Parathyroid hormone-related peptide stimulates DNA synthesis and insulin secretion in pancreatic islets

Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancrea tic islet. Recent data in transgenic mice suggest that PTHrP might modulate islet mass and insulin secretion, In the present study, we assessed the ef fect of the N-terminal PTH-like region of PTHrP on DNA synthesis in isolate d rat islets. PTHrP (1-34), between 1 pM and 10 nM, for 48 h stimulated [H- 3]thymidine incorporation into rat islets. This effect was maximally induce d, about 2.5-fold over control, by 10 pM of this peptide, decreasing therea fter. In contrast, PTHrP (38-64) amide or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using reverse transcription followed by PCR, we confirmed that rat islets express PTHrP and the type I PTH/PTHr P receptor. Addition of a neutralizing anti-PTHrP antibody to the incubatio n medium of proliferating islets decreased islet DNA synthesis by 30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (P KC) inhibitor, but not by 25 mu M adenosine 3',5'-cyclic monophosphorothioa te, Rp-isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-my ristate-13-acetate for 48 h also increased DNA synthesis 2-fold over contro ls in islets. PTHrP (1-34), at 100 nM, in contrast to 50 mu M forskolin or 10 mM NaF, failed to affect adenylate cyclase activity in islet mem branes. PTHrP, at 30 pM, was also found to increase 2-fold insulin released into t he islet-conditioned medium within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet growth and/or function by a PKC-mediated mechanism.