Introduction
The genetically diabetic C57BL/KsJ (db/db) mouse provides an animal model of type 2 diabetes, characterized by obesity, hyperglycemia and insulin resistance with hyperinsulinemia. Recent studies have demonstrated a marked reduction in ventricular function and altered metabolism in isolated hearts from db/db mice (Belke et al. in press). The purpose of this study was to examine the effect of a novel insulin sensitizer (BM 17.0744 from Roche) on energy substrate metabolism in hearts from db/db mice, using the isolated perfused working mouse heart model (Larsen et al. 1999).
Methods
BM 17.0744 (1.4 mg/day) was administered to the mice over a 4 week period via the drinking water. Rates of glycolysis, glucose oxidation and fatty acid oxidation were measured by inclusion of trace amounts of [5-3H]glucose, [U-14C]glucose and [9,10-3H]palmitate, respectively, in the perfusion buffer.
Results
Elevated plasma levels of glucose, fatty acids, triacylglycerol and insulin observed in non-treated db/db mice (30.4±2.5, 1.6±0.2, 1.0±0.2 mmol/l and 262±43 mU/ml, respectively) were normalised following treatment with BM 17.0744 (11.2±0.5, 1.2±0.1, 0.6±0.1 mmol/l and 46±6 mU/ml, p<0.05). Water intake and body weight gain were also reduced; 16±0.3 vs 4.0±0.3 ml/day and 28±3% vs 18±2% (both p<0.05). Rates of glycolysis and glucose oxidation were increased by 1.5 (4.5±0.4 vs 6.7±0.7 mmol/g dry wt, p<0.05) and 2.1 fold (1.0±0.2 vs 2.1±0.3 mmol/g dry, wt p<0.05), respectively, while palmitate oxidation was reduced to 40% (from 0.6±0.1 to 0.25±0.05 mmol/g dry wt, p<0.05) of that in untreated controls.
Conclusions
Thus, the present pharmacological intervention favoured increased myocardial glucose metabolism at the expense of fatty acids. Current investigations will determine whether these metabolic alterations are associated with improvement in left ventricular contractile function.
References
Belke, D.D., Larsen, T. S., Gibbs, E.M. & Severson, D.L. Am J Physiol (in press).
Larsen TS, Belke DD. Sas R, Giles WR, Severson, D.L., Lopaschuk, G. & Tyberg, J.V. 1999. Pflugers Arch 437, 979-985
We are grateful to Dr. Pill (Roche, Germany) for providing the insulin sensitizer. This study was supported by the Norwegian Research Council for Science and the Humanities (Grant #129769/310).