Parathyroid Hormone-Related Protein Enhances Human ß-cell Proliferation and Function With Associated Induction of Cyclin-Dependent Kinase 2 and Cyclin E Expression

Diabetes. 2010 Dec;59(12):3131-8. doi: 10.2337/db09-1796. Epub 2010 Sep 28.

Abstract

Objective: Inducing human β-cell growth while enhancing function is a major goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP) enhances rodent β-cell growth and function through the parathyroid hormone-1 receptor (PTH1R). Based on this, we hypothesized that PTH1R is expressed in human β-cells and that PTHrP has the potential to enhance human β-cell proliferation and/or function.

Research design and methods: PTH1R expression, β-cell proliferation, glucose-stimulated insulin secretion (GSIS), and expression of differentiation and cell-cycle genes were analyzed in human islets transduced with adenoviral PTHrP constructs or treated with PTHrP peptides. The effect of overexpression of late G1/S cell cycle molecules was also assessed on human β-cell proliferation.

Results: We found that human β-cells express PTH1R. More importantly, overexpression of PTHrP causes a significant approximately threefold increase in human β-cell proliferation. Furthermore, the amino terminus PTHrP(1-36) peptide is sufficient to increase replication as well as expression of the late G1/S cell-cycle proteins cyclin E and cyclin-dependent kinase 2 (cdk2) in human islets. Notably, PTHrP(1-36) also enhances GSIS. Finally, overexpression of cyclin E alone, but not cdk2, augments human β-cell proliferation, and when both molecules are expressed simultaneously there is a further marked synergistic increase in replication.

Conclusions: PTHrP(1-36) peptide enhances human β-cell proliferation as well as function, with associated upregulation of two specific cell-cycle activators that together can induce human β-cell proliferation several fold. The future therapeutic potential of PTHrP(1-36) for the treatment of diabetes is especially relevant given the complementary therapeutic efficacy of PTHrP(1-36) in postmenopausal osteoporosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cell Cycle / genetics
  • Cell Differentiation / genetics
  • Cell Division
  • Child
  • Child, Preschool
  • Cyclin E / genetics*
  • Cyclin-Dependent Kinase 2 / genetics*
  • Female
  • Gene Expression Regulation
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Male
  • Middle Aged
  • Osteoporosis, Postmenopausal / drug therapy
  • Parathyroid Hormone-Related Protein / genetics
  • Parathyroid Hormone-Related Protein / pharmacology
  • Parathyroid Hormone-Related Protein / physiology*
  • Parathyroid Hormone-Related Protein / therapeutic use
  • Peptide Fragments / pharmacology
  • Receptor, Parathyroid Hormone, Type 1 / genetics*

Substances

  • Cyclin E
  • Insulin
  • PTH1R protein, human
  • Parathyroid Hormone-Related Protein
  • Peptide Fragments
  • Receptor, Parathyroid Hormone, Type 1
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2