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Glucose Stimulation of Pancreatic ß-Cell Lines Induces Expression and Secretion of Dynorphin

Bartholin Instituttet (K.J., K.B., L.R.S., M.W.), Kommunehospitalet, DK-1399 Copenhagen K, Denmark; Department of Clinical Neuroscience (R.E.), Göteborg Universitet, Mölndal Hospital, S431-80 Sweden; and Kovler Viral Oncology Laboratory (M.B.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Knud Josefsen, M.D., Ph.D., Bartholin Instituttet, Kommunehospitalet, DK-1399 Copenhagen K, Denmark. E-mail: josefsen{at}dadlnet.dk

To investigate adaptive responses of pancreatic ß-cells to hyperglycemia, genes induced by glucose stimulation were identified by subtraction cloning. Among 53 clones representing differentially expressed genes, 20 encoded the endogenous opioid precursor, prodynorphin. The amino acid sequence of murine prodynorphin is identical to the rat protein in sequences comprising the opioid peptides and 86% identical in the remainder of the molecule. Stimulation of MIN6 cells increased prodynorphin RNA levels to more than 20-fold in proportion to physiological glucose concentrations. Similar induction levels were observed in murine ßTC3 and rat Rinm5F ß-cell lines. Prodynorphin RNA expression increased within 1 h of glucose stimulation, achieved maximal levels by 4 h, and remained elevated for at least 24 h. By using RIA, MIN6 cells were shown to contain and secrete increased amounts of dynorphin-A following glucose stimulation. Treatment of MIN6 cells with KCl, forskolin, or isobutyl-methyl-xanthine strongly induced prodynorphin RNA expression, suggesting that induction may be related to secretion-coupled signaling pathways. The induction of prodynorphin in several ß-cell lines is consistent with previous demonstrations of ß-cell synthesis of other endogenous opioids, including ß-endorphin, and suggests that opioids may have a potentially significant role in regulating ß-cell secretion.

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