D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic ß-Cells.

Dopamine (DA) has a vital role in the central nervous system and also modulates lipid and glucose metabolism. The present study aimed to investigate the effect of dopamine on insulin secretion and the underlying mechanisms in rat pancreatic ß-cells. Data from the radioimmunoassay indicated that dopamine inhibited insulin secretion in a glucose- and dose-dependent manner. This inhibitory effect of dopamine was mediated mainly by D2-like receptors, but not D1-like receptors. Whole-cell patch-clamp recordings showed that dopamine decreased voltage-dependent Ca2+ channel currents, which could be reversed by inhibition of the D2-like receptor. Dopamine increased voltage-dependent potassium (KV) channel currents and shortened action potential duration, which was antagonized by inhibition of D2-like receptors. Further experiments showed that D2-like receptor activation by quinpirole increased KV channel currents. In addition, using calcium imaging techniques, we found that dopamine reduced intracellular Ca2+ concentration, which was also reversed by D2-like receptor antagonists. Similarly, quinpirole was found to decrease intracellular Ca2+ levels. Taken together, these findings demonstrate that dopamine inhibits insulin secretion mainly by acting on D2-like receptors, inhibiting Ca2+ channels, and activating Kv channels. This process results in shortened action potential duration and decreased intracellular Ca2+ levels in ß-cells. This work offers new insights into a glucose-dependent mechanism whereby dopamine regulates insulin secretion.

Inhibition of voltage-dependent potassium channels mediates cAMP-potentiated insulin secretion in rat pancreatic ß cells.

Insulin secretion is essential for maintenance of glucose homeostasis. An important intracellular signal regulating insulin secretion is cAMP. In this report, we showed that an increase of cAMP induced by adenylyl cyclase (AC) activator forskolin or by cAMP analog db-cAMP not only potentiated insulin secretion but also inhibited Kv channels, and these effects were reversed by AC inhibitor SQ22536. The cAMP-mediated Kv channel inhibition resulted in prolongation of action potential duration, which partly accounts for the elevation of intracellular Ca2+ induced by activation of cAMP signaling. Taken together, the results suggest that Kv channels are involved in cAMP-potentiated insulin secretion in pancreatic ß cells.

The PLC/PKC/Ras/MEK/Kv channel pathway is involved in uncarboxylated osteocalcin-regulated insulin secretion in rats.

Uncarboxylated osteocalcin, a bone matrix protein, has been proposed to regulate glucose metabolism by increasing insulin secretion, improving insulin sensitivity and stimulating ß cell proliferation. Our previous study also indicated that uncarboxylated osteocalcin stimulates insulin secretion by inhibiting voltage-gated potassium (KV) channels. The goal of this study is to further investigate the underlying mechanisms for the regulation of Kv channels and insulin secretion by uncarboxylated osteocalcin. Insulin secretion and Kv channel currents were examined by radioimmunoassay and patch-clamp technique, respectively. Calcium imaging system was applied to measure intracellular Ca2+ concentration ([Ca2+]i). The protein levels were detected by western blot. The results showed that uncarboxylated osteocalcin potentiated insulin secretion, inhibited Kv channels and increased [Ca2+]i compared to control. These effects were suppressed by phospholipase-C (PLC)/protein kinase C (PKC)/Ras/MAPK-ERK kinase (MEK) signaling pathway, indicating that this signaling pathway plays an important role in uncarboxylated osteocalcin-regulated insulinotropic effect. In addition, the results also showed that adenylyl cyclase (AC) did not influence the effect of uncarboxylated osteocalcin on insulin secretion and Kv channels, suggesting that AC is not involved in uncarboxylated osteocalcin-stimulated insulin secretion. These findings provide new insight into the mechanism of uncarboxylated osteocalcin-regulated insulin secretion.

Geniposide acutely stimulates insulin secretion in pancreatic ß-cells by regulating GLP-1 receptor/cAMP signaling and ion channels.

Geniposide, an iridoid glycoside, has antidiabetic effects. The present study aimed to evaluate whether geniposide has direct effects on insulin secretion from rat pancreatic islets. The results demonstrated that geniposide potentiated insulin secretion via activating the glucagon-like-1 receptor (GLP-1R) as well as the adenylyl cyclase (AC)/cAMP signaling pathway. Inhibition of protein kinase A (PKA) suppressed the insulinotropic effect of geniposide. Geniposide also inhibited voltage-dependent potassium (Kv) channels, and this effect could be attenuated by inhibition of GLP-1R or PKA. Current-clamp recording showed that geniposide prolonged action potential duration. These results collectively imply that inhibition of Kv channels is linked to geniposide-potentiated insulin secretion by acting downstream of the GLP-1R/cAMP/PKA signaling pathway. Moreover, activation of Ca(2+) channels by geniposide was observed, indicating that the Ca(2+) channel is also an important player in the geniposide effects. Together, these findings provide new insight into the mechanism underlying geniposide-regulated insulin secretion.

Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic ß cells.

Insulin secretion from pancreatic ß cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating ß cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin-regulated insulin secretion and voltage-gated potassium (KV) channels, voltage-gated calcium channels in rat ß cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca(2+) concentration ([Ca(2+)]i). The data show that under 16.7mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca(2+)]i, but with no such effects on insulin secretion and [Ca(2+)]i in the presence of a KV channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited KV currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that KV channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic ß cells. By inhibiting KV channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca(2+) concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion.