Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Tuesday Speaker Abstracts

INSULIN EXOCYTOSIS: NORMAL PHYSIOLOGY AND DISRUPTION IN TYPE-2 DIABETES Patrik Rorsman 1,2 ; 1 OCDEM, Radcliffe Department of Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom 2 Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden Insulin is the body’s only blood glucose-lowering hormone. Insufficient release of insulin leads to diabetes, a disease that affects at least 5% of the population. Insulin is released by the beta- cells of the pancreatic islets (the endocrine part of the pancreas). The beta-cells are electrically excitable and glucose (as well as other insulin secretagogues) initiates Ca 2+ -dependent action potential firing and the associated increase in intracellular Ca 2+ triggers exocytosis of insulin- containing secretory granules. Electrical activity in the beta-cell is controlled by ATP-regulated potassium channels that close in response to a glucose-induced increase in the cytoplasmic ATP/ADP ratio. Exocytosis in beta-cells proceeds at very high rates despite the a Ca 2+ channel density being only 5-10% of that found in other neuroendocrine cells. This is because the Ca 2+ channels physically associate with release-competent secretory granules, allowing economical use of Ca 2+ entering the beta-cells. Disruption of this arrangement selectively interferes with rapid depolarization-evoked exocytosis but does not affect ‘asynchronous’ release. Experimental conditions emulating diabetes (such as chronic exposure to non-esterified fatty acids) results in the disassembly of the Ca 2+ channel/secretory granule complexes and reduces glucose-induced insulin secretion in a way resembling that seen in clinical diabetes. Experiments using fluorescently tagged Ca 2+ channels confirm that they normally cluster close to insulin granules undergoing exocytosis and but that the formation of such clusters is prevented following exposure to NEFA and not seen in beta-cells from donors diagnosed with type-2 diabetes. We propose that tight coupling of Ca 2+ entry to the release machinery provides the insulin-secreting beta-cells with the means of high-capacity exocytosis at minimal expenditure of metabolic energy to buffer Ca 2+ . This prevents reactivation of the ATP-sensitive potassium channels and inhibition of electrical activity/insulin secretion that would otherwise occur.

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