Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR13-Systemic Regulation of Islet Development & Function
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:45 PM
Room 304 (Moscone Center)
Ramamani Arumugam*1, Donald Edward Fleenor2, Jennifer Moss1, Danhong Lu1 and Michael Freemark1
1Duke University Medical Center, Durham, NC, 2Duke Univ Med Ctr, Durham, NC
Background: While immune interventions have reduced the rate of decline in insulin secretion in type 1 diabetic (T1D) patients they have failed to increase human beta cell mass or endogenous insulin production. Since beta cell mass is largely depleted by diagnosis, the effective treatment of T1D will require induction of beta cell regeneration in combination with suppression of autoimmunity.   Regeneration can be achieved through replication of pre-existing beta cells and/or neogenesis from cellular precursors.  But the rates of beta cell replication and neogenesis in human adolescents and adults are far lower than in human fetuses, infants, and toddlers.  This makes endogenous regeneration of beta cells in older children and adults with T1D difficult to achieve. 

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

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Support: Duke Perinatal Research Institute, Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center.
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