Abstract. A number of patients with hyperlipidemia are prescribed 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that are concomitantly used along with the treatment of diabetes mellitus. The effects of atorvastatin and pravastatin on insulin-induced glucose uptake and the related signal transduction in 3T3L1 adipocytes were studied. 3T3L1 fibroblasts were differentiated into adipocytes, pretreated with atorvastatin or pravastatin, and then exposed to insulin. Glucose uptake and the amount of insulin signal proteins were measured. Atorvastatin significantly decreased insulin-stimulated 2-deoxyglucose uptake in 3T3L1 adipocytes associated with the prevention of translocation of GLUT4 into the plasma membrane. The amounts of Rab4 and RhoA that required lipid modification with farnesyl or geranylgeranyl pyrophosphate, in the membrane fraction were decreased by atorvastatin. Insulin-induced tyrosine phosphorylation of IRS-1 and serine / threonine phosphorylation of Akt were reduced by atorvastatin. Pravastatin did not modify these insulin-induced changes in the signal transduction. Inhibitors of the RhoA / Rho kinase system, C3 and Y27632, as well as atorvastatin reduced insulin-induced changes in signal transduction. Atorvastatin and pravastatin did not affect messenger RNA expression, protein level, and tyrosine phosphorylation of insulin receptors. In conclusion, hydrophobic atorvastatin decreases the glucose uptake by 3T3L1 adipocytes since it can enter the cell and prevents lipid modification of some proteins that are involved in the insulin signal transduction process.
It is well known that diabetes mellitus is one of the risk factors for atherosclerosis and cardiovascular diseases. 1,2)The majority of patients with hypercholesterolemia and hyperlipidemia are associated with diabetes mellitus. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for such patients. Diabetic patients treated with simvastatin and atorvastatin have safety characteristics similar to non-diabetic patients.3) Both statins also improve insulin resistance in non-insulin dependent diabetic patients in association with lowering plasma triglyceride concentration.4) Cerivastatin improves insulin secretion and increases insulin-mediated glucose uptake in the early state of obese type 2 diabetes. 5) A post hoc analysis in the West of Scotland Coronary Prevention Study database provided evidence for the protective treatment effect of pravastatin on the development of diabetes. 6) On the other hand, lovastatin disrupts early events in insulin signaling. 7) Simvastatin also suppresses glucose-induced insulin release from the rat islet b-cells.8) These findings in vitro suggest dysfunction of insulin secretion with statins. Whether statin treatment is beneficial for patients with diabetes still remains to be clarified. In our preliminary experiments, streptozotocin at a regular dose (50 mg/kg)-induced diabetic rats and spontaneously diabetic model rats such as Goto-Kakizaki rats 9) did not show any influence of statins on their glucose metabolism. In such diabetic model rats, the diabetes induced may be too severe to detect influence of a drug on the diabetic state.The aim of the present study was to examine the influence of atorvastatin and pravastatin on glucose tolerance in the diabetic model animals. For this purpose, rats were made more mildly diabetic by decreasing the dose of streptozotocin. MATERIALS AND METHODS This investigation conforms to the Guiding Principles for the Care and Use of Experimental Animals in Hokkaido College of Pharmacy (published in 2001).Diabetic Animal Model Male Sprague-Dawley rats 8-weeks-old weighing 180-200 g were fasted for 20 h before inducing diabetes with streptozotocin. Under sodium pentobarbital (30 mg/kg, i.p.) anesthesia, animals were injected with saline (non-diabetic) or streptozotocin (diabetic) into the left femoral vein. Streptozotocin was dissolved in saline solution pre-cooled on ice just before each injection.10) The volume injected was fixed at 0.2 ml/100 g body weight. After the injection, all animals were housed and allowed access to food and water ad libitum.Experimental Protocol To determine the dose of streptozotocin inducing mild diabetes, 50, 32, or 24 mg/kg streptozotocin was injected. A week later, an oral glucose tolerance test (OGTT) was performed by oral administration of 0.5 g/ml glucose solution at 1 ml/100 g body weight (5 g/kg).In the experiments with statins, diabetic rats induced by 24 mg/kg streptozotocin were used. Oral administration of 0.5% CMC solution, 8 mg/kg pravastatin, or 8 mg/kg atorvastati...
ABSTRACT. Canine coronavirus (CCoV) has been reported to cause acute diarrhea mainly in young pups. CCoV and feline coronavirus are classified as group 1 coronaviruses. However, it has recently been reported in the United Kingdom that the group 2 coronavirus gene, which is more closely related to the bovine coronavirus (BCoV) and human coronavirus strain OC43, has been detected in respiratory tract tissue samples from dogs with respiratory disease. In this study, we examined the prevalence of antibodies to group 2 coronaviruses in domestic dogs and cats in Japan by a neutralization test using BCoV. All 104 feline serum samples were negative (<1:5) for antiBCoV antibodies. In contrast, of the 898 canine serum samples, 160 (17.8%) were positive for anti-BCoV antibodies, and the antibody titers ranged from 1:5 to more than 1:640, with 1:160 being the most frequent. No correlation was found between the titers of the antiBCoV and anti-CCoV antibodies in the 198 serum samples of dogs with a known history of CCoV vaccination. We amplified, by RT-PCR, group 2 coronavirus-specific hemagglutination/esterase genes in the oral swabs of a total of 10 young pups presenting with or having recovered from respiratory signs, or having anti-BCoV antibodies, with the result that 2 pups were positive for the hemagglutination/ esterase genes. These results strongly suggest that an unknown group 2 coronavirus as well as the known enteritis-causing CCoV (group 1 coronavirus) is prevalent among domestic dogs in Japan. KEY WORDS: bovine coronavirus, canine coronavirus, group 2 coronavirus, respiratory disease.
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