Parathyroid Hormone–Related Protein Enhances Human β-Cell Proliferation and Function With Associated Induction of Cyclin-Dependent Kinase 2 and Cyclin E Expression
- Nagesha Guthalu Kondegowda,
- Sheela Joshi-Gokhale,
- George Harb,
- Katoura Williams,
- Xiao Ying Zhang,
- Karen K. Takane,
- Pili Zhang,
- Donald K. Scott,
- Andrew F. Stewart,
- Adolfo Garcia-Ocaña and
- Rupangi C. Vasavada
- Corresponding author: Rupangi C. Vasavada, .
N.G.K. and S.J.-G. contributed equally to this study.
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.
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- Received December 9, 2009.
- Accepted September 8, 2010.
- © 2010 by the American Diabetes Association.
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