Modulating Somatostatin in the Islet
As the major hormone-producing cells of the pancreatic Islets of Langerhans, the insulin-secreting β-cells and glucagon-secreting α-cells are the primary modulators of glucose homeostasis. However, through the production of somatostatin, which suppresses the secretion of both insulin and glucagon, the δ-cells play an equally important, though somewhat subtler role. Somatostatin secretion in the δ-cell depends mainly on the influx of Ca2+ through voltage-dependent calcium channels; however growing evidence suggests that calcium-induced calcium release (CICR) from the endoplasmic reticulum (ER) is also involved. Stimulated by increases in intracellular Ca2+ (Ca2+c), CICR is facilitated when stores of Ca2+ in the ER (Ca2+ER) are high. Thus, somatostatin secretion is suppressed in δ-cells treated with inhibitors of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), which pumps Ca2+ into the ER. In contrast, glucose metabolism stimulates SERCA activity, thereby augmenting somatostatin secretion. These observations led Vanderbilt Basic Sciences investigator David Jacobson and his laboratory to hypothesize that the TALK-1 potassium channel may modulate somatostatin secretion in δ-cells. The Jacobson lab had previously shown that in β-cells, TALK-1 promotes the exit of Ca2+ from the ER by facilitating a compensatory flow of K+ across the ER membrane. In their new studies, they discovered that δ-cells from both human and mouse islets express functional TALK-1 channels in their ER. Furthermore, they found that δ-cells from mice deficient in TALK-1 (TALK-1 KO) exhibited larger and more frequent oscillations in Ca2+c, both under low glucose conditions and in the presence of high glucose, when the oscillations became coordinated with those of neighboring β-cells. Somatostatin secretion was also higher by TALK-1 KO than wild-type δ-cells under both low (20%) and high (60%) glucose conditions. Further studies showed that Ca2+ER levels and release of Ca2+ER in response to depolarization were higher in TALK-1 KO than wild-type δ-cells. These differences in Ca2+ homeostasis and somatostatin secretion between the wild-type and TALK-1 KO δ-cells were eliminated when the cells were treated with a SERCA inhibitor. Glucagon secretion by islets from TALK-1 KO mice was lower than that by islets from wild-type mice. This was true, even though TALK-1 protein was not expressed in α-cells, suggesting that the suppression of glucagon secretion in the absence of TALK-1 might be due to increased somatostatin produced by neighboring δ-cells. This hypothesis was supported by the increased glucagon production in TALK-1 KO islets treated with an antagonist of the somatostatin receptor. The investigators also showed that Ca2+ oscillations in response to low glucose were suppressed in α-cells in intact islets from TALK-1 KO mice as compared to wild-type mice. These differences disappeared when the α-cells were studied in isolation, suggesting that they were the result of an interaction between cells in the islet. Together the data support the hypothesis that TALK-1 suppresses δ-cell somatostatin secretion by reducing levels of Ca2+ER and that this reduction in somatostatin levels in the islet promotes secretion of glucagon by nearby α-cells. The work is published in the journal Molecular Metabolism [N. C. Vierra, et al., (2018) Mol. Metab. Published online January 31, DOI: https://doi.org/10.1016/j.molmet.2018.01.016]