity and low islet mass associations with PI:C ratios were only partially mediated by hyperglycemia. PI:C ratios were elevated at a median of 10 years after TPIAT. These findings support the concept that metabolic stress is a cause of islet attrition in TPIAT and that having fewer islets, poor glycemic control, or unhealthy body weight may contribute to islet function decline. ARTICLE HIGHLIGHTS: β-Cell stress after total pancreatectomy with islet autotransplantation has been proposed an important cause of islet loss. We measured circulating proinsulin-to-C-peptide ratios, measured to determine whether total pancreatectomy with islet autotransplantation recipients exhibit β-cell stress, and whether this is associated with hyperglycemia and other clinical factors. Proinsulin-to-C-peptide ratio levels were elevated twofold or more compared with healthy control volunteers and were higher with hyperglycemia, high BMI, and low islet mass. These results support the hypothesis that metabolic stress is a cause of long-term islet attrition and suggest potential opportunity to reduce β-cell stress through maintaining healthy body weight and avoiding significant time in hyperglycemia.