Effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on proteomics and autophagy in mice with type 2 diabetes mellitus induced by high-fat diet coupled with streptozotocin / 中国中药杂志

To compare the pancreatic proteomics and autophagy between Rehmanniae Radix-and Rehmanniae Radix Praeparata-treated mice with type 2 diabetes mellitus(T2DM). The T2DM mouse model was established by high-fat diet coupled with streptozotocin(STZ, intraperitoneal injection, 100 mg·kg~(-1), once a day for three consecutive days). The mice were then randomly assigned into a control group, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) catalpol groups, low-(5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) Rehmanniae Radix Praeparata groups, low-(150 mg·kg~(-1)) and high-dose(300 mg·kg~(-1)) 5-hydroxymethyl furfuraldehyde(5-HMF) groups, and a metformin(250 mg·kg~(-1)) group. In addition, a normal group was also set and each group included 8 mice. The pancreas was collected after four weeks of administration and proteomics tools were employed to study the effects of Rehmanniae Radix and Rehmanniae Radix Praeparata on protein expression in the pancreas of T2DM mice. The expression levels of proteins involved in autophagy, inflammation, and oxidative stress response in the pancreatic tissues of T2DM mice were determined by western blotting, immunohistochemical assay, and transmission electron microscopy. The results showed that the differential proteins between the model group and Rehmanniae Radix/Rehmanniae Radix Prae-parata group were enriched in 7 KEGG pathways, such as autophagy-animal, which indicated that the 7 pathways may be associated with T2DM. Compared with the control group, drug administration significantly up-regulated the expression levels of beclin1 and phosphorylated mammalian target of rapamycin(p-mTOR)/mTOR and down-regulated those of the inflammation indicators, Toll-like receptor-4(TLR4) and Nod-like receptor protein 3(NLRP3), in the pancreas of T2DM mice, and Rehmanniae Radix showed better performance. In addition, the expression levels of inducible nitric oxide synthase(iNOS), nuclear factor erythroid 2-related factor 2(Nrf2), and heine oxygenase-1(HO-1) in the pancreas of T2DM mice were down-regulated after drug administration, and Rehmanniae Radix Praeparata demonstrated better performance. The results indicate that both Rehmanniae Radix and Rehmanniae Radix Praeparata can alleviate the inflammatory symptoms, reduce oxidative stress response, and increase the autophagy level in the pancreas of T2DM mice, while they exert the effect on different autophagy pathways.

Wogonoside alleviates high glucose-induced dysfunction of retinal microvascular endothelial cells and diabetic retinopathy in rats by up-regulating SIRT1 / 南方医科大学学报

OBJECTIVE@#To investigate the effects of wogonoside on high glucose-induced dysfunction of human retinal microvascular endothelial cells (hRMECs) and streptozotocin (STZ)-induced diabetic retinopathy in rats and explore the underlying molecular mechanism.@*METHODS@#HRMECs in routine culture were treated with 25 mmol/L mannitol or exposed to high glucose (30 mmol/L glucose) and treatment with 10, 20, 30, 40 μmol/L wogonoside. CCK-8 assay and Transwell assay were used to examine cell proliferation and migration, and the changes in tube formation and monolayer cell membrane permeability were tested. ROS, NO and GSH-ST kits were used to evaluate oxidative stress levels in the cells. The expressions of IL-1β and IL-6 in the cells were examined with qRT-PCR and ELISA, and the protein expressions of VEGF, HIF-1α and SIRT1 were detected using Western blotting. We also tested the effect of wogonoside on retinal injury and expressions of HIF-1α, ROS, VEGF, TNF-α, IL-1β, IL-6 and SIRT1 proteins in rat models of STZ-induced diabetic retinopathy.@*RESULTS@#High glucose exposure caused abnormal proliferation and migration, promoted angiogenesis, increased membrane permeability (P < 0.05), and induced inflammation and oxidative stress in hRMECs (P < 0.05). Wogonoside treatment concentration-dependently inhibited high glucose-induced changes in hRMECs. High glucose exposure significantly lowered the expression of SIRT1 in hRMECs, which was partially reversed by wogonoside (30 μmol/L) treatment; interference of SIRT1 obviously attenuated the inhibitory effects of wogonoside against high glucose-induced changes in proliferation, migration, angiogenesis, membrane permeability, inflammation and oxidative stress in hRMECs. In rat models of STZ-induced diabetic retinopathy, wogonoside effectively suppressed retinal thickening (P < 0.05), alleviated STZ-induced retinal injury, and increased the expression of SIRT1 in the retinal tissues (P < 0.001).@*CONCLUSION@#Wogonoside alleviates retinal damage caused by diabetic retinopathy by up-regulating SIRT1 expression.

Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats / Antagonista (p425) do fator de inibição da migração de macrófagos (MIF) melhora as alterações histopatológicas e funcionais renais em ratos diabéticos

Abstract Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.

Resumo Introdução: Supõe-se que elevações da expressão do fator de inibição da migração de macrófagos (MIF) possam contribuir para a patogênese da nefropatia diabética (ND). O objetivo do presente estudo foi investigar os efeitos renais da inibição do MIF em um modelo experimental diabético. Métodos: Dezoito ratos Wistar machos (230 ± 20g) foram divididos em três grupos: 1) controle, 2) diabético (STZ 50 mg/kg dissolvida em soro fisiológico, IP), 3) diabético + antagonista do MIF (p425 1 mg/kg por dia IP no 21o dia por 21 dias consecutivos). O tratamento começou após a identificação de aumento significativo na albuminúria nos ratos diabéticos em relação aos controles. Os ratos foram mantidos individualmente em gaiolas metabólicas (8h-14h) e amostras de urina foram colhidas no 21o e no 42o dia. Ao final do estudo, amostras de sangue e tecido foram colhidas para análises bioquímicas (BS, excreção urinária de proteína, excreção urinária de GAGs, BUN, Cr, Na e K) e histológicas. Resultados: O presente estudo demonstrou que o antagonista do MIF (p425) diminuiu significativamente proteinúria, excreção urinária de GAGs , relação proteína/creatinina na urina, BUN e Cr no grupo com ND induzida por estreptozotocina. As alterações patológicas foram significativamente abrandadas nos ratos com ND que receberam antagonista do MIF (p425). Conclusão: Coletivamente, os dados sugerem que o antagonista do MIF (p425) teve efeito protetor contra lesões funcionais e histopatológicas da ND.

Rutin restores adenosine deaminase activity in serum and the liver and improves biochemical parameters in streptozotocin-induced diabetic rats / Rutina restaura a atividade da Adenosina desaminase no soro e no fígado e melhora os parâmetros bioquímicos em ratos diabéticos induzidos por estreptozotocina

ABSTRACT denosine deaminase (ADA) is a critical control point in the regulation of adenosine levels. This study aimed to investigate the effects of a polyphenolic flavonoid, rutin, on the activity of ADA in serum, the cerebral cortex, liver, kidney, and biochemical parameters in diabetic rats. The animals were divided into four groups (n=6) for the following treatments: control; diabetic (streptozotocin 55 mg/kg); diabetic with rutin (100 mg/kg/day); diabetic with glibenclamide (10 mg/kg/day). After 30 days, ADA activity and biochemical parameters were analyzed. The ADA activity in the serum was significantly elevated in the diabetic group compared to the control group (p<0.01). The treatment with rutin prevented the increase in ADA activity in the STZ-induced rats when compared to control group. Our data showed that rutin reduced glucose, LDL levels, and hepatic enzymes in comparison with the control group. These results demonstrate that the increase of ADA activity observed in diabetic rats may be an important indicator of the immunopathogenesis of hyperglycemic disorders and suggest that rutin is important for regulating the enzymatic activities associated with immune, hyperglycemic, and inflammatory response in diabetes mellitus.

RESUMO A Adenosina desaminase (ADA) representa um ponto de controle crítico na regulação dos níveis de adenosina. A rutina, um flavonóide polifenólico presente em muitas plantas, foi testado para verificar a sua influência na atividade da ADA no soro, córtex cerebral, fígado rim e parâmetros bioquímicos em ratos diabéticos. Os animais foram divididos em quatro grupos cada grupo com 6 animais), tal como: controle; diabética (estreptozotocina 55 mg/kg); diabética + rutina (100 mg/kg/dia); diabético + glibenclamida (10 mg/kg/dia). Após 30 dias foram analisadas a atividade da ADA sérica e tecidual e parâmetros bioquímicos. A atividade de ADA no soro foi significativamente elevada no grupo diabético quando comparado ao grupo controle (p<0,01). O tratamento com Rutina preveniu o aumento na atividade da ADA nos ratos diabéticos, quando comparado com o grupo controle. Os resultados mostraram que a rutina reduziu a glicose, os níveis de LDL e as enzimas hepáticas, em comparação com o grupo controle. Estes resultados mostram que o aumento da atividade da ADA observado em ratos diabéticos pode ser um indicador importante da imuno-patogênese de perturbações hiperglicêmicas e sugerem que a Rutina é importante na regulação das atividades enzimáticas associadas com a resposta imunitária, hiperglicêmica e inflamatória no Diabetes mellitus.

Interval training attenuates the metabolic disturbances in type 1 diabetes rat model / Treinamento intervalado atenua os distúrbios metabólicos em modelo de ratos diabéticos do tipo 1

OBJECTIVE: This study investigated the effect of interval training on blood biochemistry and immune parameters in type 1 diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into four groups: sedentary (SE, n = 15), interval training (IT, n = 17), diabetic sedentary (DSE, n = 17), diabetic interval training (DIT, n = 17). Diabetes was induced by i.v. injection of streptozotocin (60 mg/kg). Swimming Interval Training consisted of 30-s exercise with 30-s rest, for 30 minutes, during 6 weeks, four times a week, with an overload of 15% of body mass. Plasma glucose, lactate, triacylglycerol and total cholesterol concentrations, phagocytic capacity, cationic vesicle content, and superoxide anion and hydrogen peroxide production by blood neutrophils and peritoneal macrophages were evaluated. Proliferation of mesenteric lymphocytes was also estimated. RESULTS: Interval training resulted in attenuation of the resting hyperglycemic state and decreased blood lipids in the DIT group. Diabetes increased the functionality of blood neutrophils and peritoneal macrophages in the DSE group. Interval training increased all functionality parameters of peritoneal macrophages in the IT group. Interval training also led to a twofold increase in the proliferation of mesenteric lymphocytes after 6 weeks of exercise in the DIT group. CONCLUSION: Low-volume high-intensity physical exercise attenuates hyperglycemia and dislipidemia induced by type 1 diabetes, and induces changes in the functionality of innate and acquired immunity.

OBJETIVO: Este estudo investigou os efeitos do treinamento intervalado sobre parâmetros bioquímicos e imunológicos em ratos diabéticos do tipo 1. MATERIAIS E MÉTODOS: Ratos Wistar machos foram divididos em quatro grupos: sedentário (SE, n = 15), treinamento intervalado (TI, n = 17), sedentário diabético (SED, n = 17) e treinamento intervalado diabético (TID, n = 17). O diabetes foi induzido por uma injeção intravenosa de estreptozotocina (60 mg/kg). O treinamento intervalado de natação consistiu de 30s de exercício com 30s de recuperação, 30 minutos, durante 6 semanas, 4 vezes por semana, com sobrecarga de 15% da massa corporal. Foram avaliados glicemia, lactato sanguíneo, concentração de triacilglicerol e colesterol total, capacidade fagocítica, conteúdo de vesículas catiô­nicas, produção de ânion superóxido e peróxido de hidrogênio por neutrófilos sanguíneos e macrófagos peritoneais. A proliferação de linfócitos mesentéricos também foi avaliada. RESULTADOS: O treinamento intervalado resultou em atenuação do estado hiperglicêmico e diminuiu os lipídeos sanguíneos no grupo TID. O diabetes aumentou a funcionalidade dos neutrófilos sanguíneos e macrófagos peritoneais do grupo SED. O treinamento intervalado aumentou todos os parâmetros funcionais dos macrófagos peritoneais do grupo TI. O treinamento intervalado também aumentou duas vezes a proliferação dos linfócitos mesentéricos após seis semanas de exercício do grupo TID. CONCLUSÃO: O treinamento intervalado atenua a hiperglicemia e a dislipidemia induzida pelo diabetes do tipo 1 e induz mudanças na funcionalidade da imunidade inata e adquirida.

Efeito da estreptozotocina sobre os perfis glicêmico e lipídico e o estresse oxidativo em hamsters / Effect of streptozotocin on the glycemic and lipid profiles and oxidative stress in hamsters

OBJETIVO: Este estudo avaliou os efeitos da estreptozotocina nos perfis glicêmico e lipídico e marcadores de estresse oxidativo em hamsteres. MATERIAIS E MÉTODOS: Hamsteres machos Golden Syrian foram divididos em dois grupos: grupo diabético (D), que recebeu uma única injeção de estreptozotocina (STZ - 50 mg/kg), e grupo controle (C), que recebeu injeção de tampão citrato. Os animais foram eutanasiados após 10 dias de experimento e o sangue, o fígado e rins foram coletados. RESULTADOS: O grupo diabético apresentou níveis maiores de glicose, triacilgliceróis e colesterol séricos e maior concentração de substâncias reativas ao ácido tiobarbitúrico (TBARs) no fígado e nos rins. Também apresentou significativo aumento da concentração de glutationa no fígado e menores atividades da paraoxonase e do superóxido dismutase. CONCLUSÃO: Hamsteres fornecem um bom modelo para o diabetes melito do tipo I e estresse oxidativo, similar ao da síndrome humana, e poderão ser adequados para a análise de compostos antidiabéticos.

OBJECTIVE: This study evaluated the effects of streptozotocin on glycemic and lipid profiles and oxidative stress status in hamsters. MATERIALS AND METHODS: Male Golden Syrian hamsters were divided in diabetic group (D) which received a streptozotocin single injection (STZ - 50 mg/kg), and control group (C) which received a single injection of the vehicle citrate buffer. Animals were euthanized after 10 days of experiment and blood, liver and kidneys were collected. RESULTS: The diabetic group had higher levels of glucose, triacylglycerols and cholesterol in serum and thiobarbituric acid reactive substances (TBARS) concentration increased in the liver and kidneys. Diabetes induced a significant increase in glutathione concentration in the liver and decreased paraoxonase and superoxide dismutase activities. CONCLUSION: Hamsters provide a novel animal model for diabetes mellitus and oxidative stress, similar to the human syndrome, which may be suitable for the testing of antidiabetic compounds.

Dietary restriction prevents diabetogenic effect of streptozotocin in mice.

The beneficial role of dietary restriction (DR) was studied in streptozotocin (STZ)-induced diabetes in mice. The DR mice exhibited the lower blood glucose (mg/dl) level as compared to ad libitum (AL) fed ones. After 3 months’ DR, STZ treatment to both AL and DR mice showed significant (p<0.001) elevation of the blood glucose level in AL-fed mice, while a lower level of glucose was maintained in DR-fed mice. The ability of maintaining a low blood glucose level in STZ-treated DR mice indicated that STZ might have been ineffective from its action on beta cells of pancreas by long-term DR. Thus, these findings suggested that DR may be an important tool for preventing the diabetic conditions. However, further studies are required to know the mechanism(s) of DR protection against diabetogenic action of STZ in experimental animals.

Altered kidney morphology and enzymes in streptozotocin induced diabetic rats / Morfología y enzimas renales alteradas en ratas con diabetes inducida por estreptozotocin

We studied the effects of streptozotocin (STZ)-induced diabetes on kidney morphology, anatomy, architecture and on the activities of aminotransferases (AST and ALT), alkaline phosphatase (ALP) and pseudocholinesterase (PChE) in albino rats. The aim of the study was to investigate the association between diabetic kidney complications and kidney enzyme alterations. This study was performed in the Department of Anatomy and Institute of Pharmaceutical Sciences, Baqai Medical University, Karachi and Pathology department of College of Physicians & Surgeons (CPSP) Pakistan in 2007-08. Diabetes was induced by a single dose of STZ (45 mg/kg, b.w.) given intraperitoneally in sodium citrate buffer at pH 4.5. Eighty (80) albino rats were divided into five groups: control (A) and STZ treated (B, C, D, and E) which were sacrificed 2, 4, 6 and 8 weeks post treatment respectively. Histopathology of kidney showed lesions similar to human glomerulosclerosis, glomerular membrane thickening, arteriolar hyalinization and tubular necrosis. Increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and pseudocholinesterase (PChE) were observed in the kidney. It seems that the diabetic complications in the kidney are likely to be associated with alterations in enzyme levels.

Se estudiaron los efectos de la diabetes inducida por estreptozotocin (STZ) sobre la morfología, anatomía, arquitectura y sobre las actividades de aminotransferasas (ALT y AST), fosfatasa alcalina (ALP) y pseudocolinesterasa (PChE) en los riñones de ratas albinas. El objetivo del estudio fue investigar la asociación entre las complicaciones renales diabéticas y la alteración de las enzimas renales. Este estudio se realizó en el Departamento de Anatomía y el Instituto de Ciencias Farmacéuticas, Universidad de Medicina Baqai, Karachi y el departamento de Patología de Colegio de Médicos y Cirujanos (CPSP) Pakistán entre el 2007-2008. La diabetes fue inducida por una dosis única de STZ (45 mg / kg de peso corporal) administrada por vía intraperitoneal en tampón de citrato de sodio a pH 4.5. Ochenta (80) ratas albinas fueron divididas en cinco grupos: control (A) y STZ tratados (B, C, D y E), que se sacrificaron a las 2, 4, 6 y 8 semanas después del tratamiento, respectivamente. La histopatología del riñón mostró lesiones similares a la glomeruloesclerosis en humanos, engrosamiento de la membrana glomerular, hialinización arteriolar y necrosis tubular. Aumento de los niveles de aspartato aminotransferasa (AST), alanina aminotransferasa (ALT), fosfatasa alcalina (ALP) y pseudocolinesterasa (PChE) fueron observados en el riñón. Parece que las complicaciones de la diabetes en el riñón están directamente asociadas con alteraciones en los niveles de las enzimas.

Effect of plantain banana on gastric ulceration in NIDDM rats: role of gastric mucosal glycoproteins, cell proliferation, antioxidants and free radicals.

Methanolic extract of Musa sapientum var. Paradisiaca (MSE, 100 mg/kg) was studied for its antiulcer and mucosal defensive factors in normal and non-insulin dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by administering streptozotocin (STZ, 70 mg/kg, ip) to 5 days old rat pups. The animals showing blood glucose level >140mg/dL after 12 weeks of STZ administration were considered as NIDDM positive. Effects of MSE were compared with known ulcer protective drug, sucralfate (SFT, 500 mg/kg) and anti-diabetic drug glibenclamide (GLC, 0.6 mg/kg) when administered orally, once daily for 6 days against gastric ulcers (GU) induced by cold-restraint stress (CRS) and ethanol and subsequent changes in gastric mucosal glycoproteins, cell proliferation, free radicals (lipid peroxidation and nitric oxide) and anti-oxidants enzymes (super oxide dismutase and catalase) and glutathione (GSH) levels. MSE showed better ulcer protective effect in NIDDM rats compared with SFT and GLC in CRS-induced GU. NIDDM caused a significant decrease in gastric mucosal glycoprotein level without having any effect on cell proliferation. However, all the test drugs reversed the decrease in glycoprotein level in NIDDM rats, but cell proliferation was enhanced in case of MSE alone. Both CRS or NIDDM as such enhanced gastric mucosal LPO, NO and SOD, but decreased CAT levels while CRS plus NIDDM rats caused further increase in LPO and NO level without causing any further changes in SOD and CAT level. MSE pretreatment showed reversal in the levels of all the above parameters better than GLC. Ethanol caused a decrease in glutathione level which was further reduced in NIDDM-ethanol rats. MSE reversed the above changes significantly in both normal as well as in NIDDM rats, while GLC reversed it only in NIDDM rats. However, SFT was ineffective in reversing the changes induced by CRS or ethanol or when given in NIDDM-CRS or NIDDM-ethanol rats. The results indicated that the ulcer protective effect of MSE could be due to its predominant effect on mucosal glycoprotein, cell proliferation, free radicals and antioxidant systems.

Efeitos do tratamento oral com sulfato de vanadila em ratos diabéticos jovens / Effects of oral vanadyl sulfate treatment in young diabetic rats

Neste trabalho avaliamos os efeitos do tratamento oral de sulfato de vanadila (VOSO4, 1mg/mL), administrado durante 19 e 29 dias em ratos jovens tornados diabéticos por meio de estreptozotocina. Em vários tempos de tratamento foram realizadas determinaçöes de peso corporal, ingestäo hídrica e alimentar, glicemia, glicosúria e uréia urinária. Os animais foram sacrificados no 19§ e 29§ dias de tratamento, sendo determinada a glicemia, assim como realizadas as pesagens do pâncreas, dos músculos Soleus e Extensor digitorum longus (EDL) e das gorduras epididimal e retroperitonial. Os resultados mostraram que o tratamento de ratos diabéticos jovens com VOSO4 leva à reduçäo da hiperglicemia (p<0,01), ingestäo hídrica e alimentar e do peso corporal (p<0,05). Os pesos dos tecidos e do pâncreas näo apresentaram alteraçäo em relaçäo aos controles, o mesmo ocorrendo com os níveis de uréia urinária. Concluímos que o tratamento com VOSO4 no período estudado foi capaz de reduzir as principais alteraçöes metabólicas freqüentemente encontradas no diabetes. Essas informaçöes säo muito úteis e importantes para futuros estudos sobre os efeitos de VOSO4 no metabolismo protéico muscular em ratos diabéticos jovens.

Time course of changes in heart rate and blood pressure variability in streptozotocin-induced diabetic rats treated with insulin

Autonomic neuropathy is a frequent complication of diabetes associated with higher morbidity and mortality in symptomatic patients, possibly because it affects autonomic regulation of the sinus node, reducing heart rate (HR) variability which predisposes to fatal arrhythmias. We evaluated the time course of arterial pressure and HR and indirectly of autonomic function (by evaluation of mean arterial pressure (MAP) variability) in rats (164.5 + 1.7 g) 7, 14, 30 and 120 days after streptozotocin (STZ) injection, treated with insulin, using measurements of arterial pressure, HR and MAP variability. HR variability was evaluated by the standard deviation of RR intervals (SDNN) and root mean square of successive difference of RR intervals (RMSSD). MAP variability was evaluated by the standard deviation of the mean of MAP and by 4 indices (P1, P2, P3 and MN) derived from the three-dimensional return map constructed by plotting MAPn x [(MAPn+1) - (MAPn)] x density. The indices represent the maximum concentration of points (P1), the longitudinal axis (P2), and the transversal axis (P3) and MN represents P1 x P2 x P3 x 10(-3), STZ induced increased urinary glucose in diabetic (D) rats compared to controls (C). Seven days after STZ, diabetes reduced resting HR from 380.6 + 12.9 to 319,2 + 19.8 bpm, increased HR variability, as demonstrated by increased SDNN, from 11.77 + 1.67 to 19.87 + 2.60 ms, did not change MAP, and reduced P1 from 61.0 + 5.3 to 51.5 + 1.8 arbitrary units (AU), P2 from 41.3 + 0.3 to 29.0 + 1.8 AU, and MN from 171.1. + 30.2 to 77.2 + 9.6 AU of MAP. These indices, as well as HR and MAP, were similar for D and C animals 14, 30 and 120 days after STZ. Seven-day rats showed a negative correlation of urinary glucose with resting HR (r=-0.76, P=0.03) as well as with the MN index (r=-0.83, P=0.01). We conclude that rats with short-term diabetes mellitus induced by STZ presented modified autonomic control of HR and MAP which was reversible. The metabolic control may influence the results, suggesting that insulin treatment and a better metabolic control in this model may modify arterial pressure, HR and MAP variability.

Morphological and quantative study of the myenteric plexus of the duodenum of streptozotocin-induced diabetic rats

The purpose of this work was to study the morphological and quantitative alterations of the myenteric plexus neurons of the duodenum of rats with acute and chronic streptozotocin-induced diabetes and establish a comparison with non-diabetic animals. Samples of duodenum were destined to histological sections stained by Hematoxilin-Eosin and to membrane preparings stained by the Giemsa and NADH-diaphorasis methods. Semall, medium and large neurons were found, with a predominance of medium ones on chronic and acute diabetic animals. It was verified that most of the neurons of diabetic and non-diabetic animals have an eccentrical nucleus and thus this characteristic is not an indicative of degenerative process. It was observed that in diabetes there is a decrease in the number of myenteric neurons. It is argued that this initial decrease is due to the toxic effects of the drug and not to the physiopathology of diabetes itself, and also that the expressive smaller proportion of neurons on the chronically diabetic animals is due to the immediate loss related to streptozotocin and the further consequences of aging during nine weeks of diabetes.

Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats

Several investigators have demonstrated that streptozotocin (STZ) diabetes induces changes in the autonomic control of the cardiovascular system. Changes in cardiovascular function may be related to peripheral neuropathy. The aim of the present study was to a changes in heart rate (HR) and arterial pressure (AP) as well as baroreflex and chemoreflex sensitivity in STZ-induced diabetic male Wistar rats (STZ, 50 mg/kg, iv, 15 days). Intra-arterial blood pressure signals were obtained for control and diabetic rats (N = 9, each group). Data were processed in a data acquisition system (CODAS, 1 kHz). Baroreflex sensitivity was evaluated by measuring heart rate changes induced by arterial pressure varíation produced by phenyiephrine and sodium nitroprusside injection. Increasing doses of potassium cyanide (KCN) were used to evaluate bradycardic and pressor responses evoked by chemoreflex activation. STZ induced hyperglycemia (447 ñ 49 vs 126 ñ 3 mg/dl), and a reduction in AP (99 + 3 vs 118 + 2mmHg), resting HR (296 ñ 11 vs 355 ñ 16 bpm) and plasma insulin levels (16 ñ 1 vs 57 + 11 muU/ml). We also observed that the reflex bradycardia (-1.68 ñ 0.1 vs -1.25 ñ 0.1 bpm/mmHg, in the diabetic group) and tachycardia (-3.68 ñ 0.5 vs -1.75 ñ 0.3 bpm/mmHg, in the diabetic group) produced by vasopressor and depressor agents were impaired in the diabetic group. Bradycardia evoked by chemoreflex activation was attenuated in diabetic rats (control: -l7 + 1,-86 + 19,-l85 ñ 18, -208 + 17 vs diabetic: -7 + 1,-23 ñ 5,-95 ñ 13, - 140 + 13 bpm), as also was the pressor response (control: 6 ñ 1,30 ñ 7,54 + 59 ñ 5 vs diabetic: 6 ñ 1,8 ñ 2,33 ñ 4,42 ñ 5 mmhg). In conclusion the cardiovascular responses evoked by baroreflex and chemoreflex activation are impaired in diabetic rats. The alterations of caradiovascular responses may be secondary to the autonomic dysfunction of cardiovascular control.

Streptozotocin alters pancreatic beta-cell responsiveness to glucose within six hours of injection into rats

A 24-hour glycaemic profile following streptozotocin (80 mg/kg. ip) injection was investigated in fasted rats. The most prominent changes in blood glucose were hyperglycaemia associated with low levels of plasma insulin after two hours followed by hypoglycaemia associated with high levels of plasma insulin after six hours; subsequently hyperglycaemia progressively developed and this was associated with decreasing levels of plasma insulin. Further probing revealed that at two hours after streptozotocin injection, the pancreatic ß-cells could not respond to an oral glucose load while, at six hours after, there was an apparent return of ß-cell responsiveness, but subsequently ß-cell responsiveness was progressively lost and histological examination revealed cellular damage. From these results, it is concluded that within six hours of injection, stretozotocin initiates pancreatic ß-cell damage which leads to the development of diabetes mellitus.

Glycemia and immunohistochemical changes in the endocrine pancreas of the turtle Chrysemys dorbigni treated with streptozotocin

The diabetogenic action of streptozotocin (SZ) was inbestigated in the turtle Chrysemys dorbigni after a 1-or 14-day fast. SZ (130 or 250 mg/Kg) was inected intravenously, and blood glucose and plasma insulin were measured. Pancreatic endocrine cells were stained immunohistochemically by the immunoperoxidase avidin-biotin-peroxidase complex method. Only 14% of the SZ-treated turtles showed hyperglycemia. Prolonged fasting did not increase the percentage of hyperglycemic animals. In control turtles, insulin (ß-, glucagon (alfa)-and somatostatin (delta)-immunoreactive cells were detected in increasing order of frequency. The qualitative changes seen in cells from the hyperglycemic SZ-treated turtles were more evident in ß and delta cells

Menor oxidación de cuerpos cetónicos por mitocondrias de corazón en la diabetes / Decreased oxidation of ketone bodies in heart mitochondrias in diabetes

Ratas diabéticas por inyección de estreptozotocina presentaron concentraciones de 3-hidroxibutirato y acetoacetato en sangre 4,2 y 1,7 veces superiores a las normales, respectivamente. Al mismo tiempo, en las mitocondrias de corazón disminuyó la actividad de las enzimas iniciadoras del metabolismo oxidativo de esos cuerpos cetónicos, a saber, la 3-hidroxibutirato deshidrogenasa (72%) y la succinil-CoA: acetoacetil-CoA (3 - oxoácido - CoA) transferasa (50%). En cambio, la acetoacetil-CoA tiolasa, no varió. La oxidación del 3-hidroxibutirato y el acetoacetato por las mitocondrias enteras de ratas diabéticas, suplementadas con ADP (en estado metabólico "3") disminuyó 42 y 48%, respectivamente, en relación a los testigos normales, no así la oxidación del piruvato o del L-glutamato más L-malato que no varió significativamente. Estas observaciones implican una modificación selectiva de las enzimas correspondientes a los cuerpos cetónicos. La composición lipídica y la depolarización de la fluorescencia del difenil hexatrieno en las mitocondrias diabéticas no presentaron diferencias respecto a las normales, de manera que las variaciones enzimáticas descriptas se pueden atribuir a una síntesis defectuosa de las proteínas mitocondriales

Age-reletad changes in the diabetic alterations of the hypohysis-thyroid-testicular axis in male rat

The effects of streptozotocin diabetes on the male reproductive tract were studied in young rats in different ages (25 to 60 days old). The data showed that diabetes caused atrophy of pituitary, testes and sexual accessory glands as well as testicular and pituitary functions, as evaluated by the circulating levels of LH and testosterone. In addition, an impairment of thyroidal function was detected since thyroxine serum levels were decreased. It is also seen that prolactin levels were reduced as a consequence of streptozotocin treated rats. Since younger animals were more drasticaly affected, we conclude that hypothyroidism that follows after the onset of diabetes could contribute to the picture on the basis of the importance of thyroidal function in the developing animal. Also it seems that reduction of prolactin levels due to hypothalamic TRH impairment would bring about a lack of the so important sinergistic action of this hormone and androgens in maintenance of androgen targetorgans.

Effect of STZ induced hyperglycemia on circulating insulin and glucagon

Streptozotocin [STZ] hyperglycemia was induced by subcutaneous injection of initial dose amounting to 27.5 mg/Kg, followed by four booster doses amounting to 11.25 mg/Kg administered weekly to the test rats. The diabetogenic effect of STZ over 45 days comprises three stages of hyperglycemia. During the first stage, STZ caused hypersecretion of glucagon followed by an increase of c-AMP. Secondly, using a higher dose of STZ, the hypersecretion of glucagon was followed by a well marked increase of the insulin level. The elevation of c-AMP persisted. Lastly, severe diabetes, coupled with very highly significant reduction in the level of insulin, was indicated at the end of the experimental period