Quantitative Analysis of Myocardial Structure in Insulin-Dependent Diabetes Mellitus: Effects of Immediate and Delayed Insulin Replacement

Abstract

The effects of severe, chronic diabetes mellitus and of immediate or delayed insulin replacement on the different components of the myocardium and cardiocytes were quantified and correlated. A significant decrease in cardiocyte cross-sectional area occurred during the first 12 weeks of diabetes and then stabilized. This was accompanied by decreases in the relative volume densities (RVDs) of myofibrils and mitochondria, resulting in absolute loss of more than 40% of each of these cellular components after 26 weeks of diabetes. Interstitial and perivascular deposition of extracellular matrix produced a tripling of its RVD in the myocardium over 26 weeks of diabetes at the expense of both cardiocytes and capillaries. Capillary density and diameter also exhibited progressive decreases of more than 20% over 26 weeks of diabetes. Insulin treatment which maintained euglycemia and restored normal growth prevented this structural pathology when begun three days after induction of diabetes. When delayed for 12 weeks, insulin reversed the changes in cardiocyte and capillary RVD, and in capillary diameter within 6 weeks, ultrastructural changes within 12 weeks, and cardiocyte cross-sectional area after 26 weeks. However, even after 26 weeks of treatment, the extracellular matrix remained more than twice that observed in nondiabetic animals, with a consequent decrease in the number of capillaries per unit volume of tissue. This study demonstrates that diabetes produces a progressive, marked disorganization of the myocardium which can be prevented, but only selectively reversed, by insulin treatment. These structural changes are relevant to the functional changes which occur in diabetic cardiomyopathy.

Determinants of subclinical diabetic heart disease

“…Insulin therapy has been shown to reverse passive-elastic changes in diabetic rats [18] and to normalise sarcoplasmic reticulum protein expression and function [25]. Furthermore, progressive structural changes in the myocardium caused by diabetes might be prevented by early insulin treatment and selectively reversed by delayed insulin treatment [26]. Finally, some indirect evidence also supports a beneficial effect of insulin therapy on diastolic dysfunction.…”

Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model

“…Our preliminary experiments showed that OLETF rats exhibited a significant reduction in the coronary capillary density at the late stage (unpublished observation), probably due to declined expressions of VEGF and KDR. Indeed, the progressive decreases in the capillary density in myocardium resulting from severe, chronic diabetes has been demonstrated in alloxan-induced IDDM rats (38). Furthermore, chronic diabetic patients suffering from ischemic heart disease show significantly low capillary densities in the hearts (45).…”

Nitric Oxide Reduces Myocardial Contractility in Isoproterenol-Stimulated Rat Hearts by a Mechanism Independent of Cyclic GMP or Cyclic AMP

“…18.21.26], Nitroprusside may affect cardiac myocytes differently than other agents that alter cyclic GMP [29], There may also be some differences in responses between endogenously and exogenously produced ni tric oxide [20]. The blockade of endogenous myocardial nitric oxide production has been reported to have no effects [30] or even nega tive functional effects on the heart [ 18].…”