Persistence of proinsulin‐only secretion in people with long‐duration diabetes and minimal residual insulin secretion

BACKGROUND AND AIMS: In all forms of diabetes, beta cell failure is associated with disproportionate proinsulin secretion, a marker of endoplasmic reticulum stress. Histopathological studies have suggested that defective expression of prohormone convertases may lead to proinsulin becoming the predominant secretory product. We analysed meal-stimulated proinsulin secretion in people with minimal residual C-peptide secretion. MATERIALS AND METHODS: We studied a cohort of 320 individuals, among whom 55 exhibited poorly stimulated C-peptide levels (peak <0.3 nmol/L) during a 2-h mixed-meal tolerance test (MMTT; carbohydrates (60 g), lipids (5.5 g), proteins (10 g)). Serum C-peptide (Diasorin, LOQ 0.01 nmol/L) and proinsulin (ELISA, Mercodia, LOQ 0.5 pmol/L) were measured at baseline and at 60 and 120 min. Responses were assessed using peak values and peak-to-basal ratios. Results are expressed as median [interquartile range]. RESULTS: Among these 55 individuals, most had type 1 diabetes (n = 44); other aetiologies included type 2 diabetes (n = 1) and other forms (n = 10). Diabetes duration was 18 [8-25] years, HbA1c was 61 mmol/mol (7.7%), and all subjects were insulin-treated (0.6 [0.47-0.79] U/kg/day). Peak C-peptide was 0.03 [0.001-0.12] nmol/L, peak proinsulin was 0.8 [0.5-1.75] pmol/L. Among participants with non-stimulated C-peptide (n = 14) following MMTT, 5 showed stimulated proinsulin secretion. CONCLUSION: The presence of stimulated proinsulin secretion in long-standing diabetes with minimal residual C-peptide secretion suggests the persistence of dysfunctional yet meal-responsive beta cells.