Diabetologia

, Volume 45, Issue 1, pp 56–65

5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice

  • X. M. Song
  • M. Fiedler
  • D. Galuska
  • J. W. Ryder
  • M. Fernström
  • A. V. Chibalin
  • H. Wallberg-Henriksson
  • J. R. Zierath
Article

DOI: 10.1007/s125-002-8245-8

Cite this article as:
Song, X., Fiedler, M., Galuska, D. et al. Diabetologia (2002) 45: 56. doi:10.1007/s125-002-8245-8

Abstract.

Aims/hypothesis:

The 5'AMP-activated protein kinase is an important mediator of muscle contraction-induced glucose transport and a target for pharmacological treatment of Type II (non-insulin-dependent) diabetes mellitus. The 5'AMP-activated protein kinase can be activated by 5-aminoimidazole-4-carboxamide ribonucleoside. We hypothesised that 5-aminoimidazole-4-carboxamide ribonucleoside treatment could restore glucose homeostasis in ob/ob mice.

Methods:

Lean and ob/ob mice were given 5-aminoimidazole-4-carboxamide ribonucleoside (1 mg · g body wt–1· day–1 s.c) or 0.9 % NaCl (vehicle) for 1–7 days.

Results:

Short-term 5-aminoimidazole-4-carboxamide ribonucleoside treatment normalised glucose concentrations in ob/ob mice within 1 h, with effects persisting over 4 h. After 1 week of daily injections, 5-aminoimidazole-4-carboxamide ribonucleoside treatment corrected hyperglycaemia, improved glucose tolerance, and increased GLUT4 and hexokinase II protein expression in skeletal muscle, but had deleterious effects on plasma non-esterified fatty acids and triglycerides. Treatment with 5-aminoimidazole-4-carboxamide ribonucleoside increased liver glycogen in fasted and fed ob/ob mice and muscle glycogen in fasted, but not fed ob/ob and lean mice. Defects in insulin-stimulated phosphatidylinositol 3-kinase and glucose transport in skeletal muscle from ob/ob mice were not corrected by 5-aminoimidazole-4-carboxamide ribonucleoside treatment. While ex vivo insulin-stimulated glucose transport was reduced in isolated muscle from ob/ob mice, the 5-aminoimidazole-4-carboxamide ribonucleoside stimulated response was normal.

Conclusion/interpretation:

The 5-aminoimidazole-4-carboxamide ribonucleoside mediated improvements in glucose homeostasis in ob/ob mice can be explained by effects in skeletal muscle and liver. Due to the apparently deleterious effects of 5-aminoimidazole-4-carboxamide ribonucleoside on the blood lipid profile, strategies to develop tissue-specific and pathway-specific activators of 5'AMP-activated protein kinase should be considered in order to improve glucose homeostasis. [Diabetologia (2002) 45: 56–65]

Keywords Glucose transportglycogenlipidsinsulin signallingglucose toleranceobesityGLUT4hexokinase IIglycogen synthasemyocyte enhancer factor 2.
Download to read the full article text

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • X. M. Song
    • 1
  • M. Fiedler
    • 2
  • D. Galuska
    • 1
  • J. W. Ryder
    • 1
  • M. Fernström
    • 3
  • A. V. Chibalin
    • 3
  • H. Wallberg-Henriksson
    • 1
  • J. R. Zierath
    • 1
  1. 1.Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SwedenSE
  2. 2.Biovitrum, Department of Pharmacology, Uppsala, SwedenSE
  3. 3.Department of Clinical Physiology, Karolinska Hospital, Stockholm, SwedenSE