Gap junctions and other mechanisms of cell–cell communication regulate basal insulin secretion in the pancreatic islet

• Published in: The Journal of physiology 2011-11, Vol.589 (22), p.5453-5466
• Main Authors: Benninger, R. K. P., Head, W. Steven, Zhang, Min, Satin, Leslie S., Piston, David W.
• Format: Article
• Language: English
• Subjects: Animals; Calcium - physiology; Cell Communication - physiology; Cells, Cultured; Connexins - deficiency; Connexins - physiology; Cyclic AMP - physiology; Cyclic AMP-Dependent Protein Kinases - physiology; Gap Junction delta-2 Protein; Gap Junctions - physiology; Glucose; Glucose - pharmacology; In Vitro Techniques; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - physiology; Islets of Langerhans - physiology; Membrane Potentials; Mice; Mice, Knockout; Pancreas; Renal and Endocrine
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.218909

Non‐Technical Summary  The islet of Langerhans secretes the hormone insulin in response to elevated glucose. Interactions between cells within the islet is important for the regulation of insulin secretion, to both suppress basal insulin secretion and enhance the glucose‐stimulated response. We show that multiple mechanisms of cell–cell communication are required for the suppression of basal insulin release. First, gap junctions suppress spontaneous calcium signals which suppresses triggering of insulin release. Second, other juxtacrine mechanisms, regulated by cAMP and glucose, suppress more distal steps in the regulation of insulin granule exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still fully suppress basal insulin release. This new insight into the function of islet of Langerhans is important for understanding the development and treatment of diabetes.   Cell–cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap‐junctions coordinate oscillations in intracellular free‐calcium ([Ca2+]i) and insulin secretion in the islet following elevated glucose. Gap‐junctions can also ensure that oscillatory [Ca2+]i ceases when glucose is at a basal levels. We determine the roles of gap‐junctions and other cell–cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap‐junction coupling following deletion of connexion36 (Cx36−/−), and these results were compared to those obtained using fully isolated β‐cells. KATP loss‐of‐function islets provide a further experimental model to specifically study gap‐junction mediated suppression of electrical activity. In isolated β‐cells or Cx36−/− islets, elevations in [Ca2+]i persisted in a subset of cells even at basal glucose. Isolated β‐cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36−/− islets was minimally altered. [Ca2+]i was further elevated under basal conditions, but insulin release still suppressed in KATP loss‐of‐function islets. Forced elevation of cAMP led to PKA‐mediated increases in insulin secretion from islets lacking gap‐junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell–cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca2+