Bhagat, V.; Gill, J.; Lopes, M.; Verchere, C. B.

The global incidence of type 1 diabetes (T1D) continues to rise, yet reliable biomarkers for predicting disease onset remain limited. Studies have demonstrated persistent proinsulin secretion in individuals living with T1D, suggesting a processing impairment. Proinsulin is processed into mature active insulin by the prohormone convertases PC1/3, PC2, and carboxypeptidase E. We hypothesized that elevated circulating proinsulin-to-C-peptide (PI:C) ratios precede the onset of diabetes and are associated with reduced expression of PC1/3 in pancreatic beta cells. Non-obese diabetic (NOD) mice were monitored for changes in plasma proinsulin, C-peptide, and beta cell Pc1/3 levels prior to diabetes onset. Female NOD mice that progressed to diabetes exhibited increased plasma proinsulin and PI:C ratios several weeks before the onset of diabetes compared to mice that remained normoglycemic. Plasma proinsulin levels were predictive of diabetes onset, with earlier elevations observed in mice that progressed to disease more rapidly. These increases in plasma proinsulin and PI:C ratios correlated with reduced beta cell Pc1/3 expression. These findings support the potential of plasma proinsulin and PI:C ratios as predictive biomarkers for T1D development and implicate diminished Pc1/3 expression as a possible mechanism underlying impaired proinsulin processing.