This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yu, J. Articles by Barker, C. J. Search for Related Content PubMed PubMed Citation Articles by Yu, J. Articles by Barker, C. J.

An Autocrine Insulin Feedback Loop Maintains Pancreatic ß-Cell 3-Phosphorylated Inositol Lipids

The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Per-Olof Berggren, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. E-mail: per-olof.berggren{at}ki.se.

Phosphatidylinositol 3-kinases (PI3Ks) have a central role in pancreatic ß-cell function. Downstream events include the regulation of K_ATP channel activity, insulin secretion, gene transcription, and cell survival. Fewer data are available on the 3-phosphorylated inositol lipids (3-PIs) that are the primary products of these kinases. We characterized these PI3K products in insulin-secreting HIT T15 cells and were able to demonstrate, for the first time the presence of phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P₂]. We then showed that glucose can significantly increase PtdIns(3,4,5)P₃, PtdIns(3,4)P₂, and notably PtdIns(3,5)P₂. We investigated the mechanism(s) whereby these molecules are generated under both basal and glucose-stimulated conditions. We postulated that insulin exocytosis could drive the rises in 3-PIs. In our experimental system, we could detect a rise in insulin secretion within 1 min of glucose stimulation, thus allowing the possibility that early rises in 3-PIs are regulated by secreted insulin. This was confirmed because blockade of the ß-cell insulin receptor completely abrogated the glucose-mediated increase of all three lipids, driving their concentrations below basal levels. Using primary pancreatic islets and either blockade of the insulin receptor or antibodies to insulin, we verified that basal insulin secretion is responsible for the maintenance of 3-PIs. Therefore, autocrine insulin signaling, a feature compromised in diabetes, is essential to up-regulate both basal and glucose-stimulated levels of a vital family of second messengers that preserve and drive pancreatic ß-cell function.