title: Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication.
abstract: Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary β cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases β-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Annes
authors.forename: Jennifer Hyoje
authors.initials: JH
authors.lastname: Ryu
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Carolan
authors.forename: Katrina
authors.initials: K
authors.lastname: Utz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Gordon
authors.initials: G
authors.lastname: Weir
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Melton
mesh_terms: D000248:Adenosine Kinase / Q000494:pharmacology*; D000818:Animals; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D000248:Adenosine Kinase; D058570:TOR Serine-Threonine Kinases; D005947:Glucose