Triggering and amplification of insulin secretion by dimethyl alpha-ketoglutarate, a membrane permeable alpha-ketoglutarate analogue

Eur J Pharmacol. 2009 Apr 1;607(1-3):41-6. doi: 10.1016/j.ejphar.2009.02.014. Epub 2009 Feb 20.


Cytosolic alpha-ketoglutarate is a potential signalling compound at late steps of stimulus-secretion-coupling in the course of insulin secretion induced by glucose and other fuels. This hypothesis is mainly based on the insulin-releasing effect of the membrane permeable ester dimethyl alpha-ketoglutarate which enters the beta-cell and is cleaved to produce cytosolic monomethyl alpha-ketoglutarate and eventually alpha-ketoglutarate. The present study tested this hypothesis. Insulin release, K(ATP) channel currents, membrane potential, ATP/ADP ratio and fluorescence of NAD(P)H (reduced pyridine nucleotides) were measured in mouse pancreatic islets and beta-cells. At a substimulatory glucose concentration (5 mM), dimethyl alpha-ketoglutarate (15 mM) produced a sustained insulin release, but no change of the islet ATP/ADP ratio and NAD(P)H fluorescence. In the absence of glucose, however, dimethyl alpha-ketoglutarate (15 mM) did not stimulate insulin release although it increased the ATP/ADP ratio and NAD(P)H fluorescence. Insulin secretion induced by a maximally effective concentration of the K(ATP) channel-blocking sulfonylurea glipizide was strongly amplified by dimethyl alpha-ketoglutarate in the presence of 5 mM glucose, but only moderately in the absence of glucose. Dimethyl alpha-ketoglutarate directly inhibited K(ATP) channels in inside-out membrane patches, depolarized the plasma membrane of intact beta-cells and generated action potentials. In conclusion, the stimulation of insulin secretion by extracellularly applied dimethyl alpha-ketoglutarate depends on inhibition of beta-cell K(ATP) channels by direct action of dimethyl alpha-ketoglutarate. The metabolism of alpha-ketoglutarate generated intracellularly by ester cleavage contributes to stimulation of insulin secretion both by indirect K(ATP) channel inhibition (via activation of ATP production) and by an amplifying effect.

MeSH terms

  • Action Potentials / drug effects
  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Electrophysiology
  • Female
  • Fluorescence
  • Glucose / administration & dosage
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • KATP Channels / antagonists & inhibitors*
  • Ketoglutaric Acids / pharmacokinetics
  • Ketoglutaric Acids / pharmacology*
  • Mice
  • NADP / metabolism
  • Potassium Channel Blockers / pharmacokinetics
  • Potassium Channel Blockers / pharmacology*


  • Insulin
  • KATP Channels
  • Ketoglutaric Acids
  • Potassium Channel Blockers
  • dimethyl alpha-ketoglutarate
  • NADP
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Glucose