A Novel Intron-Encoded Neuropilin-1 Isoform in Pancreatic Islets Associated With Very Young Age of Onset of Type 1 Diabetes

Net synthesis of pancreatic beta cells peaks before two years of life. Beta cell mass is set within the first five years of life. Inframe translational readthrough of the NRP1 gene exon 9 into intron 9 generates a truncated neuropilin-1 protein lacking downstream sequence necessary for binding VEGF that stimulates beta cell replication. VEGF is critical for developing but not adult islet neogenesis. Herein we show that cells in human pancreatic islets containing the full length neuropilin-1 possess insulin, but cells that contain the truncated neuropilin-1 are devoid of insulin. Decreased insulin cells increases susceptibility to onset of type 1 diabetes at a younger age. We also show that a genetic marker in NRP1 intron 9 is higher in patients with onset of type 1 diabetes before age 4 years (31.8%), including 0.67-2 and 2-4 years, compared with onset at 4-8 years, 8-12 years, and after 16 years (16.1%) that equals its frequency in nondiabetic subjects (16.0%). Decreased insulin cells plus the genetic data are consistent with a low effect mechanism that alters the onset of type 1 diabetes to a very young age in some patients thus supporting the endotype concept that type 1 diabetes is a heterogeneous disease.