Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D

Sims, E. K.; Nyalwidhe, J.; Syed, F.; Bahnson, H. T.; Haataja, L.; Speake, C.; Morris, M.; Mirmira, R. G.; Nadler, J.; Mastracci, T. L.; Arvan, P.; Greenbaum, C. J.; Evans-Molina, C.

doi:10.1101/542027

bioRxiv · 10.1101/542027

Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D

Sims, E. K.·Nyalwidhe, J.·Syed, F.·Bahnson, H. T.·Haataja, L.·Speake, C.·Morris, M.·Mirmira, R. G.·Nadler, J.·Mastracci, T. L.·Arvan, P.·Greenbaum, C. J.·Evans-Molina, C.

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Abstract

Work by our group and others has suggested that elevations in circulating proinsulin relative to C-peptide is associated with development of Type 1 diabetes (T1D). We recently described the persistence of detectable serum proinsulin in a large majority (95.9%) of individuals with longstanding T1D, including individuals with undetectable serum C-peptide. Here we describe analyses performed on human pancreatic sections from the nPOD collection (n=30) and isolated human islets (n=10) to further explore mechanistic etiologies of persistent proinsulin secretion in T1D. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with an inflammatory cytokine cocktail reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced {beta} cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.

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Sims, E. K., Nyalwidhe, J., Syed, F., Bahnson, H. T., Haataja, L., Speake, C., Morris, M., Mirmira, R. G., Nadler, J., Mastracci, T. L., Arvan, P., Greenbaum, C. J., Evans-Molina, C.. 2019-02-08. Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D. https://doi.org/10.1101/542027

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