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Scientific article
English

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

Published inDiabetes, vol. 62, no. 2, p. 519-530
Publication date2013
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/physiology
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental/physiopathology
  • Diabetes Mellitus, Type 1/chemically induced/physiopathology
  • Electrophysiological Phenomena
  • Exocytosis/physiology
  • Glucagon/analysis/blood/secretion
  • Glucagon-Secreting Cells/pathology/physiology
  • Glucose Intolerance/physiopathology
  • Hyperglycemia/blood/physiopathology
  • Mice
  • Potassium Channels, Voltage-Gated/physiology
  • Secretory Vesicles/physiology
  • Voltage-Gated Sodium Channels/physiology
Citation (ISO format)
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. 519–530. doi: 10.2337/db11-0786
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Article (Published version)
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Identifiers
ISSN of the journal0012-1797
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