title: In situ electrophysiological examination of pancreatic α cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion.
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.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Huang
authors.forename: Marjan S
authors.initials: MS
authors.lastname: Rupnik
authors.forename: Negar
authors.initials: N
authors.lastname: Karimian
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Patrick
authors.initials: P
authors.lastname: Gilon
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000503:physiopathology*; D055724:Electrophysiological Phenomena; D005089:Exocytosis / Q000502:physiology; D005934:Glucagon / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000473:pathology / Q000502:physiology*; D018149:Glucose Intolerance / Q000503:physiopathology; D006943:Hyperglycemia / Q000097:blood / Q000503:physiopathology; D051379:Mice; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D022142:Secretory Vesicles / Q000502:physiology; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels; D005934:Glucagon