Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition

Endocrinology. 2006 May;147(5):2155-62. doi: 10.1210/en.2005-1249. Epub 2006 Feb 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Adenosine Triphosphate / metabolism*
  • Androstadienes / pharmacology
  • Animals
  • Body Weight
  • Cell Line
  • Diabetes Mellitus / metabolism
  • Dose-Response Relationship, Drug
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / cytology
  • Glucose / metabolism
  • Glutamic Acid / chemistry
  • Glutamic Acid / metabolism
  • Green Fluorescent Proteins / metabolism
  • Guinea Pigs
  • Humans
  • Inhibitory Concentration 50
  • Insulin / metabolism*
  • Islets of Langerhans / metabolism
  • Mice
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Phosphatidylinositol 3-Kinases / metabolism
  • Potassium / chemistry*
  • Potassium / metabolism
  • Rabbits
  • Signal Transduction
  • Wortmannin


  • Androstadienes
  • Insulin
  • Green Fluorescent Proteins
  • Glutamic Acid
  • Adenosine Triphosphate
  • Glucagon
  • Phosphatidylinositol 3-Kinases
  • Glucose
  • Potassium
  • Wortmannin