Crosstalk between membrane potential and cytosolic Ca2+ concentration in beta cells from Sur1−/− mice

Abstract

Aims/hypothesis: Islets or beta cells from Sur1 −/− mice were used to determine whether changes in plasma membrane potential (V m

ABCC8 and ABCC9: ABC transporters that regulate K+ channels

“…This study confirmed the lack of first-phase response and showed further that increasing glucose metabolism stimulated insulin release, demonstrating the augmentation pathway (see 67, 68 for review) is intact in the Sur1KO animals. Similar glucosestimulated insulin secretion was reported by Haspel et al [65], and Muñoz et al [105] showed increased insulin release from Sur1KO islets in low glucose plus amino acids. Studies on the Sur1KO animals generated by Shiota et al [137] have usually failed to show insulin secretion under hypoglycemic conditions or a significant increase in secretion when glucose is elevated, thus leading to the conclusion that loss of SUR1 impairs insulin release [41,87], although Eliasson et al [48] reported glucose-stimulated insulin release using this strain.…”

“…Newborn Sur1KO mice were found to exhibit significant hypoglycemia secondary to hyperinsulinemia, but this resolved within several days [133], and the KO animals then remain normoglycemic [65,108,133]. Intraperitoneal glucose tolerance tests on adult mice showed that knockout animals fail to release insulin in response to a glucose challenge [133,137], whereas fasted knockout animals are able to secrete insulin in response to feeding [137] consistent with stimulation via the CNS.…”

“…The activation of a low-conductance, Ca 2+ -dependent K + current, termed "I Kslow ," has been implicated in the oscillatory activity of wild-type β cells [61,62]. Haspel et al [65] showed that Sur1KO β cells have a similar Ca 2+ -dependent K + current that is inhibited when [Ca 2+ ] c is reduced using D600, an L-type Ca 2+ channel blocker, and stimulated using BayK 8644, a Ca 2+ channel opener. K ATP channels control oscillations of V m and [Ca 2+ ] c in wild-type β cells, but a secondary oscillatory mechanism must exist in Sur1KO cells.…”

“…Doliba et al [41] argue secretion is impaired in the Sur1KO mice and suggest acetylcholine, released in response to feeding, enhances insulin secretion, thus contributing to their euglycemia. Amino acids are also known to potentiate insulin secretion, and several studies have reported amino acids stimulate insulin release from Sur1KO islets [65,87,105]. K ATP channels are part of a brain-liver circuit that modulates hepatic glucose production SUR1/K IR 6.2 channels are known to be present throughout the CNS and are implicated in neuroprotection during periods of anoxia (reviewed in 16).…”

Regulation by Glucose of Oscillatory Electrical Activity and 5-HT/Insulin Release from Single Mouse Pancreatic Islets in Absence of Functional KATP Channels

“…Glucose appears to inhibit the component of I K,slow admittedly ascribed to K ATP channels [13,15], leading to the hypothesis that it might provide the hyperpolarizing current necessary to terminate the burst. Bursting electrical activity and underlying [Ca 2+ ] i oscillations are nonetheless present in mouse β-cells lacking the SUR1 gene [16][17][18][19], suggesting that channels distinct from the K ATP channel might account in part for physiological bursting and raising the possibility that they might mediate the graded electrical response to glucose. These channels may thus represent significant, albeit undervalued additional targets for glucose action downstream K ATP channel inhibition.…”