Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am J Physiol Heart Circ Physiol 283: H976-H982, 2002; 10.1152/ ajpheart.00088.2002.-Control db/ϩ and diabetic db/db mice at 6 and 12 wk of age were subjected to echocardiography to determine whether contractile function was reduced in vivo and restored in transgenic db/db-human glucose transporter 4 (hGLUT4) mice (12 wk old) in which cardiac metabolism has been normalized. Systolic function was unchanged in 6-wk-old db/db mice, but fractional shortening and velocity of circumferential fiber shortening were reduced in 12-wk-old db/db mice (43.8 Ϯ 2.1% and 8.3 Ϯ 0.5 circs/s, respectively) relative to db/ϩ control mice (59.5 Ϯ 2.3% and 11.8 Ϯ 0.4 circs/s, respectively). Doppler flow measurements were unchanged in 6-wk-old db/db mice. The ratio of E and A transmitral flows was reduced from 3.56 Ϯ 0.29 in db/ϩ mice to 2.40 Ϯ 0.20 in 12-wk-old db/db mice, indicating diastolic dysfunction. Thus a diabetic cardiomyopathy with systolic and diastolic dysfunction was evident in 12-wk-old diabetic db/db mice. Cardiac function was normalized in transgenic db/db-hGLUT4 mice, indicating that altered cardiac metabolism can produce contractile dysfunction in diabetic db/db hearts. echocardiography; human glucose transporter 4 THE MOST PREVALENT FORM (90%) of diabetes mellitus is Type 2 (non-insulin-dependent) diabetes, resulting from the combination of insulin resistance and a ␤-cell secretory defect (6). Increased cardiovascular disease is the most common complication of diabetes (18,19). Cardiac complications associated with type 2 diabetes are due to 1) increased coronary heart disease secondary to accelerated atherosclerosis because of associated risk factors (20) such as hypertension, obesity, and dyslipidemia (metabolic syndrome); and 2) a diabetic cardiomyopathy producing abnormalities in ventricular function in the absence of coronary heart disease or hypertension (31,36).Experimental studies with rodent models of diabetes allow assessment of direct deleterious effects of a diabetic cardiomyopathy without contributions from atherosclerotic coronary heart disease. However, most reports of diabetes-induced cardiac dysfunction have used insulin-deficient (Type 1) models (28,35,40). Relatively few studies on cardiac function have been conducted with type 2 diabetic animal models (29). Diabetic db/db mice provide an animal model of Type 2 diabetes (24). The natural history of the diabetic progression in db/db mice, with initial insulin resistance followed by an insulin secretion defect (37), is similar to the pathogenesis of Type 2 diabetes in humans (6).Recently, we examined contractile function and metabolism using isolated perfused (ex vivo) working hearts from diabetic db/db mice (10-14 wk of age) compared with hearts from control (db/ϩ) heterozygotes (2). Cardiac mechanical performance was significantly reduced with an increase in left ventricular (LV) end-diastolic pressure, decreased LV developed pressure, and reductio...

Triacylglycerol (TG) hydrolase activities were characterized in myocytes isolated from rat hearts. Acid hydrolase activity with a pH optimum of 5 could be measured in myocyte homogenates, and the subcellular distribution suggested that this activity originated in lysosomes. Lipoprotein lipase (LPL) was also present in myocyte homogenates, as evidenced by TG hydrolase activity that was stimulated by serum and apolipoprotein CII, and inhibited by apolipoprotein CIII2, high ionic strength (NaCl and MgCl2, I = 1 M) and antibodies to LPL. Serum-independent neutral (pH 7.5) TG hydrolase activity was less sensitive to inhibition by 1 M-NaCl, by antibodies to LPL and by preincubation at 40 degrees C than was serum-stimulated hydrolase activity. Furthermore, there were modest but significant differences in the subcellular distribution of the serum-independent and serum-stimulated hydrolase activities. Hydrolase activities in myocyte homogenates could be solubilized by 7.2 mM-deoxycholate. Acid hydrolase activity was recovered in the unbound fraction after heparin-Sepharose chromatography, whereas LPL was bound to the affinity column and was eluted by 0.9-1.2 M-NaCl. Approximately one-third of the serum-independent TG hydrolase activity was not bound to the heparin-Sepharose affinity column. This unbound TG hydrolase activity had a pH optimum of 7 and was stimulated by 50 mM-MgCl2, but not by serum and was resistant to inhibition by high ionic strength (1 M-NaCl), to preincubation at 40 degrees C for 2 h, and by antibodies to LPL. It is concluded that, in addition to an acid lysosomal TG hydrolase and LPL, myocytes from rat heart contain a serum-independent TG hydrolase with unique characteristics.

Echocardiograms have been assessed only at 56 days in mice overexpressing calcineurin (CN mice). Age-dependent echocardiographic changes were evaluated because the development of sudden death is time dependent. Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed. In wild-type (WT) mice, the left ventricular (LV) internal end-diastolic dimension (LVIDd) increased and the LV mass index (LVMI) decreased with age. In CN mice, two distinct phases of pathophysiology were found. After 14 days, in CN mice, the LVIDd and LVMI were significantly increased, but sudden death had not occurred. After 28 days, in CN mice, relative dilation of the left ventricle occurred, whereas the LVMI decreased. Sudden death developed during progressive dilation associated with systolic and diastolic dysfunction. CsA treatment reversed hypertrophy in CN mice but did not reverse systolic and diastolic dysfunction and exaggerated sudden death. Sudden cardiac death was associated with systolic and diastolic dysfunction but was not related to isolated cardiac hypertrophy in CN mice.

Calcium-tolerant myocytes were isolated from rat hearts. Isoproterenol produced a dose-dependent increase in glycerol output (lipolysis) that could be blocked by propranolol. The presence of glucose in the incubation medium enhanced the release of glycerol from myocytes but had no effect on the decline in triacylglycerol content. No incorporation of radioactivity from [U-14C]glucose into glycerol could be detected. In incubations with isoproterenol, there was a stoichiometric relationship between the glycerol output and the decrease in triacylglycerol levels. The addition of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine resulted in an increase in the basal glycerol output and an enhancement of the isoproterenol-stimulated lipolytic rate. Forskolin and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate also produced a concentration-dependent stimulation of lipolysis in myocytes. Therefore, lipolysis in isolated myocytes must be regulated by adenosine 3',5'-cyclic monophosphate-dependent mechanisms. These results demonstrate that lipolysis can be observed in myocardial cells and that the lipolytic response to isoproterenol cannot be secondary to a physiological (inotropic) response since these myocyte preparations are quiescent.

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