title: Systemic and acute administration of parathyroid hormone-related peptide(1-36) stimulates endogenous beta cell proliferation while preserving function in adult mice.
abstract: OBJECTIVE
  A major focus in the treatment of diabetes is to identify factors that stimulate endogenous beta cell growth while preserving function. The first 36 amino acids of parathyroid hormone-related protein (PTHrP) are sufficient to enhance proliferation and function in rodent and human beta cells in vitro. This study examined whether acute and systemic administration of the amino-terminal PTHrP(1-36) peptide can achieve similar effects in rodent beta cells in vivo.
  
  
  METHODS
  Adult male mice were injected with 40, 80 or 160 μg of PTHrP(1-36) per kg body weight or with vehicle for 25 days. Glucose and beta cell homeostasis, as well as expression of differentiation markers and cell cycle genes were analysed.
  
  
  RESULTS
  All three doses of PTHrP(1-36) significantly enhanced beta cell proliferation in vivo at day 25, with 160 μg/kg PTHrP(1-36) increasing proliferation as early as day 5. Importantly, the two higher doses of PTHrP(1-36) caused a significant 30% expansion of beta cell mass, with a short-term improvement in glucose tolerance. PTHrP(1-36) did not cause hypercalcaemia, or change islet number, beta cell size, beta cell death or expression of differentiation markers. Analysis of islet G1/S cell cycle proteins revealed that chronic overabundance of PTHrP(1-139) in the beta cell significantly increased the cell cycle activator cyclin D2 and decreased levels of cyclin-dependent kinase 4 inhibitor (p16( Ink4a ) [Ink4a also known as Cdkn2a]), but acute treatment with PTHrP(1-36) did not.
  
  
  CONCLUSIONS
  Acute and systemic administration of PTHrP(1-36) increases rodent beta cell proliferation and mass without negatively affecting function or survival. These findings highlight the future potential therapeutic effectiveness of this peptide under diabetes-related pathophysiological conditions.
authors.affiliation: Division of Endocrinology, University of Pittsburgh, 200 Lothrop St, BST-E1157, Pittsburgh, PA 15261, USA.
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Abanquah
authors.forename: S
authors.initials: S
authors.lastname: Joshi-Gokhale
authors.forename: A
authors.initials: A
authors.lastname: Otero
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: N K
authors.initials: NK
authors.lastname: Guthalu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Mozar
authors.forename: A
authors.initials: A
authors.lastname: Bisello
authors.forename: A F
authors.initials: AF
authors.lastname: Stewart
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: R C
authors.initials: RC
authors.lastname: Vasavada
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000009:adverse effects / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D055571:Secretory Pathway / Q000187:drug effects*
chemical_list: D000943:Antigens, Differentiation; C486196:Ccnd2 protein, mouse; C417743:Cdkn2a protein, mouse; D056742:Cyclin D2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007004:Hypoglycemic Agents; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; C079957:parathyroid hormone-related peptide (1-36)