Although it is known that
insulin-dependent (
type 1) diabetes results in depressed contractile performance associated with diminished sarcoendoplasmic reticular Ca2+-
ATPase (SERCA2a) activity, findings in
insulin-resistant (
type 2) diabetes suggest a less clear association. The db/db
insulin-resistant mouse model exhibits decreased cardiac performance both in situ and in isolated ex vivo working hearts. In this study, contractile performance and
calcium transients were measured in Langendorff-perfused hearts and isolated cardiac myocytes. Diabetic (db/db) mouse hearts demonstrated decreased rates of contraction, relaxation, and pressure development.
Calcium transients from isolated myocytes revealed significantly lower diastolic and systolic levels of
calcium in diabetic hearts. Furthermore, the decay rate of the
calcium transient was significantly reduced in diabetic myocytes, suggesting a diminished capacity for cytosolic
calcium removal not associated with a change in
sodium-calcium exchanger activity.
Calcium leakage from the sarcoplasmic reticulum (SR) measured using
tetracaine was significantly increased in diabetic myocytes. Western blot analysis indicated only a small decrease in SERCA2a expression in diabetic mice, but a large increase in
phospholamban expression. Expression of the
ryanodine receptor did not differ between groups. In conclusion, the decreased contractile function observed in the db/db diabetic mouse model appears to be related to decreased
calcium handling by the SR.