Correlation between Metabolic and Histopathological Changes in the Myocardium of the KK Mouse. Effect of Diltiazem on the Diabetic Heart.

Serial changes in myocardial parameters related to non-insulin-dependent diabetes mellitus were investigated in DDY mice (control), untreated KK mice, and KK mice treated with diltiazem (150 micrograms/kg body weight, KKd1: or 300 micrograms/kg body weight diltiazem, KKd2). The isozyme ratio of lactate dehydrogenase (LDH) [(LDH1+LDH2)/(LDH4+LDH5)] was used as an index of aerobic metabolism of myocardial tissue. Mean blood sugar levels did not vary between 5 weeks and 30 weeks of age, ranging from 108 (range 60-198) mg/dl in DDY mice to 170 (range 110-282) mg/dl in KK mice. The ratio of heart weight to body weight was larger in KK mice than in DDY mice at 20 weeks of age, but was unaffected by diltiazem treatment. The LDH isozyme ratio showed that DDY mice were in an aerobic state at 15 and 20 weeks of age, while KK mice were in an anaerobic state at 10 and 15 weeks of age. The KKd1 and KKd2 groups exhibited the same LDH isozyme ratios as untreated KK mice; diltiazem had no effect on the LDH isozyme ratio at 20 and 30 weeks of age. The mean diameter of myocytes was increased in KK mice but diltiazem had no effect on this parameter. Interstitial fibrotic changes appeared at 15 weeks in untreated KK mice and progressed with age. These changes were completely suppressed in KK mice treated with diltiazem. These results suggest that hyperglycemia induces an anaerobic state in heart muscle, leading to muscle hypertrophy, degeneration, and fibrosis and that calcium antagonists may suppress these pathological changes.