Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats (original) (raw)
2004
The goal of this study was to determine whether changes in cardiac metabolism in Type-2 diabetes were associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty rats (ZDF) and lean Controls were isolated, perfused and glucose, lactate, pyruvate and palmitate oxidation rates and glycolytic rates determined during baseline perfusion, low flow ischemia (LFI; 0.3mls/min for 30min) and following LFI and reperfusion.
Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation
American Journal of Physiology-Endocrinology and Metabolism, 1999
The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-13C]lactate, and [U-13C]palmitate. Substrate oxidation rates were determined by combining13C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences ...
Cardiovascular Diabetology, 2015
Background: The effects of streptozotocin (STZ)-induced diabetes on heart metabolism and function after myocardial infarction (MI) remodelling were investigated in rats. Methods: Fifteen days after STZ (50 mg/kg b.w. i.v.) injection, MI was induced by surgical occlusion of the left coronary artery. Two weeks after MI induction, contents of glycogen, ATP, free fatty acids and triacylglycerols (TG) and enzyme activities of glycolysis and Krebs cycle (hexokinase, glucose-6-phosphate dehydrogenase, phosphofructokinase, citrate synthase) and expression of carnitine palmitoyl-CoA transferase I (a key enzyme of mitochondrial fatty acid oxidation) were measured in the left ventricle (LV). Plasma glucose, free fatty acids and triacylglycerol levels were determined. Ejection fraction (EF) and shortening fraction (SF) were also measured by echocardiography. Results: Glycogen and TG contents were increased (p < 0.05) whereas ATP content was decreased in the LV of the non-infarcted diabetic group when compared to the control group (p < 0.05). When compared to infarcted control rats (MI), the diabetic infarcted rats (DI) showed (p < 0.05): increased plasma glucose and TG levels, elevated free fatty acid levels and increased activity of, citrate synthase and decreased ATP levels in the LV. Infarct size was smaller in the DI group when compared to MI rats (p < 0.05), and this was associated with higher EF and SF (p < 0.05). Conclusions: Systolic function was preserved or recovered more efficiently in the heart from diabetic rats two weeks after MI, possibly due to the high provision of glucose and free fatty acids from both plasma and heart glycogen and triacylglycerol stores.
American Journal of Physiology-Endocrinology and Metabolism, 2007
Hearts from type 2 diabetic ( db/ db) mice demonstrate altered substrate utilization with high rates of fatty acid oxidation, decreased functional recovery following ischemia, and reduced cardiac efficiency. Although db/ db mice show overall insulin resistance in vivo, we recently reported that insulin induces a marked shift toward glucose oxidation in isolated perfused db/ db hearts. We hypothesize that such a shift in metabolism should improve cardiac efficiency and consequently increase functional recovery following low-flow ischemia. Hearts from db/ db and nondiabetic ( db/+) mice were perfused with 0.7 mM palmitate plus either 5 mM glucose (G), 5 mM glucose and 300 μU/ml insulin (GI), or 33 mM glucose and 900 μU/ml insulin (HGHI). Substrate oxidation and postischemic recovery were only moderately affected by GI and HGHI in db/+ hearts. In contrast, GI and particularly HGHI markedly increased glucose oxidation and improved postischemic functional recovery in db/ db hearts. Cardi...
Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice
Diabetes, 2006
Altered cardiac metabolism and function (diabetic cardiomyopathy) has been observed in diabetes. We hypothesize that cardiac efficiency, the ratio of cardiac work (pressure-volume area [PVA]) and myocardial oxygen consumption (MVo2), is reduced in diabetic hearts. Experiments used ex vivo working hearts from control db/+, db/db (type 2 diabetes), and db/+ mice given streptozotocin (STZ; type 1 diabetes). PVA and ventricular function were assessed with a 1.4-F pressure-volume catheter at low (0.3 mmol/l) and high (1.4 mmol/l) fatty acid concentrations with simultaneous measurements of MVo2. Substrate oxidation and mitochondrial respiration were measured in separate experiments. Diabetic hearts showed decreased cardiac efficiency, revealed as an 86 and 57% increase in unloaded MVo2 in db/db and STZ-administered hearts, respectively. The slope of the PVA-MVo2 regression line was increased for db/db hearts after elevation of fatty acids, suggesting that contractile inefficiency could al...
Endocrinology, 2005
Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater du...
The Journal of Nutritional Biochemistry, 2000
Male Wistar rats chronically (15 weeks) fed a sucrose-rich diet (SRD; 63% w/w) developed hypertriglyceridemia and impaired glucose homeostasis. Hearts from these animals were isolated and perfused using the Langendorff recirculating method. Glucose at levels similar to those found in the animal in vivo was used as the only exogenous substrate. The hearts were perfused for 30 minutes in the presence or absence of insulin (30 mU/mL) in the perfusion medium. In the absence of the hormone, glucose uptake was impaired and the glucose utilization was reduced, with a significant increase of lactate release. Glucose oxidation, which was estimated from the activation state of the enzyme pyruvate dehydrogenase complex (PDHc), was depressed mainly due to both an increase of PDH kinase and a decrease of PDHa (active form of PDHc) activities. Although the addition of insulin in the perfusion medium improved the above parameters, it was unable to normalize them. The present results suggest that at least two different mechanisms might contribute to insulin resistance and to the impaired glucose metabolism in the perfused hearts of the dyslipemic SRD-fed animals: (1) reduced basal and insulin-stimulated glucose uptake and its utilization or (2) increased availability and oxidation of lipids (low PDHa and high PDH kinase activities), which in turn decrease glucose uptake and utilization. Thus, this nutritional experimental model may be useful to study how impaired glucose homeostasis, increases plasma free fatty acid levels and hypertriglyceridemia could contribute to heart tissue malfunction. (J. Nutr. Biochem. 11: 30 -37, 2000)