What is the clinical evidence from this study?

Study design: Other. Population: Diabetes. Intervention: Diabetic db/db genotype vs. Control (db/+) mice. Primary outcome: Palmitate and carbohydrate metabolism, contractile function, and postischemic recovery.

February 1, 2003Open Access

Age-Dependent Changes in Metabolism, Contractile Function, and Ischemic Sensitivity in Hearts From db/db Mice

EAEllen AasumCentre for Arctic Gas Hydrate, Environment and Climate AHAnne D. HafstadBritish Heart Foundation DSDavid L. SeversonHeart Failure / Cardiomyopathy

Key Result

Diabetic db/db mice exhibited signs of a progressive cardiomyopathy, where increased fatty acid oxidation preceded reductions in carbohydrate oxidation and reduced postischemic recovery of function.

Structured PICO

Population

Control and diabetic db/db mice evaluated at 6, 10-12, and 16-18 weeks of age to assess age-dependent changes in cardiac metabolism and contractile function.

Exposure

Peroxisome proliferator-activated receptor-alpha treatment (3 weeks) and age progression

Comparator

Control (db/+) mice and baseline age (6 weeks)

Outcome

Glucose and palmitate metabolism, contractile function, and mechanical function after ischemia-reperfusionsurrogate

Diabetic db/db mice exhibit a progressive cardiomyopathy characterized by early increases in fatty acid oxidation followed by reduced carbohydrate oxidation and impaired contractile and postischemic function.

Abstract

Glucose and palmitate metabolism and contractile function were measured with ex vivo perfused working hearts from control (db/+) and diabetic (db/db) female mice at 6, 10-12, and 16-18 weeks of age. Palmitate oxidation was increased by 2.2-fold in 6-week-old db/db hearts and remained elevated in 10- to 12- and 16- to 18-week-old hearts. Carbohydrate oxidation was normal at 6 weeks but was reduced to 27 and 23% of control at 10-12 and 16-18 weeks, respectively. At 6 weeks, db/db hearts exhibited a slight reduction in mechanical function, whereas marked signs of dysfunction were evident at 10-12 and 16-18 weeks. Mechanical function after ischemia-reperfusion was examined in hearts from male mice; at 6 weeks, db/db hearts showed normal recovery, whereas at 12 weeks it was markedly reduced. Fatty acid oxidation was the predominant substrate used after reperfusion. Thus, diabetic db/db hearts exhibit signs of a progressive cardiomyopathy; increased fatty acid oxidation preceded reductions in carbohydrate oxidation. Postischemic recovery of function was reduced in db/db hearts, in parallel with age-dependent changes in normoxic contractile performance. Finally, peroxisome proliferator-activated receptor-alpha treatment (3 weeks) did not affect sensitivity to ischemia-reperfusion, even though carbohydrate oxidation was increased and palmitate oxidation was decreased.

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