Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Troglitazone is a thiazolidinedione used for the treatment of NIDDM and potentially for other insulin-resistant disease states. Troglitazone has recently been shown to increase cardiac output and stroke volume in human subjects. These actions are thought to be mediated by the reduction of peripheral resistance, but a potential direct effect on cardiac function has not been studied. Therefore, we investigated the direct cardiac hemodynamic effects of troglitazone in isolated perfused rat hearts. Five groups of hearts were studied. Hearts were tested under isovolumetric contraction with a constant coronary flow, and troglitazone (0.2, 0.5, and 1.0 micromol) was administered by bolus injection. Peak isovolumetric left ventricular pressure (LVPmax), peak rate of rise of LVP (dP/dt(max)), and peak rate of fall of LVP (dP/dt(min)) were significantly increased 1 min after troglitazone administration in a dose-dependent manner, while the heart rate (HR) and coronary perfusion pressure (CPP) were significantly decreased (P < 0.05). HR was then fixed by pacing and/or CPP was fixed with nitroprusside to eliminate any effect of the two variables on the action of troglitazone. With constant HR and/or constant CPP, the effect of troglitazone on LVPmax, dP/dt(max), and dP/dt(min) was still unchanged. In addition, the positive inotropic, positive lusitropic, and negative chronotropic actions of troglitazone were not influenced even when hearts were pretreated with prazosin, propranolol, or nifedipine. In conclusion, troglitazone has direct positive inotropic, positive lusitropic, negative chronotropic, and coronary artery dilating effects. The inotropic and chronotropic actions of troglitazone are not mediated via adrenergic receptors or calcium channels. These findings have important clinical implications for diabetic patients with congestive heart failure.
Diabetes 1999 Mar
PMID:Hemodynamic basis for the acute cardiac effects of troglitazone in isolated perfused rat hearts. 1007 64

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-(13)C]lactate, and [U-(13)C]palmitate. Substrate oxidation rates were determined by combining (13)C-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 in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.
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PMID:Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation. 1044 31

Capillary endothelial cells are thought to limit the transport of insulin across the endothelium, resulting in attenuated insulin action at target sites. Whether endothelial insulin transport is altered in dysglycemic insulin-resistant states is not clear and was therefore investigated in the JCR:LA-cp corpulent male rat, which exhibits the metabolic syndrome of obesity, insulin resistance, hyperlipidemia, and hyperinsulinemia. Lean littermates that did not develop these alterations served as controls. Animals of both groups were normotensive (mean arterial pressure 136+/-2 mmHg). Hearts from obese and lean rats aged 7 (n = 6) or 18 (n = 8) weeks were perfused in vitro at 10 ml/min per gram wet wt over 51 min with Krebs-Henseleit buffer containing 0.1 or 0.5 U human insulin/l (equivalent to 0.6 and 3 nmol/l). Interstitial fluid was collected using a validated method, and interstitial insulin was determined with a radioimmunoassay. At 0.1 U/l, insulin transfer velocity was similar in both experimental groups (half-times of transfer: 11+/-0.2 min in obese and 18+/-4 min in lean rats; NS), but at 0.5 U/l, the respective half-times were 7+/-1 min in lean and 13+/-2 min in obese rats (P < 0.05). The steady-state level of insulin in the interstitium was 34+/-1% of the vascular level at 0.1 U/l and reached the vascular level (102+/-2%) at 0.5 U/l in both lean and obese rats. In rats aged 18 weeks, the half-times of insulin transfer were 31+/-2 and 14+/-l min in obese rats and 10+/-0.3 and 7+/-0.3 min in lean rats (P < 0.05). Again, interstitial steady-state levels were similar in both groups. Finally, postprandial insulin dynamics were simulated over a period of 120 min with a peak concentration of 0.8 U/l in rats aged 27 weeks (n = 4). The maximal interstitial level was 0.38+/-0.02 U/l in lean rats and 0.24+/-0.02 U/l in obese rats (P < 0.05), and a similar difference was noted throughout insulin infusion (areas under the transudate concentration-time curves: 17 and 11 U/min per 1, respectively). These data show, for the first time in a genetic animal model of insulin resistance, that transfer of insulin across the endothelium is substantially delayed in obese insulin-resistant rats and that it likely contributes to the postprandial alterations of glucose metabolism observed in the metabolic syndrome.
Diabetes 2000 May
PMID:Delayed insulin transport across endothelium in insulin-resistant JCR:LA-cp rats. 1090 90

The simultaneous release and uptake of lactate by the heart has been observed both in vivo and ex vivo; however, the pathways underlying these observations have not been satisfactorily explained. Consequently, the purpose of this study was to test the hypothesis that hearts release lactate from glycolysis while simultaneously taking up exogenous lactate. Therefore, we determined the effects of fatty acids and diabetes on the regulation of lactate uptake and release. Hearts from control and 1-wk diabetic animals were perfused with 5 mM glucose, 0.5 mM [3-(13)C]lactate, and 0, 0.1, 0.32, or 1.0 mM palmitate. Parameters measured include perfusate lactate concentrations, fractional enrichment, and coronary flow rates, which enabled the simultaneous, but independent, measurements of the rates of 1) uptake of exogenous [(13)C]lactate and 2) efflux of unlabeled lactate from metabolism of glucose. Although the rates of lactate uptake and efflux were both similarly inhibited by the addition of palmitate, (i.e., the ratio of lactate uptake to efflux remained constant), the ratio of lactate uptake to efflux was significantly higher in the controls compared with the diabetic group (1.00 +/- 0.14 vs. 0.50 +/- 0.07, P < 0.002). These data, combined with heterogeneous (13)C enrichment of tissue lactate, pyruvate, and alanine, suggest that glycolytically derived lactate production and oxidation of exogenous lactate operate as functionally separate metabolic pathways. These results are consistent with the concept of an intracellular lactate shuttle.
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PMID:Evidence of separate pathways for lactate uptake and release by the perfused rat heart. 1155 57

Studies have shown that evoked calcium release from sarcoplasmic reticulum is compromised in diabetic rat hearts. The present study was undertaken to determine whether this decrease might be ascribed to a reduction in expression and/or alteration in function of ryanodine receptor (RyR2) and whether changes could be minimized with insulin treatment. Hearts were isolated from 4- and 6-week streptozotocin (STZ)-induced diabetic, 4-week diabetic/2-week insulin-treated, and age-matched control rats. RyR2 mRNA and protein levels were determined using reverse transcription-polymerase chain reactions and polyacrylamide gel electrophoresis, respectively, whereas the functional integrity of RyR2 was assessed from their ability to bind [3H]ryanodine. RyR2 protein was unchanged with up to 6 weeks of untreated STZ-induced diabetes. Two weeks of insulin treatment initiated after 4 weeks of diabetes increased RyR2 mRNA levels by 42% and RyR2 protein levels by 45 to 61%. At equivalent amounts, RyR2 protein from 4-week STZ-induced diabetic rat hearts bound 9% less [3H]ryanodine than age-matched control rats (74.1 +/- 3.9 versus 67.4 +/- 3.4 fmol/microg RyR2), whereas that from 6-week STZ-diabetic rats bound 36% less than control rats (47.9 +/- 4.8 versus 74.2 +/- 4.5 fmol/microg RyR2, p < 0.05). RyR2 from insulin-treated animals bound significantly less [3H]ryanodine than control rats (65.2 +/- 4.9 fmol/microg RyR2, p < 0.05). Apparent affinity of ryanodine for RyR2 was similar among all groups (K(d) approximately 1.04 +/- 0.08 nM). Because expression did not change significantly but ryanodine binding decreased, these data suggest that the functional integrity of RyR2 is compromised in diabetic rat hearts, and these changes can be attenuated with 2 weeks of insulin treatment.
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PMID:Ryanodine receptor dysfunction in hearts of streptozotocin-induced diabetic rats. 1172 43

We examined the contribution of hypothyroidism to streptozotocin diabetes-induced alterations in the arrhythmia susceptibility of ex vivo hearts to regional zero-flow ischaemia. Diabetic rats received either protamine zinc insulin (10 IU/kg/day, s.c.) or triiodothyronine (10 microg/kg/day, s.c.) for 8 weeks commencing 72 h after injection of streptozotocin (60 mg/kg, i.p.). Arrhythmias were determined in ex vivo Langendorff-perfused hearts, subjected to a 30-min main left coronary artery occlusion, followed by 30-min reperfusion. Serum free thyroxine concentrations, rectal temperature and ex vivo heart rate were significantly decreased in the 8-week diabetic group (P<0.001). These changes were prevented by administration of triiodothyronine or insulin. Ventricular fibrillation during reperfusion was abolished in hearts from diabetic rats. This protection was prevented by treatment with either triiodothyronine or insulin. Hearts from methimazole-hypothyroid rats also showed no ventricular fibrillation during reperfusion. The protection against ischaemia-reperfusion-arrhythmias observed in hearts from streptozotocin-diabetic rats may be due to diabetes-induced hypothyroidism.
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PMID:Streptozotocin diabetes protects against arrhythmias in rat isolated hearts: role of hypothyroidism. 1182 Oct 37

Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml small middle dot min(-1) small middle dot grams wet wt(-1) and reperfusion. D[2-(3)H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.
Diabetes 2002 Apr
PMID:Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. 1191 33

This study was conducted to evaluate whether treatment of normal and diabetic rat hearts with rosiglitazone, a high-affinity ligand of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) used for the treatment of type 2 diabetes, improves postischemic functional recovery. The effects of acute rosiglitazone administration were investigated using working hearts isolated from normal rat or rats diabetic for 4 weeks after streptozotocin (STZ) injection. Hearts were subjected to 30 min of normothermic, zero-flow ischemia followed by 30-min reperfusion. Rosiglitazone (1 micromol/l) administered before ischemia had no effect on cardiac function during baseline perfusion, but it significantly improved aortic flow during reperfusion in both normal and diabetic hearts. In a chronic protocol in which rosiglitazone was given by daily gavage (10 micromol/kg body wt) immediately after STZ injection, rosiglitazone also prevented postischemic injury and significantly improved functional recovery. Using Western immunoblotting, it was demonstrated that the acute cardioprotective effect of rosiglitazone is associated with an inhibition of Jun NH(2)-terminal kinase phosphorylation in both normal and diabetic rat hearts. Furthermore, rosiglitazone also inhibited activating protein-1 DNA-binding activity. These data, demonstrating that rosiglitazone limits postischemic injury in isolated hearts, suggest an important function for PPAR-gamma in the heart.
Diabetes 2002 May
PMID:Rosiglitazone, a peroxisome proliferator-activated receptor-gamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. 1197 49

Because elevated oxidative stress may exacerbate cardiovascular complications of diabetes mellitus, the current study aimed to investigate the effects of treatment with either vitamin A, an antioxidant, or with insulin on lipid peroxidation products and antioxidant enzyme activities of diabetic rat heart. Also to evaluate whether a combination of vitamin A and insulin exerts more beneficial effects than treatment with each agent alone. Rats were made diabetic with a single injection of streptozotocin (STZ, 55 mg kg(-1) i.p.). Two days after STZ-injection, one group of diabetic rats was treated with vitamin A (retinol acetate, 30 mg kg(-1) day(-1) i.o.) for 12 weeks. A second group of diabetic rats was untreated for 6 weeks and then treated for another 6 weeks with insulin (8-10 IU rat(-1) day(-1) s.c.). Both therapies were applied to another group of diabetic rats for assessment of combined therapy with vitamin A plus insulin. Hearts from 12-week untreated diabetic animals showed about a four-fold increase in the level of thiobarbituric acid reactive substances (TBARS), indicative of increased lipid peroxidation. This was accompanied by approximately 100% increase in both catalase and glutathione peroxidase (GSHPx) enzyme activities. Therapy with insulin alone caused a small but significant improvement in plasma TBARS as well as GSHPx activities, but no significant change in plasma catalase in diabetic animals. Diabetes-induced disturbance in TBARS was almost completely prevented by vitamin A therapy. Although, a similar degree of activities for GSHPx was determined in diabetic animals treated with each agent alone, combination therapy was found to be more effective than single therapies in the recovery of GSHPx of diabetic heart. In contrast to insulin single therapy, vitamin A alone significantly prevented an increase in catalase activity of diabetic heart, and a combination of these agents did not supply any further benefit. Superoxide dismutase (SOD) activity was not found significantly different among the experimental groups. STZ-diabetes also resulted in less plasma retinol and retinol-binding protein (RBP), which was significantly improved by insulin single therapy while vitamin A used alone, failed to increase plasma retinol and RBP levels of diabetic animals. Our findings suggest that single therapy with insulin is unable to preclude oxidative reactions in diabetic heart to the same extent as obtained by vitamin A therapy alone, in spite of allowing recovery of normal growth rate and improved vitamin A metabolism in diabetic rats. A combination of insulin with vitamin A may provide more benefits than use of either agent alone in the treatment of general characteristics of diabetes and the maintenance of antioxidant defence of diabetic heart and thus in the reduction of peroxidative stress-induced cardiac injury.
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PMID:Effects of vitamin A and insulin on the antioxidative state of diabetic rat heart: a comparison study with combination treatment. 1197

Hearts from diabetic db/db mice, a model of Type 2 diabetes, exhibit left ventricular failure and altered metabolism of exogenous substrates. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands reduce plasma lipid and glucose concentrations and improve insulin sensitivity in db/db mice. Consequently, the effect of 4- to 5-wk treatment of db/db mice with a novel PPAR-alpha ligand (BM 17.0744; 25-38 mg x kg(-1) x day(-1)), commencing at 8 wk of age, on ex vivo cardiac function and metabolism was determined. Elevated plasma concentrations of glucose, fatty acids, and triacylglycerol (34.0 +/- 3.6, 2.0 +/- 0.4, and 0.9 +/- 0.1 mM, respectively) were reduced to normal after treatment with BM 17.0744 (10.8 +/- 0.6, 1.1 +/- 0.1, and 0.6 +/- 0.1 mM). Plasma insulin was also reduced significantly in treated compared with untreated db/db mice. Chronic treatment of db/db mice with the PPAR-alpha agonist resulted in a 50% reduction in rates of fatty acid oxidation, with a concomitant increase in glycolysis (1.7-fold) and glucose oxidation (2.3- fold). Correction of the diabetes-induced abnormalities in systemic and cardiac metabolism after BM 17.0744 treatment did not, however, improve left ventricular contractile function.
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PMID:Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator. 1218 Nov 23


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