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)

Our group has documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins may be responsible for the mechanical defects in the streptozotocin (STZ)-diabetic hearts. Previously, the major focus of our research on contractile proteins in abnormal states has concentrated on myosin ATPase and its isoenzymes. Our present study is based on the overall hypothesis that regulatory proteins, in addition to contractile protein, myosin contribute to altered cardiac contractile performance in the rat model of diabetic cardiomyopathy. The purpose of our research was to define the role of cardiac regulatory proteins (troponin-tropomyosin) in the regulation of actomyosin system in diabetic cardiomyopathy. For baseline data, myofibrillar ATPase studies were conducted in the myofibrils from control and diabetic rats. To focus on the regulatory proteins (troponin and tropomyosin), individual proteins of the cardiac system were reconstituted under controlled conditions. By this approach, myosin plus actin and troponin-tropomyosin from the normal and diabetic animals could be studied enzymatically. The proteins were isolated from the cardiac muscle of control and STZ-diabetic (4 weeks) rats. Sodium dodecyl sulfate gel electrophoretic patterns demonstrate differences in the cardiac TnT and TnI regions of diabetic animals suggesting the different amounts of TnT and/or TnI or possibly different cardiac isozymes in the regulatory protein complex. Myofibrils probed with a monoclonal antibody TnI-1 (specific for adult cardiac TnI) show a downregulation of cardiac TnI in diabetics when compared to its controls. Enzymatic data confirm a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. Actomyosin ATPase activity in the hearts of diabetic animals was partially reversed when myosin from diabetic rats was regulated with the regulatory protein complex isolated from control hearts. To our knowledge, this is the first study which demonstrates that the regulatory proteins from normal hearts can upregulate cardiac myosin isolated from a pathologic rat model of diabetes. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) may be partially responsible for the impaired cardiac function in the hearts of chronic diabetic rats.
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PMID:Troponin subunits contribute to altered myosin ATPase activity in diabetic cardiomyopathy. 856 62

Membrane NA+/H+ exchanger regulates cell pH, volume, and growth. Abnormal activities have been reported in essential hypertension and type I insulin-dependent diabetes mellitus (IDDM). The aim of this study was to analyze the relationship between erythrocyte NA+/H+ antiport activity and myocardial anatomical and functional parameters in normotensive type I insulin-dependent diabetic patients. We evaluated 26 insulin-dependent diabetic patients (20 normo- and 6 microalbuminuric) and 17 age- and sex-matched healthy controls. Plasma and urine analytes as well as erythrocyte NA+/H+ antiport rate were measured. M-Mode- and 2D echocardiograms with Doppler analysis were performed in all subjects. Diabetic people, both normo- and microalbuminuric, had a Na+/H+ antiport activity significantly higher than control subjects (p < 0.01). All echocardiographic parameters relative to left ventricular volume, cardiac mass and systolic function overlapped in the study groups. Of Doppler indexes, evaluating the left ventricular diastolic filling, the late peak flow velocity (peak A) was significantly higher in diabetic patients (p < 0.01). E/A ratio was heightened in the control group compared to diabetics, as a whole as well separately considered (p < 0.01). Antiport significantly correlated with PWTh, STh, E/A, UAER, serum sodium, and gender (p < 0.0001). The linear and significant correlation found between Na+/H+ exchange and some cardiac indexes suggest the increased Na+/H+ antiport activity as possible predictive risk factor for the development of diabetic cardiomyopathy.
J Diabetes Complications
PMID:Integrated analysis of erythrocyte Na+/H+ antiport activity and left ventricular myocardial function in type I insulin-dependent diabetes mellitus. 857 28

Patients with diabetes mellitus that exhibit cardiac pump failure display compromised stroke volume, ejection fraction, and slower rates of rise and fall of left ventricular (LV) dP/dt in the absence of ischemic injury. We hypothesized that diabetic cardiomyopathy may involve decrements in adrenergic sensitivity, with specific molecular alterations in the beta-adrenergic receptor (beta AR)- G protein- adenylyl cyclase (AC) signal transduction system. We assessed the effects of 3 months of streptozotocin-induced diabetes (125 mg/kg i.v.; DIAB, n = 10) on myocardial signal transduction in mini-pigs. DIAB were hyperglycemic compared to controls (CON, n = 10; 20.92 +/- 2.64 v 5.24 +/- 0.35 mM glucose), and had lower fasting insulin levels (6.46 +/- 0.97 v 13.68 +/- 3.91 microU/ml). Transmural LV free wall homogenates from DIAB exhibited similar beta AR density as CON, but decreased cAMP production (pmol cAMP/mg prot.min) using these pharmacological stimulators: 10 microM Isoproterenol plus 100 microM GTP (74 +/- 5 v 97 +/- 11); 100 microM Gpp(NH)p (116 +/- 7 v 161 +/- 17); 10 mM fluoride ion (266 +/- 16 v 324 +/- 25). No differences between DIAB and CON were observed when stimulated by 100 microM forskolin (440 +/- 20 v 429 +/- 33), suggesting no alterations in the catalytic subunit of AC. In DIAB, quantitative immunoblotting indicated slightly depressed levels of Gs (552 +/- 44 v 630 +/- 59 pmol/g ww; NS), but a significant redistribution of alpha s from the sarcolemma to the cytosol (32.7 +/- 0.82% v 25.9 +/- 1.7%). Significantly elevated levels of cardiac Gi were seen in DIAB homogenates compared to CON ventricles (2326 +/- 145 v 1522 +/- 181 pmol/g ww), with no alpha i subunit redistribution. We conclude that despite maintained beta AR density, receptor-dependent and G protein-dependent stimulation of AC is depressed so that streptozotocin-induced diabetic LV is affected by increased cardiac Gi, redistribution of Gs alpha to the cytosol, and an increase in the Gi/Gs ratio. These results help explain depressed catecholamine responsiveness and cardiac performance exhibited by diabetic patients.
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PMID:Adrenergic desensitization in left ventricle from streptozotocin diabetic swine. 857 46

The increased incidence of congestive heart failure and the increased mortality and morbidity in the diabetic patient following myocardial infarction or coronary artery bypass graft can be explained by the presence of diabetic cardiomyopathy. Noninvasive studies in young diabetic patients show no cardiac abnormality, but in older diabetic patients mild cardiac diastolic dysfunction is detectable. This mild cardiomyopathy can become clinically detectable in the presence of hypertension and can be severe in the presence of myocardial ischemia. Microvascular disease is unlikely to cause diabetic cardiomyopathy. Cellular changes, including defects in calcium transport and fatty acid metabolism, may lead to myocellular hypertrophy and myocardial fibrosis, initially causing diastolic dysfunction that may advance to systolic dysfunction. Glycemic control, energetic detection and treatment of hypertension with appropriate antihypertensive agents, and early detection and treatment of ischemic heart disease are essential in preventing and treating diabetic cardiomyopathy.
Diabetes Care 1995 May
PMID:Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? 858 13

In order to elucidate further the abnormal myocardial Ca2+ metabolism in diabetes mellitus, voltage-gated Ca2+ channels and beta-receptors were quantified in myocardial membranes of short- and long-term diabetic rats. Diabetes was induced by an injection of streptozotocin (STZ). Animals were killed 2, 4, 7, 90 and 200 days after STZ. A group of diabetic animals were treated with insulin for 20 days following 180 days of untreated diabetes. Diabetic animals developed low triiodothyronine syndrome. During short-term diabetes, the maximum binding capacity (MBC) for Ca2+ channels was reduced by 25% at day 4 (p < 0.05) and the beta-receptor MBC was reduced by 48% (p < 0.05). A normalizing tendency was observed at day 7 for both receptor types; insulin-treated rats did not differ from controls at that time. After 90 and 200 days of untreated diabetes the Ca2+ channel MBC had increased by 36% and 27%, respectively (p < 0.05). Twenty days of strictly regulated blood glucose following 180 days of untreated diabetes totally normalized the Ca2+ channel MBC. This is in contrast to a previous report where insulin treatment did not normalize the Ca2+ channel MBC. Total beta-receptor MBCs did not differ from control values 90 and 200 days after STZ. In conclusion, an increase in rat myocardial Ca2+ channel MBC during long-term diabetes was fully normalized by short-term insulin treatment. The increase in sarcolemmal Ca2+ channels could serve to compensate for a defect coupling of the beta-receptor to adenylate cyclase. An elevated Ca2+ channel number may, at least theoretically, lead to increased Ca2+ flow across the cardiac sarcolemma and in this way contribute to the diabetic cardiomyopathy by increasing the intracellular Ca2+ concentration.
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PMID:Increased number of myocardial voltage-gated Ca2+ channels and unchanged total beta-receptor number in long-term streptozotocin-diabetic rats. 859 Sep 44

Streptozotocin-diabetes as a model for insulin-deficient Type 1 diabetes leads to cardiomyopathy, characterized by a 50% reduced glucose uptake (P < 0.001) and increased lactate and pyruvate levels (P < 0.001), i.e. a reduced glucose utilization by the heart. As thioctic acid (TA) has favourable effects on glucose metabolism, the influence of this drug at two different doses (0.1 mg/ml and 0.5 mg/ml, added to the perfusion medium) was investigated in the heart after 2 weeks of diabetes, using the working rat heart model at physiological workload about 45 min. TA at high doses led to a normalization of glucose uptake (P < 0.001) and glucose utilization, and consequently to a normalization of oxygen uptake (P < 0.001), myocardial ATP levels (P < 0.001) as well as cardiac output (P < 0.05). Whereas a low dose of TA resulted in a normalization of lactate and pyruvate production (P < 0.001), neither a normalization of glucose utilization nor of cardiac output was achieved by this low dosage. Additionally, TA improved at both doses utilization of endogenous glycogen in the diabetic heart (P < 0.001), the latter here already delivering 45% of the utilized glucose. TA acts especially by increasing glucose uptake, glycogen breakdown and glucose oxidation. Thus, metabolic and hemodynamic sequelae of insulin-deficiency in the heart can be corrected by TA. Due to its anti-diabetic effects on cardiac metabolism, TA could be considered an adjuvant therapy in diabetic cardiomyopathy.
Diabetes Res Clin Pract 1995 Jul
PMID:The influence of thioctic acid on metabolism and function of the diabetic heart. 859 55

The existence of diabetic cardiomyopathy has been substantiated in patients with diabetes mellitus. In this study we evaluated two mice with diabetes mellites (DM) and two control mice to determine whether the fatty acid metabolism of the myocardium is abnormal when 125I-BMIPP is used. 125I-BMIPP of 0.74 MBq (20 microCi) was injected, and 30 min later, the mice were slaughtered. Heart, lungs, liver, spleen and kidneys were removed. After freezing the heart, myocardium was sliced into 20 micron sections using a cryostat. Each slice was placed in contact with an imaging plate for autoradiography. A bioimaging analyzer was used to analyze the data. The percent injected dose/g of heart was lower in the DM group than in the control group (11.6 +/- 0.49 vs 18.3 +/- 1.27). Each slice of the DM group also had fewer counts than slices in the control group (p < 0.05 or p < 0.01). These results indicated that fatty acid metabolism in the myocardium was less in the DM group than in the control group.
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PMID:[Autoradiographic study of myocardial fatty acid metabolism in diabetic mouse using 125I-BMIPP]. 872 41

To examine the role of free radicals in diabetic cardiomyopathy, myocardial antioxidants as well as lipid peroxide content were examined in rats made diabetic with a single injection of streptozotocin (65 mg/kg i.v). At 4 wk, the left ventricular peak systolic (LVSP) as well as aortic pressures were depressed in the diabetic group. Hearts from diabetic animals showed about a 100% increase in thiobarbituric acid reactive substances (TBARS), indicating increased lipid peroxidation. This was accompanied by about a 50% decrease in superoxide dismutase (SOD) and 60% decrease in glutathione peroxidase (GSHPx) enzyme activities. Catalase activity in these hearts showed a small but significant increase. Treatment with probucol (10 mg/kg i.p., on alternate days), a known lipid-lowering drug with strong antioxidant properties, was initiated 1 d after the induction of diabetes and was continued for 4 wk. In probucol-treated diabetic animals, LVSP was not different from controls. Probucol treatment caused a small but significant improvement in serum insulin and decrease in glucose levels as well as increased myocardial SOD, GSHPx, and catalase activities with a concomitant decrease in TBARS in the diabetic animals. These data provide evidence that diabetic cardiomyopathy is associated with an antioxidant deficit, and a better cardiac function due to treatment with probucol may be related to the improved insulin levels as well as maintenance of the antioxidant status of the heart.
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PMID:Probucol improves antioxidant activity and modulates development of diabetic cardiomyopathy. 874 20

The aim of the present experimental study in the rat heart was to assess cardiac performance and metabolism in mild diabetes of 2 months' duration (postprandial blood sugar levels of 307 +/- 101 mg/dl and nearly normal fasting blood glucose of 102 +/- 40 mg/dl) using the working rat heart model at physiological workload with a perfusion time of 60 min. We also compared the effect of two forms of therapy for diabetes, islet transplantation and insulin therapy (s.c.), after 2 months. A 36% reduction in glucose utilization is metabolically characteristic for the diabetic heart, mainly caused by a 55% reduced glucose uptake (P < 0.001), but also by a nearly twofold increased lactate and pyruvate production (P < 0.001). This reduced carbohydrate metabolism is accompanied by a 37% reduction of oxygen uptake (P < 0.001) as well as a significant reduction in myocardial ATP and CP levels (P < 0.001), resulting in a significantly reduced cardiac output (P < 0.001). Moreover, the balance of energy reveals that the diabetic heart obtains 46% of its energy requirements for 1 h from endogenous glycogen, whereas the control heart obtains 91% of its energy needs (i.e. preferentially) from exogenous glucose (only 9% from endogenous glycogen). Both investigated therapeutic interventions led to a complete reversibility of the hemodynamic and metabolic alterations, indicating that the cause of diabetic cardiomyopathy in this model of mild and short-term diabetes is due to a defect in cardiac carbohydrate metabolism, which is correctable by insulin administration.
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PMID:Glucose metabolism and left ventricular dysfunction are normalized by insulin and islet transplantation in mild diabetes in the rat. 875 Jul 62

The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.
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PMID:Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart. 876 Jan 75


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