Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography.

Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age- and weight-matched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose (FDG), blood flow was measured by the H2(15)O method. Myocardial glucose utilization was measured in regions with normal perfusion and wall motion as assessed by radionuclide ventriculography. Whole-body glucose uptake was 37+/-4 micromol x min(-1) x kg(-1) in controls and 14+/-2 mciromol x min(-1) x kg(-1) in patients (P = 0.001). Myocardial blood flow (1.09+/-0.06 vs. 0.97+/-0.04 ml x min(-1) x g(-1), controls vs. patients) and skeletal muscle (arm) blood flow (0.046+/-0.012 vs. 0.043+/-0.006 ml x min(-1) x g(-1)) were similar in the two groups (P = NS for both). In contrast, in patients both myocardial (0.38+/-0.03 vs. 0.70+/-0.03 micromol x min(-1) x g(-1), P = 0.0005) and muscle glucose uptake (0.026+/-0.004 vs. 0.056+/-0.006 micromol x min(-1) x g(-1), P = 0.005) were markedly reduced in comparison with controls. In the whole dataset, a direct relationship existed between insulin-stimulated glucose uptake in heart and skeletal muscle. Patients with a history of myocardial infarction and a low ejection fraction are insulin resistant. This insulin resistance affects both the myocardium and skeletal muscle and is independent of blood flow.

Age-associated cardiac dysfunction in Drosophila melanogaster.

The fruit fly, Drosophila melanogaster, has served as a valuable model/organism for the study of aging and was the first organism possessing a circulatory system to have its genome completely sequenced. However, little is known about the function of the heartlike organ of flies during the aging process. We have developed methods for studying cardiac function in vivo in adult flies. Using 2 different cardiovascular stress methods (elevated ambient temperature and external electrical pacing), we found that maximal heart rate is significantly and reproducibly reduced with aging in Drosophila, analogous to observations in elderly humans. We also describe for the first time several other aspects of the cardiac physiology of young adult and aging Drosophila, including an age-associated increase in rhythm disturbances. These observations suggest that the study of declining cardiac function in aging flies may serve as a genetically tractable model for genome-wide mutational screening for genes that participate in or protect against cardiac aging and disease.

Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart.

OBJECTIVES: Insulin resistance in skeletal muscle and adipose tissue often accompanies hypertension; however, it has not been shown that heart muscle is similarly affected. The aims of this study were to determine whether basal and insulin-stimulated glucose transport and glucose transporter mRNA content are altered in the spontaneously hypertensive rat (SHR) heart. METHODS: Hearts from 16-18-month-old SHRs were compared to their normotensive (WKY) controls. The accumulation of 2-deoxyglucose-6-phosphate (2DG6P), detected using 31P nuclear magnetic resonance spectroscopy, was used to assess glucose uptake before and during insulin stimulation in the isolated perfused heart. The mRNA levels of both the insulin-sensitive glucose transporter (GLUT-4) and the transporter responsible for basal glucose uptake (GLUT-1) were quantified by Northern blot analysis. RESULTS: The hypertensive rat hearts exhibited hypertrophy in that the heart/body weight ratio was increased by 59%. In these hearts, the basal rate of glucose uptake was 3-fold greater and hexokinase activity was 1.6 fold greater than that of the control rat hearts. On exposure to insulin, accumulation of 2DG6P increased 5-fold in the control hearts, but only 1.4-fold in the SHR hearts. Thus, in the presence of insulin, the rate of glucose uptake by the hypertensive rat heart was significantly (P < 0.05) reduced, being 82% of control. GLUT-4 mRNA content was decreased was no significant difference in the GLUT-1 mRNA content. CONCLUSION: We have demonstrated insulin resistance in the hypertrophied heart of the hypertensive rat that may have a molecular basis in a lower GLUT-4 content.

Insulin resistance in patients with cardiac hypertrophy.

OBJECTIVE: Animal studies suggest that left ventricular hypertrophy might be associated with insulin resistance and alterations in glucose transporters. We have previously demonstrated myocardial insulin resistance in patients with post-ischemic heart failure. The aim was to investigate whether myocardial insulin resistance could be demonstrated in human cardiac hypertrophy in the absence of hypertension, diabetes and coronary artery disease. METHODS: Eleven normotensive nondiabetic patients with cardiac hypertrophy due to aortic stenosis and angiographically normal coronary arteries were compared to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting (low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic hyperinsulinemia). Myocardial biopsies were obtained in order to investigate changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose transporters. RESULTS: During fasting, plasma insulin (7 +/- 1 vs. 6 +/- 1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable in patients and controls. By contrast, during clamp, MGU was markedly reduced in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1 ratio was shown by Western blot analysis in patients. CONCLUSIONS: Insulin resistance seems to be a feature of the hypertrophied heart even in the absence of hypertension, coronary artery disease and diabetes and may be explained, at least in part, by abnormalities in glucose transporters.

Cardiomyopathy in duchenne, becker, and sarcoglycanopathies: a role for coronary dysfunction?

Dilated cardiomyopathy is a feature of Duchenne and Becker muscular dystrophies and occasionally of sarcoglycanopathies. Its pathogenesis is unknown. Patients with myotonic dystrophy have an impairment of coronary smooth muscle and this could contribute to their cardiomyopathy. We used positron emission tomography (PET) to study myocardial blood flow and coronary vasodilator reserve at baseline and during hyperemia in 7 Duchenne, 8 Becker, and 5 sarcoglycanopathy patients. The study was normal in all Becker patients. In contrast, baseline myocardial blood flow was increased and coronary vasodilator reserve blunted in Duchenne and sarcoglycanopathy patients despite normal hyperemic myocardial blood flow. The reduction of coronary vasodilator reserve was due to an increased baseline myocardial blood flow. In Duchenne dystrophy, but not in sarcoglycanopathies, correction for cardiac workload normalized the coronary vasodilator reserve. In the latter patients, abnormal baseline myocardial blood flow could be due to vascular smooth muscle dysfunction.