title: Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes.
abstract: 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 overexpression 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, extracellular 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 β-cells being more functionally efficient. 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amy Pei-Ling
authors.initials: AP
authors.lastname: Chiu
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Jia
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Bierende
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Flibotte
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.affiliation: Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Taghizadeh
authors.affiliation: Faculty of Medicine, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.affiliation: Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
authors.affiliation: Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Bahira
authors.initials: B
authors.lastname: Hussein
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada rodrigue@mail.ubc.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013311:Streptozocin / Q000633:toxicity; D000099175:Heparanase
chemical_list: D005346:Fibroblast Growth Factors; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D005966:Glucuronidase; D007328:Insulin; D013311:Streptozocin; D000099175:Heparanase; C414620:fibroblast growth factor 21