Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression.
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.


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.
Guthalu Kondegowda
Nagesha
N
Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. vasavada@pitt.edu
Joshi-Gokhale
Sheela
S
Harb
George
G
Williams
Katoura
K
Zhang
Xiao Ying
XY
Takane
Karen K
KK
Zhang
Pili
P
Scott
Donald K
DK
Stewart
Andrew F
AF
Garcia-Ocaña
Adolfo
A
Vasavada
Rupangi C
RC
D000293:Adolescent; D000328:Adult; D000368:Aged; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division; D002648:Child; D002675:Child, Preschool; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*
D019927:Cyclin E; D007328:Insulin; C473449:PTH1R protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2