Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan

Diabetologia. 2002 Nov;45(11):1542-9. doi: 10.1007/s00125-002-0955-x. Epub 2002 Oct 2.

Abstract

Aims/hypothesis: We investigated the importance of the low affinity GLUT2 glucose transporter in the diabetogenic action of alloxan in bioengineered RINm5F insulin-producing cells with different expressions of the transporter.

Methods: GLUT2 glucose transporter expressing RINm5F cells were generated through stable transfection of the rat GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay.

Results: Cells expressing the GLUT2 transporter were susceptible to alloxan toxicity due to the uptake of alloxan by this specific glucose transporter isoform. The extent of the toxicity of alloxan was dependent upon the GLUT2 protein expression in the cells. The lipophilic alloxan derivative, butylalloxan, was toxic also to non-transfected control cells. Expression of the GLUT2 glucose transporter caused only a marginal increase in the toxicity of this substance. Butylalloxan, unlike alloxan itself, is not diabetogenic in vivo although, like the latter substance, it is beta-cell toxic in vitro through its ability to generate free radicals during redox cycling with glutathione.

Conclusion/interpretation: Our results are consistent with the central importance of selective uptake of alloxan through the low affinity GLUT2 glucose transporter for the pancreatic beta-cell toxicity and diabetogenicity of this substance. Redox cycling and the subsequent generation of oxygen free radicals leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as alloxan diabetes in experimental diabetes research.

MeSH terms

  • 3-O-Methylglucose / pharmacology
  • Alloxan / analogs & derivatives
  • Alloxan / antagonists & inhibitors
  • Alloxan / toxicity*
  • Animals
  • Cells, Cultured
  • Gene Expression Regulation / physiology
  • Glucose / pharmacology*
  • Glucose Transporter Type 2
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Kinetics
  • Microsomes / metabolism
  • Monosaccharide Transport Proteins / genetics*
  • Monosaccharide Transport Proteins / metabolism*
  • Rats
  • Recombinant Proteins / metabolism

Substances

  • Glucose Transporter Type 2
  • Monosaccharide Transport Proteins
  • Recombinant Proteins
  • 3-O-Methylglucose
  • Alloxan
  • Glucose