Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During diabetes, impaired glucose transport and utilization by the heart switches energy production to exclusive beta-oxidation of fatty acid (FA). In the current study, we examined the contribution of cardiac lipoprotein lipase (LPL) towards providing FA to the diabetic heart. Streptozotocin (STZ) caused an augmentation of LPL activity at the coronary lumen, an effect duplicated by diazoxide (DZ). With DZ, the amplification of LPL at the coronary luminal surface was determined to be exceptionally rapid. Interestingly, unlike DZ, the capability of hearts from STZ animals to maintain this amplified LPL activity was sustained in vitro. This increased enzyme in the hyperglycemic heart is likely unrelated to an increase in the number of capillary endothelial LPL-binding sites. Our data imply that binding sites for LPL in the control rat heart are only partly occupied by the enzyme and diabetes rapidly initiates filling of all of these sites. Phloridzin treatment of STZ animals normalized plasma glucose with no effect on luminal LPL suggesting that the effects of diabetes on LPL are also largely independent of changes in blood glucose. Both 2 and 8 U of insulin normalized plasma glucose in DZ-treated animals but only 8 U reversed DZ-induced augmentation of cardiac luminal LPL. Our data suggest that impaired intracellular glucose utilization allows rapid vectorial transfer of LPL to unoccupied binding sites to supply the diabetic heart with excess FA. The persistence of increased coronary luminal LPL even in a setting of normoglycemia may provide excessive FA to the diabetic heart with deleterious consequences over the long term.
J Mol Cell Cardiol 2003 Sep
PMID:Evidence for rapid "metabolic switching" through lipoprotein lipase occupation of endothelial-binding sites. 1296 32

Diabetic cardiomyopathy is responsible for substantial morbidity and mortality in the diabetic population. Increased oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. Multiple biochemical mechanisms have been proposed to increase oxidative stress in diabetes. The present study was aimed at elucidating the role of a potent oxidative and cellular stress-responsive system, the heme oxygenase (HO) system, in the heart in diabetes. Streptozotocin-induced diabetic rats were treated with a potent inhibitor of HO system, tin protoporphyrin IX (SnPPIX, 50 micromol/kg/d), and were compared with untreated diabetic and non-diabetic animals. All treatments began at the onset of diabetes, 48 h after injection of streptozotocin along with the confirmation of hyperglycemia. Animals were euthanized after 1 week and 1 month of treatment, and heart tissues were harvested. Frozen tissues were subjected to HO-1 and HO-2 mRNA expression by real-time RT-PCR and HO activity determination. Paraffin-embedded tissue sections were used for immunohistochemical analysis of HO-1 and HO-2. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of DNA damage, was preformed to assess damage induced by oxidative stress. In addition, tissue sections were subjected to histochemical analysis for iron. We further examined non-diabetic animals treated with a direct HO agonist, hemin (50 mg/kg/d). A possible relationship between the HO and the nitric oxide (NO) pathways was also considered by studying the mRNA levels of endothelial nitric oxide synthase (NOS) and inducible NOS, and by measuring the amount of NOS products. Our results demonstrate no significant alterations of the HO system following 1 week of diabetes. However, 1 month of diabetes caused increased oxidative stress as demonstrated by higher levels of 8-OHdG-positive cardiomyocytes (80% positive as compared to 11.25% in controls), in association with increased HO isozyme mRNA (2.7-fold increase as compared to controls) and protein expression, and augmented HO activity (759.3 as compared to 312.3 pmol BR/h/mg protein in controls). Diabetic rats further demonstrated increased number of cardiomyocytes with stainable iron. SnPPIX treatment resulted in reduced number of 8-OHdG-positive cardiomyocytes (19.5% as compared to 80% in diabetics) in parallel with reduced HO activity (569.7 as compared to 759.3 pmol BR/h/mg protein in diabetics). Non-diabetic rats treated with HO-agonist hemin exhibited abnormalities similar to diabetic rats. Our results provide the first direct demonstration that diabetes-induced oxidative stress in the heart is, in part, due to upregulated HO expression and activity. These results provide evidence of pro-oxidant activity of HO in the heart in diabetes, which could be mediated by increased redox-active iron.
J Mol Cell Cardiol 2003 Dec
PMID:Heme oxygenase in diabetes-induced oxidative stress in the heart. 1465 70

The procedures to induce insulin-deficient diabetes in rats using streptozotocin are described along with a number of insulin treatment regimes that can be used to maintain these animals at different degrees of glycemia for periods of weeks to months. Streptozotocin-diabetic rats develop tactile allodynia, hyperalgesia following paw formalin injection and abnormal responses to thermal stimulation and the detailed methods used to evaluate these behavioral indices of abnormal sensory function are provided.
Methods Mol Med 2004
PMID:Modeling diabetic sensory neuropathy in rats. 1513 29

In this study the effect of diabetes mellitus on atrial natriuretic peptide (ANP) receptors in streptozotocin- (STZ-) induced diabetic rat kidneys was studied. Moreover, plasma ANP concentration was evaluated in diabetic and control rats by using radioimmunoassay. In addition, the expression of ANP in the kidneys of control and diabetic rats was evaluated by immunohistochemistry. Body-weight loss and increased glucose levels were used as indices of diabetes mellitus in the STZ-induced rats. There was a significant loss in the body weight of the diabetic rats compared to controls. The efficacy of STZ administration was confirmed by rising blood glucose levels, which were significantly higher in diabetic rats compared to controls. Plasma ANP concentration was significantly greater in the diabetic rats in comparison with controls. Moreover, our immunohistochemical results show that the expression of ANP in diabetic rats was higher than that in age-matched controls. ANP was observed in the cells lining the proximal convoluted tubules in the cortex. The distribution and levels of ANP receptors in the kidneys of diabetic rats and age-matched controls were investigated using quantitative receptor autoradiography. Our results demonstrate significant decrease in ANP receptors in the kidneys of the diabetic rats compared to controls. The significant decrease was found in the juxtaglomerular medulla, inner medulla, and the papillae. The decrease in ANP receptors observed in the diabetic kidneys could have pathological consequences resulting in renal resistance to ANP in diabetes.
Mol Cell Biochem 2004 Jun
PMID:Alterations in atrial natriuretic peptide and its receptors in streptozotocin-induced diabetic rat kidneys. 1536 80

There is a link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alterations of endogenous antioxidants. Our aim is to study the effect of orally administered L-tryptophan (TRP), the melatonin precursor, an endogenous antioxidant, on circulating levels of glycaemia, insulin and melatonin, and on the superoxide dismutase and catalase antioxidant systems in non-diabetic (ND) and type 2 diabetic (n5-STZ) male Wistar rats. At 19:30 every day for 15 days, TRP (125 mg/kg body weight) was administered orally. At 09:00 every two days the glycaemia was measured and every day the intake of food and water was recorded. At the beginning and end of treatment (at 09:00; 21:00; 02:00) plasma insulin and melatonin levels were measured, and (at 09:00) the enzymatic activities of catalase and superoxide dismutase (SOD) in erythrocytes were also measured. Glycaemia values were greater (p < 0.01) in n5-STZ rats than in ND rats, while insulin levels were lower (p < 0.05) at all times studied and these parameters were not altered by the TRP administration. Melatonin levels at 02:00 were lower in n5-STZ than in ND rats (p < 0.05). The TRP administration did not modify the circulating melatonin levels in ND rats, but raised (p < 0.01) the levels at 02:00 in the treated n5-STZ group. In ND rats after TRP administration there was a decline in catalase activity (p < 0.05), while in n5-STZ rats there was a rise (p < 0.01) at the end of treatment. However, there were no significant changes in SOD activity. There was increased food intake (g/day) in the treated n5-STZ group (p < 0.01). In conclusion, the oral administration of TRP did not modify glycaemia or insulinaemia levels, but raised melatonin levels in diabetic rats at 02:00, lowered catalase activity in ND rats but raised it in n5-STZ rats, and increased food intake in n5-STZ rats.
Mol Cell Biochem 2004 Jun
PMID:Orally administered tryptophan and experimental type 2 diabetes. 1536 85

This investigation characterised the effects of exogenous insulin on exocrine pancreatic secretion in anaesthetised healthy and diabetic rats. Animals were rendered diabetic by a single injection of streptozotocin (STZ, 60 mg kg(-1) I.P.). Age-matched controls were injected citrate buffer. Rats were tested for hyperglycaemia 4 days after STZ injection and 7-8 weeks later when they were used for the experiments. Following anaesthesia (1 g kg(-1) urethane I.P.), laparotomy was performed and the pancreatic duct cannulated for collection of pure pancreatic juice. Basal pancreatic juice flow rate in diabetic rats was significantly (p < 0.001) increased whereas protein and amylase outputs were significantly (p < 0.001) decreased compared to control rats. Insulin (1 IU, I.P.) produced in healthy rats significant increases in pancreatic flow rate, amylase secretion and protein output compared to basal (p < 0.05). Insulin action also included a reduction in blood glucose (152.7 +/- 16.9 mg dl(-1), n = 6, prior to insulin and 42.0 +/- 8.4 mg dl(-1), n = 4, 100 min later). In fact, flow rate and glycaemia showed a strong negative correlation (p < 0.01, Pearson). Pretreatment with atropine (0.2 mg kg(-1), I.V.) abolished the effects of insulin on secretory parameters despite a similar reduction in glycaemia; in this series of experiments the correlation between flow rate and blood glucose was lost. In diabetic rats, insulin (4 IU, I.P.) did not modify exocrine pancreatic secretion. There was a fall in blood glucose (467.6 +/- 14.0 mg dl(-1), n = 10, prior to insulin and 386.6 +/- 43.6 mg dl(-1), n = 7, 120 min later). Rats, however, did not become hypoglycaemic. Similar results were observed in diabetic atropinized rats. The results of this study indicate that the effects of insulin on exocrine pancreatic secretion in anaesthetised healthy rats are mediated by hypoglycaemia-evoked vagal cholinergic activation.
Mol Cell Biochem 2004 Jun
PMID:Effect of insulin on exocrine pancreatic secretion in healthy and diabetic anaesthetised rats. 1536 92

The mechanism of diabetic embryopathy is not known. Excessive reactive oxygen species (ROS) produced in diabetes may be causally related to foetal anomalies. The objective of this study was to determine whether supplementation with the antioxidant lipoic acid (LA) could prevent maternal diabetes-related foetal malformations and intrauterine growth retardation (IUGR) in rats. Pregnant rats were non-treated (Group I) or made diabetic on gestation day (GD) 2 by injecting streptozotocin (Group II). Group III was injected with 20 mg kg(-1) of LA daily starting on GD 6 and continued through GD 19. Group IV was administered only Tris buffer on the corresponding days. Group V was a set of STZ-treated animals, which were supplemented with a daily dose of 20 mg kg(-1) of LA from GD 6 through GD 19. All fetuses were collected on GD 20. Lipoic acid did not affect the blood sugar levels of diabetic animals significantly but improved their body weight gain and reduced food and water consumption. Diabetic group had a high incidence of embryonic resorption, IUGR, craniofacial malformations, supernumerary ribs and skeletal hypoplasia. Lipoic acid significantly reduced these abnormalities. These data support the hypothesis that ROS are causally related to fetal maldevelopment and IUGR associated with maternal diabetes in the rat. They also highlight the possible role of antioxidants in the normal processes of embryo survival, growth and development.
Mol Cell Biochem 2004 Jun
PMID:Effects of alpha-lipoic acid supplementation on maternal diabetes-induced growth retardation and congenital anomalies in rat fetuses. 1536 95

Various clinically used volatile general anaesthetics (e.g. sevoflurane, halothane, isoflurane and desflurane) have been shown to have significant negative inotropic effects on normal ventricular muscle. However, little is known about their effects in ventricular tissue from diabetic animals. Streptozotocin (STZ)-induced diabetes is known to induce changes in the amplitude and time course of shortening and one report suggests that the inotropic effects of anaesthetics are ameliorated in papillary muscles from diabetic animals. The aim of these studies was to investigate this further in electrically stimulated (1 Hz) ventricular myocytes. Cells were superfused with either normal Tyrode (NT) solution or NT containing anaesthetic (1 mM) for a period of 2 min (at 30-32 degrees C). Myocytes from STZ rats were shown to have a significantly longer time to peak shortening (p > 0.001, n = 50) and the amplitude of shortening tended to be greater but this was not significant (p = 0.13, n = 50). Halothane, isoflurane, desflurane and sevoflurane significantly (p < 0.05) reduced the magnitude of shortening of control cells by 72.5 +/- 3.2%, 46.5 +/- 9.7%, 28.9 +/- 4.3% and 22.8 +/- 5.6%, respectively (n > 11 per group) but their steady-state negative inotropic effect was found to be no different in cells from STZ-treated rats (73.0 +/- 4.8%, 40.7 +/- 4.7%, 25.0 +/- 5.2% and 19.8 +/- 5.2%, respectively, n > 10 per group). Therefore, we conclude that the inotropic effects of volatile anaesthetics were not altered by STZ treatment.
Mol Cell Biochem 2004 Jun
PMID:Effects of halothane, isoflurane, sevoflurane and desflurane on contraction of ventricular myocytes from streptozotocin-induced diabetic rats. 1536 6

The sarcoplasmic reticulum (SR) plays a critical role in mediating cardiac contractility and its function is abnormal in the diabetic heart. However, the mechanisms underlying SR dysfunction in the diabetic heart are not clear. Because protein phosphorylation regulates SR function, this study examined the phosphorylation state of phospholamban, a key SR protein that regulates SR calcium (Ca2+) uptake in the heart. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (STZ; 65 mg kg(-1) i.v.), and the animals were humanely killed after 6 weeks and cardiac SR function was examined. Depressed cardiac performance was associated with reduced SR Ca2+-uptake activity in diabetic animals. The reduction in SR Ca2+-uptake was consistent with a significant decrease in the level of SR Ca2+-pump ATPase (SERCA2a) protein. The level of phospholamban (PLB) protein was also decreased, however, the ratio of PLB to SERCA2a was increased in the diabetic heart. Depressed SR Ca2+-uptake was also due to a reduction in the phosphorylation of PLB by the Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein kinase (PKA). Although the activities of the SR-associated Ca2+-calmodulin-dependent protein kinase (CaMK), cAMP-dependent protein kinase (PKA) were increased in the diabetic heart, depressed phosphorylation of PLB could partly be attributed to an increase in the SR-associated protein phosphatase activities. These results suggest that there is increased inhibition of SERCA2a by PLB and this appears to be a major defect underlying SR dysfunction in the diabetic heart.
Mol Cell Biochem 2004 Jun
PMID:Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart. 1536 10

In our previous study, after direct administration of streptozotocin (STZ; 400 microg/g) to fetuses on day 19 of gestation, the B-cell volume in fetal pancreatic islets showed a marked decrease, but gradually recovered with electron microscopic confirmation of B-cell regeneration. However, STZ at this dose often caused fetal death. In this study, therefore, we determined whether B-cells are newly generated after treatment with STZ at a smaller dose in vivo and in vitro. For in vivo experiment, fetuses were administered STZ at 40 microg/g on day 19 of gestation. The B-cell volume in pancreatic islets decreased markedly 3 hr after the administration of STZ, but it began to increase after 6 hr. The fetal plasma insulin concentration decreased from 6 to 12 hr after the administration, but recovered after 48 hr. The cell division index in fetal pancreatic islets of the STZ-treated group began to be significantly larger after 6 hr. For in vitro experiment, fetal pancreases on day 18 of gestation were pretreated with 10 mM STZ for 6 hr and cultured for 98 hr. B-cells were completely destroyed with STZ treatment; however, as these pancreases were cultured in a medium free of STZ, B-cells began to appear and insulin secretion was detected after 48 hr. After 72 hr, the cell division index was significantly greater. These results suggest that the fetal pancreas treated with STZ has the ability to regenerate B-cells both in vivo and in vitro.
Anat Rec A Discov Mol Cell Evol Biol 2004 Dec
PMID:Recovery in the fetal pancreatic islet following fetal administration of streptozotocin in the rat in vivo and in vitro. 1551 61


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