Session: OR13-Systemic Regulation of Islet Development & Function
Room 304 (Moscone Center)
Hypothesis: Beta cell replication can be induced in adult rodent islets by treatment with prolactin (PRL) or placental lactogen (PL). Conversely, a deletion of PRL receptors (PRLRs) reduces pancreatic beta cell mass. We hypothesized that over-expression of PRLRs would stimulate replication of adult rat islets cultured in the presence of fetal bovine serum (FBS), which contains endogenous bovine PRL (~50 ng/ml) and PL (10-20 ng/ml).
Methods: We transfected adult rat islets with an adenovirus expressing the rat PRLR. Control islets were treated with adenoGFP. The islets were incubated in medium with 10% FBS.
Results: After 72 hr in culture, PRLR receptor mRNA and protein levels were increased ~50 fold. Receptor protein was localized primarily to the plasma membranes of islet beta cells.
Over-expression of PRLRs stimulated a 3.2-fold increase in islet thymidine incorporation (p<0.001). The induction of DNA synthesis was accompanied by striking increases (2-3 fold, p<0.001) in the mRNA levels of cyclins A2, B1, B2, and CDK1, and lesser and variable increases in cyclin D1 and FoxM1 mRNAs (20-50%). Conversely, there were 20-50% decreases in expression of cyclin E1, p21, menin, and Bcl6 mRNAs. Cyclin D2 mRNA did not change, but D2 protein levels were mildly increased. Expression of MafA, a determinant of beta cell maturation, increased 45% (p<0.001) but contrary to expectations, Tph1 mRNA levels declined and BclXL mRNA did not change. However there was a 3.4-fold increase (p<0.001) in the mRNA levels of the anti-apoptotic protein PTTG1 (securin).
Conclusion: Over-expression of the PRLR in adult rat islets markedly increases DNA synthesis and regulates the expression of critical cell cyclins, cell cycle inhibitors, MafA, and PTTG1, a novel anti-apoptotic protein.
Implications: Our findings suggest a potential therapeutic approach for T1D by which targeted up-regulation of PRLR expression could increase beta cell replication without imposing systemic risks from treatment with PRL or placental lactogen.
Nothing to Disclose: RA, DEF, JM, DL, MF
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