title: Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition.
abstract: Glucose regulates pancreatic islet alpha-cell glucagon secretion directly by its metabolism to generate ATP in alpha-cells, and indirectly via stimulation of paracrine release of beta-cell secretory products, particularly insulin. How the cellular substrates of these pathways converge in the alpha-cell is not well known. We recently reported the use of the MIP-GFP (mouse insulin promoter-green fluorescent protein) mouse to reliably identify islet alpha- (non-green cells) and beta-cells (green cells), and characterized their ATP-sensitive K(+) (K(ATP)) channel properties, showing that alpha-cell K(ATP) channels exhibited a 5-fold higher sensitivity to ATP inhibition than beta-cell K(ATP) channels. Here, we show that insulin exerted paracrine regulation of alpha-cells by markedly reducing the sensitivity of alpha-cell K(ATP) channels to ATP (IC(50) = 0.18 and 0.50 mM in absence and presence of insulin, respectively). Insulin also desensitized beta-cell K(ATP) channels to ATP inhibition (IC(50) = 0.84 and 1.23 mM in absence and presence of insulin, respectively). Insulin effects on both islet cell K(ATP) channels were blocked by wortmannin, indicating that insulin acted on the insulin receptor-phosphatidylinositol 3-kinase signaling pathway. Insulin did not affect alpha-cell A-type K(+) currents. Glutamate, known to also inhibit alpha-cell glucagon secretion, did not activate alpha-cell K(ATP) channel opening. We conclude that a major mechanism by which insulin exerts paracrine control on alpha-cells is by modulating its K(ATP) channel sensitivity to ATP block. This may be an underlying basis for the proposed sequential glucose-insulin regulation of alpha-cell glucagon secretion, which becomes distorted in diabetes, leading to dysregulated glucagon secretion.
authors.affiliation: Departments of Medicine and Physiology, University of Toronto, Canada.
authors.forename: Yuk M
authors.initials: YM
authors.lastname: Leung
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Ahmed
authors.forename: Laura
authors.initials: L
authors.lastname: Sheu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.forename: Manami
authors.initials: M
authors.lastname: Hara
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tsushima
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Diamant
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002460:Cell Line; D003920:Diabetes Mellitus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000166:cytology; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011188:Potassium / Q000737:chemistry* / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D007328:Insulin; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005934:Glucagon; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D011188:Potassium; D000077191:Wortmannin