[Effects of pravastatin in prevention of diabetes and mechanism thereof: experiment with non-obese diabetic mice].
ABSTRACT To explore the effects of pravastatin in prevention of diabetes and mechanisms thereof.
1183 to 4-week-old female non-obese diabetic (NOD) mice were randomly divided into 4 groups: control group (n = 30), fed with regular diet, low-dose pravastatin group (n = 29), fed with 1 mg kg(-1) d(-1) pravastatin via the diet, medium-dose pravastatin group (n =29) fed with 10 mg kg(-1) d(-1) pravastatin via the diet, and high-dose pravastatin group (n = 30), fed with 40 mg kg(-1) d(-1) pravastatin via the diet. The mice were followed up till they were 30-week old. Urine glucose was measured every week. Eight 12-week old mice without onset of DM from each group were killed with the pancreas taken out to undergo insulitis scoring via microscopy. Another 8 12-week old mice without onset of DM from each group were killed with their spleens taken out. Suspension of splenocytes was made, put into a 96-well plate, and stimulated by rGAD65; and [3SH]-thymidine was incorporated. The stimulation index (SI) of the splenocytes was calculated. Flow cytometry was used to observe the population of CD4 CD25+ regulatory T cells. ELISA was used to detect the interferon (IFN)-gamma and interleukin (IL)-4 levels in the supernatants of splenocytes. RT-PCR was used to detect the mRNA expression of IFN-gamma and IL4 in the spleen.
At 30 weeks of age, the incidence rate of DM onset of the high-dose pravastatin group was significantly lower than that of the control group (P = 0.003), and the incidence rates of DM onset of the medium and low dose groups were not significantly different from that of the control group (both P >0.05). The severity of insulitis at 12 weeks of age of the high-dose pravastatin group was significantly lower than that of the controls group (P <0.001). There were no significant difference in the SI level and in the percentage of CD4+ CD25+ regulatory T cells among the four groups (all P >0.05). The IFN-gamma level in the supernatant of splenocytes of the high-dose pravastatin group was (42 + 20) pg/ml, significantly lower than that of the control group [(157 + 32) pg/ml, P = 0.000]. The IFN-gamma mRNA expression level in the spleen of the high-dose pravastatin group was 0.24 +/- 0.10, significantly lower than that of the control group (0.81 +/- 0.18, P =0.000). The IL-4 level in the supernatants of splenocytes of the high-dose pravastatin group was S (91 +/- 22) pg/m, significantly higher than that of the control group [(44 +/- 20) pg/ml, P=0.000)]. The IL4 mRNA expression level in spleen of the high-dose pravastatin group was 0.39 +/- 0.18, significantly higher than that of the control group (0.20 +/- 0.08, P = 0.002). However, there were not significant differences in the IFN-gamma and IL-4 levels in the supernatant and the IFN-gamma and IL-4 mRNA expression in spleen among the medium dose, low dose, and control groups (all P >0.05).
High-dose pravastatin therapy at early time decreases the IFN-gamma level and increases the IL-4 level, shifts the immune response to the direction of Th2, and subsequently lessens insulitis and prevents DM.
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ABSTRACT: Recent evidence suggests that the lipid-lowering agent atorvastatin is also a potent immunomodulator. The aim of this study was to investigate the possible effect of atorvastatin on the decline of residual beta cell function in recent-onset type 1 diabetes. The randomised placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and islet autoantibodies (mean age 30 years, 40% females), in 12 centres in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. An intent-to-treat analysis was performed. Fasting and stimulated C-peptide levels were not significantly different between groups at 18 months. However, median fasting serum C-peptide levels dropped from baseline to 12 and 18 months in the placebo group (from 0. 34 to 0.23 and 0.20 nmol/l, p<0.001) versus a nonsignificant decline in the atorvastatin group (from 0.34 to 0.27 and 0.30 nmol/l, ns). Median stimulated C-peptide concentrations declined between baseline and 12 months (placebo from 0.89 to 0.71 nmol/l, atorvastatin from 0.88 to 0.73 nmol/l, p<0.01 each) followed by a major loss by month 18 in the placebo group (to 0.48 nmol/l, p = 0.047) but not in the atorvastatin group (to 0.71 nmol/l, ns). Median levels of total cholesterol and C-reactive protein decreased in the atorvastatin group only (p<0.001 and p = 0.04). Metabolic control was similar between groups. Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study. ClinicalTrials.gov NCT00974740.PLoS ONE 01/2011; 6(3):e17554. · 3.73 Impact Factor
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ABSTRACT: A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin. The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin. Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators. ClinicalTrials.gov NCT00974740.PLoS ONE 01/2012; 7(3):e33108. · 3.73 Impact Factor