Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice.

@article{Belke2000AlteredMC,
  title={Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice.},
  author={Darrell D. Belke and Terje S. Larsen and E. Michael Gibbs and David L. Severson},
  journal={American journal of physiology. Endocrinology and metabolism},
  year={2000},
  volume={279 5},
  pages={
          E1104-13
        }
}
  • D. BelkeT. Larsen D. Severson
  • Published 1 November 2000
  • Biology, Medicine
  • American journal of physiology. Endocrinology and metabolism
Contractile function and substrate metabolism were characterized in perfused hearts from genetically diabetic C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and their non-diabetic lean littermates. Contractility was assessed in working hearts by measuring left ventricular pressures and cardiac power. Rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured using radiolabeled substrates ([5-(3)H]glucose, [U-(14)C]glucose, and [9,10-(3)H]palmitate) in the perfusate. Contractile… 
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Abnormal function and glucose metabolism in the type-2 diabetic db/db mouse heart.

The db/db mouse has abnormal left ventricular function in vivo, with impaired glucose uptake during ischemia, leading to increased myocardial damage, and this study examined cardiac function and glucose metabolism in the 6-month-old db/ db mouse, a model of type-2 diabetes.

Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice.

Insulin and glucose normalize cardiac metabolism, restore efficiency, and improve postischemic recovery in type 2 diabetic mouse hearts, which may in part explain the beneficial effect of glucose-insulin-potassium therapy in diabetic patients with cardiac complications.

Diabetes and Cardiac Dysfunction

The experimental evidence supporting the existence of a diabetic cardiomyopathy, defined as ventricular dysfunction in the absence of coronary artery disease, in three rodent models of type 2 diabetes produced by leptin receptor mutations is summarized.

Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin.

The results show that, despite reduced insulin-stimulated glucose uptake in isolated cardiomyocytes, isolated perfused db/db hearts are responsive to metabolic actions of insulin, and should advocate the use of insulin therapy (glucose-insulin-potassium) in diabetic patients undergoing cardiac surgery or during reperfusion after an ischemic insult.

Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice.

Diabetic db/ db hearts exhibit signs of a progressive cardiomyopathy; increased fatty acid oxidation preceded reductions in carbohydrate oxidation and postischemic recovery of function was reduced in db/db hearts, in parallel with age-dependent changes in normoxic contractile performance.

Treatment of type 2 diabetic db/db mice with a novel PPARgamma agonist improves cardiac metabolism but not contractile function.

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance, and the effect of chronic oral administration of COOH on cardiac function was assessed.

Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats.

The data suggest that in this model of diabetes, the shift from carbohydrates to fatty acids for oxidative energy production did not increase myocardial oxygen consumption and was not associated with impaired response to ischemia and reperfusion.

Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity.

Changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice).

Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts.

Insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased, but fatty acid oxidation and AMPK phosphorylated are unchanged.

Fatty acid metabolism is enhanced in type 2 diabetic hearts.

...

References

SHOWING 1-10 OF 44 REFERENCES

The Effect of Diabetes on Performance and Metabolism of Rat Hearts

It is indicated that streptozotocin diabetes in rats results in abnormal myocardial performance and is not correctable by the provision of high glucose plus insulin in the perfusion medium.

Myocardial function and energy substrate metabolism in the insulin-resistant JCR:LA corpulent rat.

Under these perfusion conditions, 40% of myocardial ATP production was derived from glucose, whereas 60% wasderived from palmitate in both cp/cp and control rats, which indicates that cardiomyopathic changes in insulin-dependent and non-insulin-dependent diabetic rats are driven by changes in energy substrate utilization.

Cardiac dysfunction in isolated perfused hearts from spontaneously diabetic BB rats.

The results suggest that the chronically diabetic state in the BB rat produces cardiac changes similar to those demonstrable after chemical diabetes induced by alloxan or STZ, or that seen during human diabetes mellitus.

Glucose and fatty acid metabolism in the isolated working mouse heart.

The metabolism of mouse hearts can be altered by fatty acid concentration in a manner similar to that observed in larger animals; increasing palmitate concentration altered the balance of substrate metabolism to increase overall energy derived from fatty acids from 64 to 92%.

Different types of postinsulin receptor defects contribute to insulin resistance in hearts of obese Zucker rats.

POCA can be used as a tool to distinguish different forms of insulin resistance in obesity: 1) a lipid metabolism-dependent defect--presumably an inhibition of phosphofructokinase and pyruvate dehydrogenase by metabolites of fatty acid oxidation, influenced by inhibition of carnitine palmitoyltransferasei, and 2) a cholesterol metabolism-independent defect in the activation of uptake of glucose and glycogen synthesis by insulin not affected by POCA.

Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart.

Selective ablation of GLUT4 in the heart initiates a series of events that results in compensated cardiac hypertrophy, and isoproterenol-stimulated isovolumic contractile performance was preserved.

Reversibility of Diabetic Cardiomyopathy with Insulin in Rats

Primary myocardial disease in the diabetic mouse. An ultrastructural study.

  • F. GiacomelliJ. Wiener
  • Biology, Medicine
    Laboratory investigation; a journal of technical methods and pathology
  • 1979
It is concluded that the pathologic lesions in the cardiac muscle cells and intramural arterial vessels and capillaries constitute a primary myocardial disease in the genetically diabetic mouse.

Preferential inhibition of lactate oxidation relative to glucose oxidation in the rat heart following diabetes.

Postischemic cardiac performance in the insulin-resistant JCR:LA-cp rat.

The results demonstrate that an insulin-resistant animal model exhibits an increased sensitivity to ischemic myocardial injury that develops with advancing age and the mechanism responsible for the enhanced sensitivity may involve augmented glycolytic metabolism.