An autocrine insulin feedback loop maintains pancreatic beta-cell 3-phosphorylated inositol lipids.
Phosphatidylinositol 3-kinases (PI3Ks) have a central role in pancreatic beta-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)P(2)]. We then showed that glucose can significantly increase PtdIns(3,4,5)P(3), PtdIns(3,4)P(2), and notably PtdIns(3,5)P(2). 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 beta-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 beta-cell function.
Yu
Jia
J
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden.
Berggren
Per-Olof
PO
Barker
Christopher J
CJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D005089:Exocytosis; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008954:Models, Biological; D015221:Potassium Channels / Q000737:chemistry; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007328:Insulin; D008055:Lipids; D015221:Potassium Channels; D007294:Inositol; D005947:Glucose