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, Rupangi C. Vasavada

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)3131-3138
Number of pages8
JournalDiabetes
Volume59
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

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