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This version published online on May 27, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0148
A more recent version of this article appeared on September 1, 2004
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Submitted on April 13, 2004
Accepted on May 19, 2004

Enhanced cAMP/Protein Kinase A signaling determines improved insulin secretion in a clonal insulin-producing {beta}-cell line (INS-1 832/13)

Shumin Yang, Ulrika Fransson, Lillian Fagerhus, Lena Stenson Holst, Hans E. Hohmeier, Erik Renström, and Hindrik Mulder*

Departments of Cell and Molecular Biology, and Physiological Sciences, at Lund University, Sweden; Sarah Stedman Center for Nutritional Studies and Duke Program in Diabetes Research, Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

* To whom correspondence should be addressed. E-mail: hindrik.mulder{at}medkem.lu.se.

In type 2 diabetes, {beta}-cells become glucose unresponsive, contributing to hyperglycemia. To address this problem, we recently created clonal insulin-producing cell lines from the INS-1 insulinoma line which exhibit glucose responsiveness ranging from poor to robust. Here, mechanisms that determine secretory performance were identified by functionally comparing glucose-responsive 832/13 {beta}-cells with glucose-unresponsive 832/2 {beta}-cells. Thus, insulin secretion from 832/13 cells maximally rose 8-fold in response to glucose, while 832/2 cells responded only 1.5-fold. Insulin content in both lines was similar, indicating that differences in stimulus-secretion coupling account for the differential secretory performance. Forskolin or isobutylmethylxanthine markedly enhanced insulin secretion from 832/13 but not from 832/2 cells, suggesting that cAMP is essential for the enhanced secretory performance of 832/13 cells. Indeed, rp-cAMPS, an inhibitor of protein kinase A (PKA), inhibited insulin secretion in response to glucose with or without forskolin. Interestingly, while forskolin markedly increased cAMP in 832/2 cells, 832/13 cells exhibited only a marginal rise in cAMP. This suggests that 832/13 cells are more sensitive to cAMP. Indeed, the cAMP-induced exocytotic response in patch-clamped 832/13 cells was two-fold greater than in 832/2 cells. Furthermore, immunoblotting revealed that expression of the catalytic subunit of PKA was 2-fold higher in 832/13 cells. Moreover, when the regulatory subunit of PKA was overexpressed in 832/13 cells, to reduce the level of unbound and catalytically active kinase, insulin secretion and PKA activity were blunted. Our findings show that cAMP-PKA signaling correlates with secretory performance in {beta}-cells.
Key words: adenovirus • catalytic subunit • clonal cells • incretin • patch clamp • regulatory subunit




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