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In situ electrophysiological examination of pancreatic α cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion

Huang, Ya-Chi
Rupnik, Marjan S
Karimian, Negar
Gilon, Patrick
Feng, Zhong-Ping
Gaisano, Herbert Y
Published in Diabetes. 2013, vol. 62, no. 2, p. 519-30
Abstract Early-stage type 1 diabetes (T1D) exhibits hyperglucagonemia by undefined cellular mechanisms. Here we characterized α-cell voltage-gated ion channels in a streptozotocin (STZ)-induced diabetes model that lead to increased glucagon secretion mimicking T1D. GYY mice expressing enhanced yellow fluorescence protein in α cells were used to identify α cells within pancreas slices. Mice treated with low-dose STZ exhibited hyperglucagonemia, hyperglycemia, and glucose intolerance, with 71% reduction of β-cell mass. Although α-cell mass of STZ-treated mice remained unchanged, total pancreatic glucagon content was elevated, coinciding with increase in size of glucagon granules. Pancreas tissue slices enabled in situ examination of α-cell electrophysiology. α cells of STZ-treated mice exhibited the following: 1) increased exocytosis (serial depolarization-induced capacitance), 2) enhanced voltage-gated Na(+) current density, 3) reduced voltage-gated K(+) current density, and 4) increased action potential (AP) amplitude and firing frequency. Hyperglucagonemia in STZ-induced diabetes is thus likely due to increased glucagon content arising from enlarged glucagon granules and increased AP firing frequency and amplitude coinciding with enhanced Na(+) and reduced K(+) currents. These alterations may prime α cells in STZ-treated mice for more glucagon release per cell in response to low glucose stimulation. Thus, our study provides the first insight that STZ treatment sensitizes release mechanisms of α cells.
Keywords Action Potentials/physiologyAnimalsCells, CulturedDiabetes Mellitus, Experimental/physiopathologyDiabetes Mellitus, Type 1/chemically induced/physiopathologyElectrophysiological PhenomenaExocytosis/physiologyGlucagon/analysis/blood/secretionGlucagon-Secreting Cells/pathology/physiologyGlucose Intolerance/physiopathologyHyperglycemia/blood/physiopathologyMicePotassium Channels, Voltage-Gated/physiologySecretory Vesicles/physiologyVoltage-Gated Sodium Channels/physiology
PMID: 23043159
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Research group Types cellulaires pancréatiques pendant l'ontogénèse (522)
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HUANG, Ya-Chi et al. In situ electrophysiological examination of pancreatic α cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion. In: Diabetes, 2013, vol. 62, n° 2, p. 519-30. doi: 10.2337/db11-0786 https://archive-ouverte.unige.ch/unige:32139

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Deposited on : 2013-12-16

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