Discovery of a Human Peptide Sequence Signaling Islet Neogenesis

Abstract

To identify triggers for islet neogenesis in humans that may lead to new treatments that address the underlying mechanism of disease for patients with type 1 or type 2 diabetes. In an effort to identify bioactive human peptide sequences that might trigger islet neogenesis, we evaluated amino acid sequences within a variety of mammalian pancreas-specific REG genes. We evaluated GenBank, the Basic Local Alignment Search Tool algorithm, and all available proteomic databases and developed large-scale protein-to-protein interaction maps. Studies of peptides of interest were conducted in human pancreatic ductal tissue, followed by investigations in mice with streptozocin-induced diabetes. Our team has defined a 14-amino acid bioactive peptide encoded by a portion of the human REG3a gene we termed Human proIslet Peptide (HIP), which is well conserved among many mammals. Treatment of human pancreatic ductal tissue with HIP stimulated the production of insulin. In diabetic mice, administration of HIP improved glycemic control and significantly increased islet number. Bioinformatics analysis, coupled with biochemical interaction studies in a human pancreatic cell line, identified the human exostoses-like protein 3 (EXTL3) as a HIP-binding protein. HIP enhanced EXTL3 translocation from the membrane to the nucleus, in support of a model whereby EXTL3 mediates HIP signaling for islet neogenesis. Our data suggest that HIP may be a potential stimulus for islet neogenesis and that the differentiation of new islets is a process distinct from beta cell proliferation within existing islets. Human clinical trials are soon to commence to determine the effect of HIP on generating new islets from one's own pancreatic progenitor cells.