In our previous study, we showed that ellagitannin- and procyanidin-rich tormentil extract (TE) decreased experimental arterial thrombosis in normoglycemic rats through platelet inhibition. TE also slightly increased coagulation and attenuated fibrinolysis; however, these effects did not nullify the antithrombotic effect of TE. The present study aimed to assess whether TE exerts antithrombotic activity in streptozotocin (STZ)-induced diabetes, which is characterized by pre-existing increased coagulation and impaired fibrinolysis, in vivo and ex vivo thrombosis assays. TE (100, 200, or 400 mg/kg, p. o.) was administered for 14 days to STZ-induced diabetic rats and mice. TE at 100 mg/kg dose decreased the thrombus area in the mice model of laser-induced thrombosis through its potent antiplatelet effect. However, TE at 200 mg/kg dose increased thrombus weight in electrically induced arterial thrombosis in rats. The prothrombotic effect could be due to increased coagulation and attenuated fibrinolysis. TE at 400 mg/kg dose also improved vascular functions, which was mainly reflected as an increase in the arterial blood flow, bleeding time prolongation, and thickening of the arterial wall. However, TE at 400 mg/kg dose did not exert antithrombotic effect. Summarizing, the present results show that TE may exert multidirectional effects on hemostasis in STZ-induced diabetic rats and mice. TE inhibited platelet activity and improved endothelial functions, but it also showed unfavorable effects by increasing the activity of the coagulation system and by inhibiting fibrinolysis. These contrasting effects could be the reason for model-specific influence of TE on the thrombotic process in STZ-induced diabetes.

Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of diabetes and a higher risk of metabolic alterations in the clinic. Furthermore, PRL stimulates β-cell proliferation, survival, and insulin production and pregnant mice lacking PRL receptors in β-cells develop gestational diabetes. To investigate the protective effect of endogenous PRL against diabetes outside pregnancy, we compared the number of cases and severity of streptozotocin (STZ)-induced hyperglycemia between C57BL/6 mice null for the PRL receptor gene (Prlr-/- ) and wild-type mice (Prlr+/+ ). STZ-treated diabetic Prlr-/- mice showed a higher number of cases and later recovery from hyperglycemia, exacerbated glucose levels, and glucose intolerance compared to the Prlr+/+ mice counterparts. Consistent with the worsening of hyperglycemia, pancreatic islet density, β-cell number, proliferation, and survival, as well as circulating insulin levels were reduced, whereas α-cell number and pancreatic inflammation were increased in the absence of PRL signaling. Deletion of the PRL receptor did not alter the metabolic parameters in vehicle-treated animals. We conclude that PRL protects whole body glucose homeostasis by reducing β-cell loss and pancreatic inflammation in STZ-induced diabetes. Medications elevating PRL circulating levels may prove to be beneficial in diabetes.

Autoimmune destruction of pancreatic beta cells is the characteristic feature of type 1 diabetes mellitus. Consequently, both short- and intermediate-acting insulin analogs are under development to compensate for the lack of endogenous insulin gene expression. Basal insulin is continuously released at low levels in response to hepatic glucose output, while post-prandial insulin is secreted in response to hyperglycemia following a meal. As an alternative to multiple daily injections of insulin, glucose-regulated insulin gene expression by gene therapy is under development to better endure postprandial glucose excursions. Controlled transcription and translation of proinsulin, presence of glucose-sensing machinery, prohormone convertase expression, and a regulated secretory pathway are the key features unique to pancreatic beta cells. To take advantage of these hallmarks, we generated a new lentiviral vector (LentiINS) with an insulin promoter driving expression of the proinsulin encoding cDNA to sustain pancreatic beta-cell-specific insulin gene expression. Intraperitoneal delivery of HIV-based LentiINS resulted in the lowering of fasting plasma glucose, improved glucose tolerance and prevented weight loss in streptozoticin (STZ)-induced diabetic Wistar rats. However, the combinatorial use of LentiINS and anti-inflammatory lentiviral vector (LentiVIP) gene therapy was required to increase serum insulin to a level sufficient to suppress non-fasting plasma glucose and diabetes-related inflammation.

OBJECTIVE: Heat preconditioning and heat-shock protein (HSP) synthesis have significant cytoprotective effects against the development of cellular injury caused by the application of a subsequent stressor, which were found to depend on the time period between the stressors. We aimed to determine the most efficient recovery time (6 h or 24 h) following heat-stress exposure and prior application of diabetic streptozotocin (STZ) on the moderation of carbohydrate and oxidative metabolic disturbances caused by diabetes.
METHODS: Experiment animals (Wistar rats) were exposed to acute heat stress at 41±1°C for 45 min, followed by 6-h or 24-h recovery times at room temperature before sacrifice or STZ administration.
RESULTS: Our findings indicate that acute heat stress with 6-h or 24-h recovery periods results in a significant rise in the hepatic heat-shock protein 70 (HSP70) levels (even more so after 24 h), glycogen breakdown and stable glycemia, followed by reduced glycolytic and gluconeogenic activity (after 24 h) (glucose-6-phosphatase, fructose-1,6-bisphosphatase); stimulates antioxidative activity (glutathione peroxidase, glutathione reductase) (after 6 h); and decreases glutathione and catalase activity (after 24 h). Heat preconditioning (with 6-h and 24-h recovery periods) prior to STZ-induced diabetes increases HSP70 levels and causes lower serum glucose levels, higher glycogen and glucose-6-phosphate levels, lower glucose-6-phosphatase levels and glycogen phosphorylase and hexokinase levels but also elevates glutathione reductase and glutathione peroxidase activity compared to untreated STZ animals.
CONCLUSIONS: Based on our findings, heat preconditioning and HSP70 induction in rats with type 1 diabetes attenuates STZ-induced metabolic alterations in hepatic carbohydrate metabolism and oxidative states. These changes are more evident at 24 h recovery post-acute heat stress, based on the most evident accumulation of HSP70 in this time frame.

Bifidobacterium longum (B. longum) could accumulate Selenium (Se) and nano-Se in the form of Se-B. longum and Nano-Se-B. longum, respectively. In this study, the effect of Nano-Se-B. longum in diabetic mice was evaluated. Physiological and metabolic parameters such as blood glucose, body weight, serum insulin level, intraperitoneal glucose tolerance test (IPGTT), food intake, water consumption and urine output were evaluated. The expression of insulin signalling pathway-related proteins was evaluated by western blotting. Haematoxylin and eosin (H&E) was used for histological examination of the liver, pancreas and kidney sections. Creatinine levels in serum (SCr) and blood urea nitrogen (BUN) were measured. Nano-Se-B. longum was the best in terms of delaying the onset of diabetes. Nano-Se-B. longum decreased blood glucose and body weight compared with those noted for the model group. IPGTT, food intake, water consumption and urine output significantly increased and serum insulin levels significantly decreased in the model group compared with those in all the Nano-Se-B. longum-treated mice. Histological results showed that the Nano-Se-B. longum-treated mice were better than the model group mice in terms of pathological changes. The expression of insulin signalling pathway-related proteins was upregulated in the Nano-Se-B. longum-treated groups. A significant increase in SCr and BUN levels was noted in the model group. This study for the first time reported the dose-dependent preventive effect of Nano-Se-B. longum on the onset of diabetes and renal damage. The mechanism may be related to changes in insulin signalling.

OBJECTIVE: Acetaldehyde dehydrogenase 2 (ALDH2) was reported for its protective properties on myocardial damage, stroke and neurodegeneration disease, but the effects and mechanisms of ALDH2 in the modulation of diabetic retinopathy remain unclear. The present study evaluated the protection effects of ALDH2 on streptozocin (STZ)-induced aged diabetic rats retinas damage.
METHODS: 24 aged male diabetic Sprague-Dawley (SD) rats induced by a single intraperitoneal injection of STZ were randomly divided into Alda1-treated group and dimethylsulfoxide (DMSO) group. Rats were intraperitoneally injected with 10 mg/kg ALDH2 activator Alda1 (or DMSO) 3 days before STZ injection and 30 days afterwards. A series of detections on retinal structural, functional and molecular levels were applied at 1 d, 7 d and 30 d after aged diabetic rats model established.
RESULTS: Optical coherence tomography (OCT) revealed that the thickness of outer nuclear layer (ONL) and whole retinas in Alda1-treated group were thicker than DMSO group. Full field electroretinograms (ffERG) showed a higher amplitude wave (dark-adaptation 3.0 and OPs) in Alda1-treated group. In addition, the levels of retinal tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) from Alda1-treated group were lower whereas superoxide dismutase (SOD) activity was notably higher. Moreover, the expressions of ALDH2, silence information regulation factor 2 related enzyme I (Sirt1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in Alda1-treated group retinas were significantly increased, while the expression of vascular endothelial growth factor (VEGF-α) was dramatically decreased.
CONCLUSIONS: ALDH2 could ameliorate early-stage STZ-induced aged diabetic rats retinas damage possibly via increasing Sirt1 and Nrf2 expression.

Myostatin (MSTN) is not only a key negative regulator of skeletal muscle secretion, however is also an endocrine factor that is transmitted to bone. To investigate the effect and possible mechanism of weight-bearing treadmill running on bone with poorly controlled Type 1 diabetes, rats were randomly divided into three groups: Normal control (NC), diabetic mellitus (DM) and diabetic exercise training groups (DM-WTR). The DM-WTR rats were trained with weight-bearing running. The results demonstrated that the levels of serum insulin, body weight, bone mass, muscle mass, grip strength, and serum calcium in the DM-WTR rats were significantly increased, whereas the levels of blood glucose, alkaline phosphatase, and tartrate-resistant acid phosphatase were markedly reduced in the DM-WTR rats compared with the DM rats. Weight-bearing running inhibited streptozocin (STZ)-induced MSTN mRNA and protein expression in the diabetic rats. The mRNA and protein expression levels of activin type IIB receptor and mothers against decapentaplegic homolog 2/3 and its phosphorylation in femur DM-WTR rats were reduced compared with DM rats. In addition, weight-bearing running enhanced the STZ-induced Wnt and β-catenin expression levels and reduced the STZ-induced glycogen synthase kinase (GSK)-3β expression in diabetic rats\' femora. In conclusion, the results suggested that weight-bearing running could partially ameliorate STZ-induced femur atrophy via MSTN downregulation, and this may be associated with the inactivation of Activin A Receptor Type 2B/Smad2/3 signaling pathways and the activation of the Wnt/GSK3β/β-catenin signaling pathway. Further studies are needed to verify these conclusions.

This study sought to investigate the possible protective role of Parkia biglobosa seed protein isolate (PBPi) against streptozotocin-induced hepatic damage and oxidative stress in diabetic male rats. Prior to animal experiments, a HPLC fingerprint of PBPi was recorded. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg body weight). Diabetic rats were orally treated daily with PBPi (200 or 400 mg/kg body weight) or insulin (5 U/kg, i.p.) for 28 days. The degree of protection was evaluated using biochemical parameters such as malondialdehyde (MDA) levels, serum transaminases (ALT and AST), total protein, total glutathione (Total GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and interleukin-6 (IL-6) activities. Histology of liver sections was also performed. The HPLC fingerprint of PBPi revealed eleven distinct peaks; PBPi at tested doses significantly attenuates STZ-induced elevated levels of serum IL-6, ALT and AST; and hepatic TBARS levels. Hepatic antioxidants (Total GSH, GST, SOD, CAT) as well as total protein were markedly restored in a dose-dependent manner. Histopathological results strongly support the protective role of PBPi. These results suggest PBPi could confer protection by ameliorating hepatic damage and oxidative stress caused by STZ in animal model possibly via its anti-inflammatory and antioxidant properties.

Parkia biglobosa seed an important household spice commonly consumed in Nigeria is believed to possess antioxidant activity that may exert modulatory effects in diabetes and diabetic complications. This study investigated the modulatory potential of Parkia biglobosa protein isolate (PBPi) on serum testosterone (sTT) level as well as its influence on biomarkers of oxidative stress in brain and testes of streptozotocin-induced diabetic male rats. Animals were made diabetic by single intraperitoneal administration of streptozotocin (STZ; 60 mg/kg body weight). PBPi (200 or 400 mg/kg body weight) was given orally by gavage or insulin (5 U/kg, i.p.) was administered daily to STZ-induced diabetic rats for 28 days. The results revealed a significant elevation in thiobarbituric acid reactive substances (TBARS) levels in the brain and testes of diabetic rats. This was closely associated with a concomitant reduction in levels of sTT and reduced testes weight, a noticeable decline in the glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) as well as total glutathione (Total GSH) level in the brain and testes of diabetic rats. Interestingly, treatment with PBPi efficiently prevented the alterations witnessed in the serum sTT and also ameliorated various alterations in the biomarkers of oxidative stress (TBARS, Total GSH, GST, SOD and CAT) in brain and testes of diabetic rats. These results provide evidence that PBPi could protect the brain and testicular tissues against oxidative stress induced by STZ, via modulation of serum testosterone concentration and also by enhancing antioxidant defence system in STZ-diabetic rats.

The cardiomyocytes are one of the major sources of hyperglycemia induced ROS generation. The present study focuses on the ameliorative role of ferulic acid in combating cardiac complications in diabetic rats. Induction of diabetes by STZ in male Wistar rats (at a dose of 50 mg kg-1 body wt, i.p.) reduced body weight and plasma insulin level, enhanced blood glucose, disturbed the intra-cellular antioxidant machineries and disintegrated the normal radiation pattern of cardiac muscle fibers. Induction of ER stress (up-regulation in the levels of CHOP, GRP78, eIF2α signaling, increased calpain-1 expression), caspase-3 activation, PARP cleavage and DNA fragmentation were evidenced from immunoblot analyses and DNA fragmentation assay. However, ferulic acid administration, (at a dose of 50 mg kg-1 body wt, orally for eight weeks) in post-hyperglycemia could reverse such adverse effects. Also, the molecule increased GLUT-4 translocation to the cardiac membrane by enhanced phosphorylation of PI3Kinase, AKT and inactivation of GSK-3β thereby altering the hyperglycemic condition in the cardiac tissue of diabetic rats. Therefore, as a potential therapeutic, ferulic acid, exhibiting antioxidant and hypoglycemic effects, may hold promise in circumventing stress mediated diabetic cardiomyopathy in rats.