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Streptozotocin-induced Diabetes (streptozotocin-induced + diabetes)
Selected Abstracts,-Lipoic acid reduces congenital malformations in the offspring of diabetic miceDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 3 2009Y. Sugimura Abstract Background The mechanism of diabetes-induced congenital malformation remains to be elucidated. It has been reported that ,-lipoic acid (LA) prevents neural tube defects (NTDs) in offsprings of rats with streptozotocin-induced diabetes. Here, we evaluate the protective effect of LA against diabetic embryopathy, including NTDs, cardiovascular malformations (CVMs), and skeletal malformations, in mice. Methods Female mice were rendered hyperglycemic using streptozotocin and then mated with normal male mouse. Pregnant diabetic or non-diabetic mice were treated daily with either LA (100 mg/kg body weight) or saline between gestational days 0 and 18. On day 18, fetuses were examined for congenital malformations. Results Plasma glucose levels on day 18 were not affected by LA treatment. No congenital malformations were observed either in the saline-treated or LA-treated non-diabetic group. In the saline-treated diabetic group, 39% of fetuses had external malformations and 30% had NTDs. In the LA-treated diabetic group, the corresponding proportions were 11 and 8%, respectively. LA treatment also decreased the incidence of CVMs from 30,3% and of skeletal malformations from 29,6%. Conclusions We conclude that LA can reduce NTDs, CVMs and skeletal malformations in the offspring of diabetic mice at term delivery. Copyright © 2009 John Wiley & Sons, Ltd. [source] Retinal capillary basement membrane thickness in diabetic mice genetically modified at the haptoglobin locusDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2007Rachel Miller-Lotan Technion Faculty of Medicine Abstract Background Individuals with diabetes mellitus (DM) homozygous for the haptoglobin (Hp) 1 allele are at decreased risk of retinopathy as compared to DM individuals with the Hp 2 allele. We sought to recapitulate these findings in DM mice genetically modified at the Hp locus. Methods An early morphological characteristic of the microangiopathy seen in diabetic retinal disease is retinal capillary basement membrane (RCBM) thickening. RCBM thickness as assessed by electron microscopy was performed on a total of 12 eyes taken from three mice in each of the four study groups (three eyes from C57Bl/6 Hp 1 and C57Bl/6 Hp 2 mice with and without streptozotocin-induced diabetes). Results The non-parametric Kruskal,Wallis ANOVA test demonstrated that there was a highly significant difference between the four groups of mice (P < 0.0001). Mann,Whitney tests for specific pair-wise comparisons demonstrated that there was no significant difference in the RCBM thickness between Hp 1 and Hp 2 mice (p = 0.70) or between DM Hp 1 and non-DM Hp 1 mice (p = 0.42). However, induction of diabetes resulted in a marked increase in RCBM thickness in Hp 2 mice compared to non-DM Hp 2 mice (p = 0.0004) and compared to DM Hp 1 mice (p = 0.0005). Conclusions A highly significant increase in RCBM thickness was observed in DM mice with the Hp 2 genotype. These data provide important support for association studies done in humans showing an increased prevalence of diabetic retinopathy in individuals with the Hp 2 genotype. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signalsFEBS JOURNAL, Issue 16 2009Joan Duran The ubiquitous isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (uPFK-2), a product of the Pfkfb3 gene, plays a crucial role in the control of glycolytic flux. In this study, we demonstrate that Pfkfb3 gene expression is increased in streptozotocin-induced diabetic mouse liver. The Pfkfb3/-3566 promoter construct linked to the luciferase reporter gene was delivered to the liver via hydrodynamic gene transfer. This promoter was upregulated in streptozotocin-induced diabetic mouse liver compared with transfected healthy cohorts. In addition, increases were observed in Pfkfb3 mRNA and uPFK-2 protein levels, and intrahepatic fructose-2,6-bisphosphate concentration. During streptozotocin-induced diabetes, phosphorylation of both p38 mitogen-activated protein kinase and Akt was detected, together with the overexpression of the proliferative markers cyclin D and E2F. These findings indicate that uPFK-2 induction is coupled to enhanced hepatocyte proliferation in streptozotocin-induced diabetic mouse liver. Expression decreased when hepatocytes were treated with either rapamycin or LY 294002. This shows that uPFK-2 regulation is phosphoinositide 3-kinase,Akt,mammalian target of rapamycin dependent. These results indicate that fructose-2,6-bisphosphate is essential to the maintenance of the glycolytic flux necessary for providing energy and biosynthetic precursors to dividing cells. [source] Assessment of the "common" 4.8-kb mitochondrial DNA deletion and identification of several closely related deletions in the dorsal root ganglion of aging and streptozotocin ratsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2002Kim K. Nickander Abstract The identification of several mitochondrial DNA (mtDNA) deletions and the accumulation of the "common" 4.8-kb mitochondrial DNA deletion (mtDNA4834) with aging and experimental streptozotocin-induced diabetes (STZ) were studied in the rat dorsal root ganglion (DRG). Twenty-one mtDNA deletions, including mtDNA4834, were identified in rat L4-L6 DRG mtDNA of 15-month-old Spraque-Dawley rats with 13 months of STZ and age-matched controls. These deletions were flanked by breakpoints that ranged from 16-bp direct repeats to no direct repeats. The sciatic nerve contained undetectable levels of mtDNA deletions. Levels of mtDNA4834 in rat DRG mtDNA significantly accumulated with age at a rate much higher than those reported in the brain, yet were not statistically different in STZ. Southern blot analysis demonstrated no significant accumulation of the total amount of mtDNA deletions in STZ over age-matched controls. The accumulation of mtDNA4834 has not been studied in rat peripheral nerve tissue. Our identification of several mtDNA deletions with and without direct repeats at their breakpoint support the hypothesis that deletions can occur by both the slip-replication model and random recombination. Although there is a significant increase in accumulation of mtDNA4834 associated with aging, the lack of significant accumulations of mtDNA deletions in STZ over age-matched controls indicates that this type of mtDNA damage is likely not a major alteration in STZ, although the changes could be confined to a small population of neurons that undergo apoptosis between 8 and 15 months. [source] Reduced Nerve Blood Flow In Diabetic Rats Is A Reflection Of Hindlimb Muscle WastingJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000Dr Tomlinson We examined the influence of muscle wasting, as a result of streptozotocin-induced diabetes, on sciatic nerve laser Doppler flux (SNLDF), as an index of nerve blood flow, and conduction velocity (NCV). We compared dietary-restricted weight-reduced non-diabetic rats with controls and with diabetic rats and we studied the effects of clenbuterol, an anabolic ,-adrenoceptor agonist, in control and diabetic rats. Dietary restriction reduced the weights of hindlimb muscles,extensor digitorum longus, soleus and gastrocnemius,half as much as did streptozotocin-diabetes and clenbuterol increased muscle weights in control and diabetic rats. This gave a hierarchy of muscle weights in the order,clenbuterol-controls, untreated controls, weight-reduced non-diabetics, clenbuterol-diabetics and untreated diabetics. Diabetes without treatment reduced SNLDF by 51% (p < 0.01); dietary restriction by 25% (p < 0.01) and there were proportional increases associated with clenbuterol treatment. Combined muscle weights regressed closely with SNLDF (r2=0.69; p < 0.001) and, when the latter was expressed relative to muscle weights, a similar value was obtained for all five groups,there were no significant differences. Thus, sciatic nerve blood flow is closely related to hindlimb muscle weight and the effect of diabetes on nerve blood flow may be secondary to muscle wasting. Sciatic/tibialis motor and sensory conduction velocities were also reduced by muscle wasting in the dietary restricted group of non-diabetic rats, but, unlike nerve Doppler flux, it was unaffected by clenbuterol. [source] Reversal of diabetes-evoked changes in mitochondrial protein expression of cardiac left ventricle by treatment with a copper(II)-selective chelatorPROTEOMICS - CLINICAL APPLICATIONS, Issue 4 2007Mia Jüllig Abstract Cardiac disease is the commonest cause of death amongst diabetic patients. Diabetic cardiomyopathy, which has a poor prognosis, is characterized by left ventricular hypertrophy and impaired cardiac function and mitochondrial damage is said to contribute to its development. We recently showed that treatment with the CuII -selective chelator, triethylenetetramine (TETA), improved cardiac structure, and function in diabetic subjects without modifying hyperglycemia. Thus, TETA has potential utility for the treatment of heart disease. To further understand the molecular mechanism by which it causes these effects, we have conducted the first study of the effect of oral TETA on protein abundance in the cardiac left ventricle of rats with severe streptozotocin-induced diabetes. Proteomic methods showed that of 211 proteins changed in diabetes, 33 recovered after treatment. Through MS, 16 proteins were identified which may constitute major targets of drug action. Remarkably, most of these were mitochondrial proteins with roles in energy metabolism. In addition to components of the mitochondrial respiratory chain and enzymes involved in fatty acid oxidation, TETA treatment normalized both myocardial expression and enzymatic activity of carnitine palmitoyltransferase 2. These findings indicate that mitochondria constitute major targets in the mechanism by which TETA restores cardiac structure and function in diabetes. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Enhancement of Both EDHF and NO/cGMP Pathways Is Necessary to Reverse Erectile Dysfunction in Diabetic RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2005Javier Angulo PhD ABSTRACT Aims and Methods., Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes. Results., After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 ± 34.1% and 268.5 ± 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 ± 88.6% of control response at 1 Hz), completely restoring erectile function. Conclusions., These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men. [source] Skin wound healing in diabetic ,6 integrin-deficient miceAPMIS, Issue 10 2010JASPER N. JACOBSEN Jacobsen JN, Steffensen B, Häkkinen L, Krogfelt KA, Larjava HS. Skin wound healing in diabetic ,6 integrin-deficient mice. APMIS 2010; 118: 753,64. Integrin ,v,6 is a heterodimeric cell surface receptor, which is absent from the normal epithelium, but is expressed in wound-edge keratinocytes during re-epithelialization. However, the function of the ,v,6 integrin in wound repair remains unclear. Impaired wound healing in patients with diabetes constitutes a major clinical problem worldwide and has been associated with the accumulation of advanced glycated endproducts (AGEs) in the tissues. AGEs may account for aberrant interactions between integrin receptors and their extracellular matrix ligands such as fibronectin (FN). In this study, we compared healing of experimental excisional skin wounds in wild-type (WT) and ,6-knockout (,6,/,) mice with streptozotocin-induced diabetes. Results showed that diabetic ,6,/, mice had a significant delay in early wound closure rate compared with diabetic WT mice, suggesting that ,v,6 integrin may serve as a protective role in re-epithelialization of diabetic wounds. To mimic the glycosylated wound matrix, we generated a methylglyoxal (MG)-glycated variant of FN. Keratinocytes utilized ,v,6 and ,1 integrins for spreading on both non-glycated and FN-MG, but their spreading was reduced on FN-MG. These findings indicated that glycation of FN and possibly other integrin ligands could hamper keratinocyte interactions with the provisional matrix proteins during re-epithelialization of diabetic wounds. [source] The effect of streptozotocin-induced diabetes on cardiac ,-adrenoceptor subtypes in the ratAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2001D. J. Sellers 1,The present study investigates the effect of short-term experimental diabetes of 14-days duration on the ,-adrenoceptor subtypes of the rat heart. 2,,-adrenoceptor-mediated functional responses to submaximal doses of isoprenaline were enhanced in Langendorff-perfused hearts from diabetic rats, manifested as greater changes in tension, heart rate and rates of tension development (+dT/dt) and decline (,dT/dt). 3,Radioligand binding data demonstrated that total cardiac ,-adrenoceptor density and affinity for [3H]-dihydroalprenolol was unchanged by diabetes, although a decrease in ,1 -adrenoceptor density and increase in ,2 -adrenoceptor density was observed. 4,In conclusion, hearts from 14-day streptozotocin-induced diabetic rats demonstrate a number of alterations within the ,-adrenoceptor system. However, the enhanced ,-adrenoceptor-mediated responses to isoprenaline were not caused by an overall increase in density of ,-adrenoceptors, but were accompanied by changes in the ratio of the ,-adrenoceptor subtypes. [source] Alteration of Ca2+ -ATPase activity in the homogenate, plasma membrane and microsomes of the salivary glands of streptozotocin-induced diabetic ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2009José Nicolau Abstract Diabetes has been implicated in the dryness of the mouth, loss of taste sensation, sialosis, and other disorders of the oral cavity, by impairment of the salivary glands. The aim of the present study was to examine the plasma membrane, microsomal, and homogenate Ca2+ -ATPase activity in the rat submandibular and parotid salivary glands of streptozotocin-induced diabetes. We have also examined the influence of the acidosis state on this parameter. Diabetes was induced by an intraperitoneal injection of streptozotocin and acidosis was induced by daily injection of NH4Cl. At 15 and 30 days after diabetes induction, the animals were euthanized and the submandibular and parotid salivary glands were removed and analyzed. Ca2+ -ATPase (total, independent, and dependent) was determined in the homogenate, microsomal, and plasma membranes of the salivary glands of diabetic and control rats. Calcium concentration was also determined in the glands and showed to be higher in the diabetic animals. Ca2+ -ATPase activity was found to be reduced in all cell fractions studied in the diabetic animals compared with control. Similar results were obtained for the submandibular salivary glands of acidotic animals; however in the parotid salivary glands it was found an increase in the enzyme activity. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||