Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men

Overview

Journal Physiol Rev

Publisher American Physiological Society

Specialty Physiology

Date 2017 Dec 8

PMID 29212789

Citations 318

Authors

Patrik Rorsman

Frances M Ashcroft

Affiliations

Soon will be listed here.

Abstract

The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca concentration and initiation of Ca-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM.

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References

Kulkarni R, Bruning J, Winnay J, Postic C, Magnuson M, Kahn C . Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999; 96(3):329-39. DOI: 10.1016/s0092-8674(00)80546-2. View

Gall D, Gromada J, Susa I, Rorsman P, Herchuelz A, Bokvist K . Significance of Na/Ca exchange for Ca2+ buffering and electrical activity in mouse pancreatic beta-cells. Biophys J. 1999; 76(4):2018-28. PMC: 1300176. DOI: 10.1016/S0006-3495(99)77359-5. View

Zerangue N, Schwappach B, Jan Y, Jan L . A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron. 1999; 22(3):537-48. DOI: 10.1016/s0896-6273(00)80708-4. View

Peterson B, DeMaria C, Adelman J, Yue D . Calmodulin is the Ca2+ sensor for Ca2+ -dependent inactivation of L-type calcium channels. Neuron. 1999; 22(3):549-58. DOI: 10.1016/s0896-6273(00)80709-6. View

Jonas J, Sharma A, Hasenkamp W, Ilkova H, Patane G, Laybutt R . Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. J Biol Chem. 1999; 274(20):14112-21. DOI: 10.1074/jbc.274.20.14112. View

Ashfield R, Gribble F, Ashcroft S, Ashcroft F . Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel. Diabetes. 1999; 48(6):1341-7. DOI: 10.2337/diabetes.48.6.1341. View

Gromada J, Hoy M, Renstrom E, Bokvist K, Eliasson L, Gopel S . CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells. J Physiol. 1999; 518 ( Pt 3):745-59. PMC: 2269462. DOI: 10.1111/j.1469-7793.1999.0745p.x. View

Joberty G, Stabila P, Coppola T, Macara I, Regazzi R . High affinity Rab3 binding is dispensable for Rabphilin-dependent potentiation of stimulated secretion. J Cell Sci. 1999; 112 ( Pt 20):3579-87. DOI: 10.1242/jcs.112.20.3579. View

Pertusa J, Sanchez-Andres J, Martin F, Soria B . Effects of calcium buffering on glucose-induced insulin release in mouse pancreatic islets: an approximation to the calcium sensor. J Physiol. 1999; 520 Pt 2:473-83. PMC: 2269605. DOI: 10.1111/j.1469-7793.1999.00473.x. View

10.

Poulsen C, Bokvist K, Olsen H, Hoy M, Capito K, Gilon P . Multiple sites of purinergic control of insulin secretion in mouse pancreatic beta-cells. Diabetes. 1999; 48(11):2171-81. DOI: 10.2337/diabetes.48.11.2171. View

11.

Srinivas M, Rozental R, Kojima T, Dermietzel R, Mehler M, Condorelli D . Functional properties of channels formed by the neuronal gap junction protein connexin36. J Neurosci. 1999; 19(22):9848-55. PMC: 6782942. View

12.

Gopel S, Kanno T, Barg S, Eliasson L, Galvanovskis J, Renstrom E . Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of action potentials in mouse pancreatic beta cells. J Gen Physiol. 1999; 114(6):759-70. PMC: 2230648. DOI: 10.1085/jgp.114.6.759. View

13.

Gopel S, Kanno T, Barg S, Galvanovskis J, Rorsman P . Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets. J Physiol. 1999; 521 Pt 3:717-28. PMC: 2269694. DOI: 10.1111/j.1469-7793.1999.00717.x. View

14.

Maechler P, Wollheim C . Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature. 1999; 402(6762):685-9. DOI: 10.1038/45280. View

15.

Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y . Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A. 1999; 96(26):14843-7. PMC: 24735. DOI: 10.1073/pnas.96.26.14843. View

16.

Zhuang H, Bhattacharjee A, Hu F, Zhang M, Goswami T, Wang L . Cloning of a T-type Ca2+ channel isoform in insulin-secreting cells. Diabetes. 2000; 49(1):59-64. DOI: 10.2337/diabetes.49.1.59. View

17.

Shapiro M, Roche J, Kaftan E, Cruzblanca H, Mackie K, Hille B . Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. J Neurosci. 2000; 20(5):1710-21. PMC: 6772928. View

18.

Seghers V, Nakazaki M, DeMayo F, Aguilar-Bryan L, Bryan J . Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem. 2000; 275(13):9270-7. DOI: 10.1074/jbc.275.13.9270. View

19.

Bokvist K, Holmqvist M, Gromada J, Rorsman P . Compound exocytosis in voltage-clamped mouse pancreatic beta-cells revealed by carbon fibre amperometry. Pflugers Arch. 2000; 439(5):634-45. DOI: 10.1007/s004249900211. View

20.

Ahren B . Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia. 2000; 43(4):393-410. DOI: 10.1007/s001250051322. View