Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 589, Issue 22, Pages 5453-5466Publisher
WILEY-BLACKWELL
DOI: 10.1113/jphysiol.2011.218909
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Funding
- NIH [K99-DK085145, R01-DK053434, P20-GM072048, R01-DK46409]
- Department of Defense
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Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](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 beta-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated beta-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subsetof cells even at basal glucose. Isolated beta-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-)islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) 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 [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.
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