5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside treatment ameliorates hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in KKAy-CETP mice.
OBJECTIVE
5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside increases 5'-AMP-activated kinase activity in insulin-sensitive tissues known to control glucose homeostasis. We hypothesised that 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside treatment could have a beneficial effect on glucose homeostasis in KKAy-CETP mice, a model of Type II (non-insulin-dependent) diabetes mellitus. Our aim was to examine potential effects of acute and chronic (7-day) 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside treatment on glucose homeostasis in KKAy-CETP diabetic mice.


METHODS
Female KKAy-CETP mice were treated with 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside by a single daily injection for 7 days (100, 300, or 500 mg. kg-1. day-1).


RESULTS
After 7 days of treatment with 500 mg. kg-1. day-1 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside, blood glucose and plasma insulin concentrations were reduced (p < 0.01). Body weight and food intake were also reduced after treatment (p < 0.01 and p < 0.05, respectively). Glucose and insulin tolerance were improved (p < 0.05), whereas endogenous glucose production was suppressed (p < 0.05). The beneficial effect of 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside on hyperglycaemia and hyperinsulinaemia was due to an inhibition of endogenous glucose production, since in vivo and in vitro basal and insulin-stimulated glucose uptake in skeletal muscle was not affected by 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside. Other features of the treatment included increased plasma of free fatty acid concentration (1.9-fold, p < 0.01) and triglycerides (1.3-fold, p < 0.05).


CONCLUSIONS
5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside treatment attenuated hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in KKAy-CETP mice, a model of Type II diabetes. The blood glucose lowering effects of 5-aminoimidazole-4-carboxy-amide-1-beta-d-ribofuranoside occurs mainly as a consequence of reduced endogenous glucose production because insulin-stimulated skeletal muscle glucose uptake has not been altered.
Fiedler
M
M
Department of Pharmacology, Biovitrum, Uppsala, Sweden.
Zierath
J R
JR
Selén
G
G
Wallberg-Henriksson
H
H
Liang
Y
Y
Sakariassen
K S
KS
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000096:biosynthesis / Q000493:pharmacokinetics; D006023:Glycoproteins; D006943:Hyperglycemia / Q000188:drug therapy*; D006946:Hyperinsulinism / Q000188:drug therapy*; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D012265:Ribonucleotides / Q000627:therapeutic use*
D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide; D005947:Glucose