Dahai Zhang, 1 Fulong Wang, 1 Nathaniel Lal, 1 Amy Pei-Ling Chiu, 1 Andrea Wan, 1 Jocelyn Jia, 1 Denise Bierende, 1 Stephane Flibotte, 1 Sunita Sinha, 1 Ali Asadi, 2 Xiaoke Hu, 2 Farnaz Taghizadeh, 2 Thomas Pulinilkunnil, 3 Corey Nislow, 1 Israel Vlodavsky, 4 James D. Johnson, 2 Timothy J. Kieffer, 2 Bahira Hussein, 1 and Brian Rodrigues 1 Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes Diabetes 2017;66:45–57 | DOI: 10.2337/db16-0761 Heparanase, a protein with enzymatic and nonenzymatic properties, contributes toward disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (hep- tg) was the discovery of improved glucose homeostasis. We examined the mechanisms that contribute toward this improved glucose metabolism. Heparanase overexpres- sion was associated with enhanced glucose-stimulated insulin secretion and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice, with >2,000 genes differentially expressed versus control. The upregulated genes were enriched for diverse functions including cell death regulation, extracel- lular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low- dose streptozotocin (STZ), hep-tg animals developed less severe hyperglycemia compared with wild-type, an effect likely related to their b-cells being more functionally effi- cient. In animals given a single high dose of STZ causing severe and rapid development of hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of fibroblast growth factor 21 and glucagon-like peptide 1. This study uncovers the opportunity to use properties of heparanase in management of diabetes. Heparan sulfate proteoglycans (HSPGs), located mainly on the cell surface and in the extracellular matrix, are composed of a core protein to which one or more heparan sulfate (HS) side chains are attached (1). HSPGs function not only as structural proteins, but also as anchors for bioactive molecules, as HS is negatively charged. Highly expressed in pancreatic islets, HS binds and guides the signaling and distribution of fibroblast growth factor (FGF) family members, which regulate pancre- atic endocrine cell differentiation, clustering, and development (2). It has been suggested that the presence of HSPG in the nucleus has a suppressive effect on histone acetyltransferase activity and may therefore modulate gene expression (3). Heparanase is an endo-b-D-glucuronidase that is ubiq- uitously expressed in many organs, with blood and endo- thelial cells having the highest expression. Heparanase is encoded as a 65-kDa latent precursor (Hep L ) that requires proteolytic cleavage to form an active enzyme (Hep A ) (4). Functionally, Hep A cleaves HS at D-glucuronic acid resi- dues, an action associated with extracellular matrix dis- ruption (5) and release of cell surface–bound molecules such as FGF (2). Aside from the function of Hep A in cleaving HS, Hep L can also activate numerous signaling 1 Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancou- ver, British Columbia, Canada 2 Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada 3 Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick, Canada 4 Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel Corresponding author: Brian Rodrigues, rodrigue@mail.ubc.ca. Received 22 June 2016 and accepted 1 October 2016. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0761/-/DC1. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Diabetes Volume 66, January 2017 45 METABOLISM