Effects of Metformin on Collagen Glycation and Diastolic Dysfunction in Diabetic Myocardium

Abstract

BACKGROUND: Collagen accumulation in the myocardial interstitium of diabetic animals is considered to promote diastolic stiffness through advanced glycosylation. Because in vitro data suggest that metformin can modify glycosylation, this study was undertaken in a canine diabetic model 4 months in duration. METHODS AND RESULTS: Untreated diabetics (group II) and diabetics treated with metformin alone (group III) or with insulin (group IV) were compared in the basal state and during volume infusion. Basal hemoglobin A(1c), heart rate, aortic pressure, and ejection fraction were comparable. Left ventricular end-diastolic pressure was significantly increased in the untreated diabetics of group II, associated with a reduced end-diastolic volume. By contrast these parameters in the metformin-treated diabetics of group III were comparable with those in the normals of group I. Similarly in group IV end-diastolic volume was higher than that in group II, but filling pressure, although lower, was not significantly so. Calculation of left ventricular chamber stiffness in the basal state indicated a higher level for group II compared with controls and the treatment groups. During the systemic infusion of dextran, the untreated diabetics of group II had the largest end-diastolic pressure increase and the smallest rise of end-diastolic volume of the treatment groups, consistent with a significantly greater chamber stiffness. Myocardial collagen concentration was increased in group II with an interstitial distribution on morphological exam. Levels of collagen-linked advanced glycosylation end products isolated from the left ventricular were significantly greater in group II than in group I. Treatment with metformin prevented the increment observed in the untreated diabetic but had no effect on the elevated collagen concentration. CONCLUSIONS: Untreated diabetics exhibited increased diastolic chamber stiffness associated with collagen-linked glycation in myocardium compared with control animals. Chronic metformin use prevented the abnormalities of function and composition.

Determinants of subclinical diabetic heart disease

“…A previous animal study demonstrated that metformin provided cardio-protection against hyperglycaemia-induced abnormalities in myocyte relaxation [31], possibly due to its effect on insulin resistance, which may prevent the increment of diastolic chamber stiffness but have no effect on elevated collagen concentration in diabetes [32]. However, other studies have shown that metformin treatment did not increase glucose oxidation or glucose disposal under conditions of physiological hyperinsulinaemia [33] and even had no significant effect on insulin sensitivity [34].…”

Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease

“…In vitro and animal studies have shown that metformin is able to react strongly with decarbonyl compounds and could thus decrease AGE formation [137]. Whether and how the risk can be lowered more considerably and consistently by lowering the meal-related glucose excursions has yet to be determined.…”

Metformin is associated with improved left ventricular diastolic function measured by tissue Doppler imaging in patients with diabetes

“…For example, one experimental study of diabetic mice demonstrated that chronic use of metformin prevented the formation of collagen-linked advanced glycosylation end products, and another study found that administration of metformin inhibited cardiac fibrosis induced by pressure overload in nondiabetic mice (31,32).…”