Diabetes mellitus affects activity of calcium/calmodulin-dependent protein kinase II alpha in rat trigeminal ganglia

The activity of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. The aim of this study was to investigate the immunoreactivity of phosphorylated CaMKIIα (pCaMKIIα) in subpopulations of trigeminal ganglion (TG) neurons in rat models of early diabetes type 1 (dm1) and 2 (dm2). DM1 model was induced with intraperitoneally (i.p.) injected streptozotocin (STZ) (55 mg/kg). DM2 rats were fed with the high fat diet (HFD) for 2 weeks and then received 35 mg/kg of STZ i.p. Two weeks and 2 months after the STZ-diabetes induction, rats were sacrificed and immunohistochemical analysis for detection of pCaMKIIα immunoreactivity and double immunofluorescence labelling with isolectin (IB4) was performed. Increased intensity of pCaMKIIα immunofluorescence, restricted to IB4-negative small-diameter neurons, was seen in TG neurons two months after STZ-DM1 induction. DM1 model, as well as the obesity (control dm2 groups) resulted in neuronal impaired growth while dm2 model led to neuron hypertrophy in TG. Observed changes may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. In future, innovative strategies for modulation of CaMKIIα activity in specific subpopulations of neurons could be a novel approach in therapy of diabetic trigeminal neuropathy.     

Reduced epidermal thickness,nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies.     

Metallothionein 2a gene expression is increased in subcutaneous adipose tissue of type 2 diabetic patients

Study backgroundInsulin resistance plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine the Mt2a gene expression levels in adipose tissues from diabetic patients and the effect of Mt treatment on adipocyte insulin sensitivity.MethodsSamples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10 ng/ml, 72 h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein.ResultsWe found that the Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to that of lean (p = 0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p = 3 × 10^? 4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p = 8 × 10^? 4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein.ConclusionsThese data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes.     

Streptozotocin-induced type 1 and 2 diabetes in rodents: a model for studying diabetic cardiac autonomic neuropathy

BackgroundSeveral animal models are continually being developed to study diabetic complication. Several conflicting regimen for diabetes induction exist in the literature with varying dose strength and regimen for different study interest in diabetes. This study aims to show the effect of high dose streptozotocin (STZ) on the one hand compared with multiple low doses after high fat diet induction on diabetic cardiac autonomic neuropathy (DCAN).MethodologyEighty-four Wistar rats were used to demonstrate DCAN induction using 2 approaches one for T1DM (STZ 50mg/kg) and the other for T2DM (HFD for 8 weeks with STZ 25mg/Kg daily for five days). DCAN features were assessed using invasive biomarkers, histology patterns and cardiac nerve densities.ResultsDiabetes induction rate was 76% and 89% in T1DM and T2DM model respectively. T1DM group had significant weight loss, reduced c-peptide, and insulin level post induction. The T2DM additionally showed significantly higher total cholesterol and Homeostatic model assessment (HOMA) compared with control. Serum levels of catecholamine, choactase, nerve growth factor and cardiac nerve density confirms development of DCAN.ConclusionHigh single dose of STZ and HFD with multiple low doses of STZ may be recommended for DCAN study in T1DM and T2DM rat model respectively.     

Synaptic degradation of cardiac autonomic nerves in streptozotocin-induced diabetic rats

Background: Cardiac autonomic neuropathy (CAN) is a common complication in type I diabetes mellitus (DM). Nevertheless, the relationship between functional and structural disturbances of cardiac autonomic nerves remains unclear. Methods and results: To clarify this relationship, we studied heart rate variability (HRV) and ultrastructural changes of cardiac autonomic nerves in streptozotocin (STZ)-induced DM in rats. STZ was injected (65 mg/kg intravenous) into the tail vein of male Wistar rats to destroy β cells in the pancreatic islets. After STZ injection, fasting blood sugar (FBS) increased from baseline values of 75 ± 3 mg/dl up to 328 ± 12 mg/dl within 1 week and it reached up to 353 ± 24 mg/dl within 17 weeks. HR in these rats was decreased within 20 days and low HR was maintained for the observation period. TP and HF power started decreasing 20 days after STZ injection, and this decrease progressed throughout the observation period. The L/H power ratio was decreased 80 days after STZ. Electron microscopic findings indicated a depletion of neurotransmitter vesicles and degradation of parasympathetic nerve endings but not of sympathetic ones in the SA node region of the heart in the early stages of DM. In the late stages of DM, the same region showed degradation of both sympathetic and parasympathetic nerve endings. Conclusion: Synaptic degradation in parasympathetic nerves immediately after the onset of DM, and in sympathetic nerves much later in the development of DM is consistent with functional derangements in cardiac autonomic nerve activities assessed by HRV analysis.     

Baseline diabetic knowledge after 5-day teaching program is an independent predictor of subclinical macroangiopathy in patients with type 1 diabetes (Poznan Prospective Study)

PurposeThe cardiovascular diseases (CVD) are the leading cause of mortality in type 1 diabetes (DM1). Carotid intima-media thickness (IMT) has been approved as a marker of subclinical atherosclerosis. The aim of this prospective study was to evaluate the relationship between baseline diabetic knowledge after five-day teaching program and IMT in patients with (DM1) treated with intensive functional insulin therapy (IFIT) from the onset of the disease.Material/methodsThe analysis included 79 subjects aged 23.4 ± 5.1 years with newly diagnosed DM1, participating in Poznan Prospective Study (PoProStu). The patients attended a five-day structured training program in IFIT at diagnosis, followed by a test consisting of 20 questions. After follow-up period of 11 years we evaluated the presence of microangiopathy and subclinical macroangiopathy. IMT of the right common carotid artery was determined using high resolution ultrasonography and calculated automatically with the Carotid Analyzer for Research program.ResultsAfter 11-year follow-up median intima-media thickness was 560 (IQR: 520–630) μm. We found a negative correlation between diabetes knowledge at baseline and IMT at the end of follow-up (r = −0.27, p = 0.017). In multivariate linear regression model baseline diabetic knowledge test result was associated with IMT at follow-up, independently from sex, age, smoking status, presence of hypertension and diabetic kidney disease (all at follow-up) and from mean follow-up LDL-cholesterol concentrations and HbA_1c results (β = −8, 95% CI −16, −1, p = 0.037).ConclusionsBaseline diabetic knowledge after 5-day teaching program is an independent predictor of subclinical macroangiopathy in patients with DM1.     

Chitosan-based dressings loaded with neurotensin—an efficient strategy to improve early diabetic wound healing

One important complication of diabetes mellitus is chronic, non-healing diabetic foot ulcers (DFUs). This study aims to develop and use dressings based on chitosan derivatives for the sustained delivery of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator in wound healing. Three different derivatives, namely N-carboxymethyl chitosan, 5-methyl pyrrolidinone chitosan (MPC) and N-succinyl chitosan, are presented as potential biomaterials for wound healing applications. Our results show that MPC has the best fluid handling capacity and delivery profile, also being non-toxic to Raw 264.7 and HaCaT cells. NT-loaded and non-loaded MPC dressings were applied to control/diabetic wounds to evaluate their in vitro/in vivo performance. The results show that the former induced more rapid healing (50% wound area reduction) in the early phases of wound healing in diabetic mice. A NT-loaded MPC foam also reduced expression of the inflammatory cytokine TNF-α (P < 0.001) and decreased the amount of inflammatory infiltrate on day 3. On day 10 MMP-9 was reduced in diabetic skin (P < 0.001), significantly increasing fibroblast migration and collagen (COL1A1, COL1A2 and COL3A1) expression and deposition. These results suggest that MPC-based dressings may work as an effective support for sustained NT release to reduce DFUs.     

Relationships between the functional PPARalpha Leu162Val polymorphism and obesity, type 2 diabetes, dyslipidaemia, and related quantitative traits in studies of 5799 middle-aged white people

Peroxisome proliferator-activated receptor-α (PPARα) is a nuclear receptor capable of regulating the expression of genes involved in peroxisomal and mitochondrial β-oxidation pathways. The common Leu162Val polymorphism in the gene encoding PPARα has inconsistently shown association with quantitative traits related to obesity, type 2 diabetes, and dyslipidaemia. We genotyped the Leu162Val polymorphism in 1383 patients with type 2 diabetes and 4401 control subjects with normal glucose tolerance (NGT) without showing any association between diabetes and genotype. In addition, the Leu162Val polymorphism was not associated with WHO-defined obesity or dyslipidaemia in case-control settings involving 961 obese and 2563 lean subjects and 1399 dyslipidaemic and 4399 normolipidaemic subjects, respectively. Quantitative trait studies of metabolic variables were carried out in 5799 middle-aged, treatment-naïve subjects showing a difference in fasting serum triglyceride concentrations among homozygous Val-carriers (Leu/Leu + Leu/Val, n = 5782, 1.33 ± 1.35 mmol/l vs. Val/Val, n = 17, 2.22 ± 2.4 mmol/l, p = 0.007). Similarly, Val/Val was associated with increased fasting serum total cholesterol concentrations (p = 0.01). In conclusion, in a relative large-scale study of middle-aged whites we found no evidence of association between the PPARα Leu162Val polymorphism and obesity or type 2 diabetes. If replicated, the Val162Val variant may, however, confer an increase in fasting levels of serum lipids.     

A therapeutic approach to treat cardiovascular dysfunction of diabetes

Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10^?5 M) and relaxation responses to acetylcholine (10^?9–10^?4 M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt_max and dp/dt_min were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.     

Association between type 1 diabetes and periodontal health

PurposeWe assessed periodontal status in patients with type 1 diabetes and healthy individuals in relation to their glycemic control, smoking and inflammatory biomarkers.Material/methodsPeriodontal status was examined in 107 patients with diabetes and 40 controls, using Oral Hygiene Index (OHI), Community Periodontal Index (CPI) and tooth number. CPI values of 0–2 and 3–4 were classified as non-periodontitis and periodontitis, respectively. Blood samples were analyzed for glucose, HbA1c, CRP, fibrinogen, interleukin-1 and tumor necrosis factor-alpha (TNF-α).ResultsPeriodontitis was found in 15.0% of the controls and 57.9% of diabetic patients, including 40.0% of these with good metabolic control (GMC) and 59.5% of those with poor metabolic control (PMC). Severe periodontitis was more frequent in the PMC than in the GMC group and in the controls (26.0% vs. 20.0% vs. 5.0%). The PMC patients had lower number of sextants with CPI 0 and higher number of sextants with CPI 3 and CPI 4 as well as lower tooth number in comparison with the controls. The patients with periodontitis had higher TNF-α (p < 0.001) and OHI (p < 0.001) than the patients without periodontitis. The number of sextants with CPI 0 correlated negatively with fibrinogen and TNF-α levels, whereas the number of sextants with CPI 3 correlated positively with TNF-α and fasting glucose level.ConclusionsThere is good evidence that type 1 diabetes increases the risk of periodontal disease. Our results suggest that poor metabolic control of diabetes together with smoking and inadequate oral hygiene increase the risk of severe periodontal destruction in patients with type 1 diabetes.     

Protective effects of epigallocatechin gallate (EGCG) on streptozotocin-induced diabetic nephropathy in mice

There is increasing evidence suggesting that antioxidants in green tea extracts may protect kidneys on the progression of end-stage renal disease. We investigated the protective impacts of (−)-epigallocatechin 3-O-gallate (EGCG) against streptozotocin (STZ)-induced diabetic nephropathy in mice. The mice were divided into 5 groups (n = 10 per group): control (saline, i.p.), STZ (200 mg/kg, i.p.), EGCG50 (50 mg/kg, S.Q.), EGCG100 (100 mg/kg, S.Q.), and EGCG200 (200 mg/kg, S.Q.). Animals were sacrificed at scheduled times after EGCG administration and then quantitative and qualitative analysis were performed. Compared with the control group, the STZ group showed an increase in levels of blood glucose, blood urea nitrogen, creatinine and urine protein amounts with a decrease in body weight. All the above parameters were significantly reversed with EGCG treatment, especially in the EGCG100 group. After STZ injection, there was a mesangial proliferation with increased renal osteopontin accumulation and its protein expression in the glomeruli and the proximal tubules. Mice kidneys after EGCG-treatment showed a reduced expression of above parameters and relatively improved histopathological findings. These results indicated that EGCG 100 mg/kg might provide an effective protection against STZ-induced diabetic nephropathy in mice by osteopontin suppression.     

Regulation of cardiac oxidative stress and lipid peroxidation in streptozotocin-induced diabetic rats treated with aqueous extract of Pimpinella tirupatiensis tuberous root

Plants with antidiabetic activities provide important source for the development of new drugs in the management of diabetes mellitus. The main aim of this study was to evaluate the protective effect of aqueous extract (AE) of Pimpinella tirupatiensis (Pt) tuberous root on cardiac oxidative stress and lipid peroxidation (LPO) in non-diabetic and streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in male Wistar rats by a single administration of STZ (40 mg/kg intraperitoneal (i.p). AE (750 mg/kg/b.w./day) and glibenclamide (GLB) (20 mg/kg/b.w./day) were administrated orally by intra oral gastric tube for 30 days. After 4 weeks of hyperglycaemia the enzymatic and non-enzymatic factors were measured in cardiac tissue of diabetic and control groups. Xanthine oxidase activity (XOD), Uric acid (UA) and malondialdehyde (MDA) content were significantly (p < 0.01) elevated by 48, 48 and 50% respectively and the contents of glutathione (GSH), ascorbic acid (AA) were significantly (p < 0.01) diminished by 45 and 42% respectively in diabetic rats when compared to normal. Treatment with AE and GLB normalized the content of UA, GSH, AA, MDA and the activity of XOD. No significant changes were observed in control rats treated with AE. This data suggests that hyperglycemia induces oxidative stress in the heart, but the oxidative stress defense mechanisms in the heart tissue are fairly efficacious against oxidative injury by the treatment with AE and GLB. The present study reveals that AE may provide a useful therapeutic option in the reversal of oxidative stress induced cardiac dysfunction in diabetes mellitus.     

Hypoglycemic and hypolipidemic effect and antioxidant activity of chronic epigallocatechin-gallate in streptozotocin-diabetic rats

Background and objective: Green tea catechins including epigallocatechin-3-gallate (EGCG) could exert beneficial health effects to ameliorate metabolic diseases. The effect of chronic administration of EGCG was evaluated on serum glucose and lipid profile and hepatic lipid peroxidation in streptozotocin (STZ)-diabetic rats. Materials and methods: Rats received EGCG 25 mg/kg/day for 8 weeks 1 week after diabetes induction. Serum glucose, triglyceride, total cholesterol, HDL- and LDL-cholesterol levels and MDA level and SOD activity in hepatic tissue were spectrophotometrically measured. Results: Treatment of diabetic rats with EGCG produced a hypoglycemic effect and there were appropriate changes regarding serum lipids in treated diabetic group. Meanwhile, EGCG treatment attenuated the increased MDA content and reduced activity of SOD in liver. Conclusion: Chronic treatment of diabetic rats with EGCG could prevent abnormal changes in blood glucose and lipid profile and attenuat hepatic lipid peroxidation.     

A preliminary study of the use of human adipose tissue-derived stem cells for the treatment of streptozotocin-induced diabetes mellitus in a rat model

The purpose of this study is to determine if intraventricular injection of human adipose tissue-derived stem cells (hADSC) are effective in treating streptozotocin (STZ)-induced diabetes mellitus (DM) in nude rats. Twenty-two adult, male nude rats (strain Crl:NIH-Fox1^RNU) were used to induce diabetes using streptozotocin. A single, 150 mg/kg STZ was injected intraperitoneally. Severity of the induced diabetic state was assessed by daily monitoring of body weight, clinical signs, and blood glucose levels. C-peptide was assessed before ADSC injection (T0) and at 3, 5, and 21 days after ADSC injection. Eight rats (40%) developed DM within 24 h after STZ injection. Of the eight rats that developed DM, five were given 2 million freshly prepared ADSC intraventricularly under echocardiography guidance 10 days after STZ injection and three were only given sterile saline for comparison. Surviving rats were humanly sacrificed 21 days after ADSC injection. The average weight of diabetic rats decreased significantly after STZ injection. ADSC injection had no effect on the body weight of rats. Non-fasting serum glucose levels increased significantly in both groups. In diabetic rats, C-peptide decreased significantly before ADSC injection and seemed to return to normal 21 days after ADSC administration. Results of this preliminary study might suggest a beneficial effect of using hADSC for the treatment of STZ-induced diabetes in adult nude rats.     

Epidermal nerve fiber quantification in the assessment of diabetic neuropathy

Assessment of cutaneous innervation in skin biopsies is emerging as a valuable means of both diagnosing and staging diabetic neuropathy. Immunolabeling, using antibodies to neuronal proteins such as protein gene product 9.5, allows for the visualization and quantification of intraepidermal nerve fibers. Multiple studies have shown reductions in intraepidermal nerve fiber density in skin biopsies from patients with both type 1 and type 2 diabetes. More recent studies have focused on correlating these changes with other measures of diabetic neuropathy. A loss of epidermal innervation similar to that observed in diabetic patients has been observed in rodent models of both type 1 and type 2 diabetes and several therapeutics have been reported to prevent reductions in intraepidermal nerve fiber density in these models. This review discusses the current literature describing diabetes-induced changes in cutaneous innervation in both human and animal models of diabetic neuropathy.     

Neuroprotective effect of preadministration with Ganoderma lucidum spore on rat hippocampus

The aim of this study was to investigate if preadministration with Ganoderma lucidum spore (GLS) could (1) alleviate oxidative stress and mitochondrial dysfunction in rat hippocampus of intracerebroventricular (ICV) injection of streptozotocin (STZ), (2) protect neurons from apoptosis, and (3) improve cognitive dysfunction. Three groups of Sprague–Dawley rats were preadministrated with GLS at doses of 2.0, 4.0 and 8.0 g/kg, respectively, for 3 weeks before the ICV STZ injury. Thereafter the rats were operated with ICV STZ (1.5 mg/kg) bilaterally on days 1 and 3. The behavioral alterations, oxidative stress indexes, ATP, cytochrome oxidase (CytOx), and histopathology of hippocampal neurons were studied. The results showed that ICV STZ model rats exhibited a significant increase of malondialdehyde (MDA), a significant decrease of glutathione reductase (GR), reduced glutathione (GSH), ATP and CytOx, accompanied with marked impairments in spatial learning and memory, and severe damage of hippocampal neuron. In conclusion, preadministration with GLS at dose of 8.0 g/kg in ICV STZ rats significantly reversed these abnormalities. In conclusion, preadministration with GLS might protect hippocampus from oxidative impairment and energy metabolism disturbance of ICV STZ. This may also provide useful information for future research on the pathogenesis and prevention of Alzheimer's disease (AD).     

The absence of longitudinal data limits the accuracy of high-throughput clinical phenotyping for identifying type 2 diabetes mellitus subjects

PurposeTo evaluate the impact of insufficient longitudinal data on the accuracy of a high-throughput clinical phenotyping (HTCP) algorithm for identifying (1) patients with type 2 diabetes mellitus (T2DM) and (2) patients with no diabetes.MethodsRetrospective study conducted at Mayo Clinic in Rochester, Minnesota. Eligible subjects were Olmsted County residents with ≥1 Mayo Clinic encounter in each of three time periods: (1) 2007, (2) from 1997 through 2006, and (3) before 1997 (N = 54,283). Diabetes relevant electronic medical record (EMR) data about diagnoses, laboratories, and medications were used. We employed the HTCP algorithm to categorize individuals as T2DM cases and non-diabetes controls. Considering the full 11 years (1997–2007) as the gold standard, we compared gold-standard categorizations with those using data for 10 subsequent intervals, ranging from 1998–2007 (10-year data) to 2007 (1-year data). Positive predictive values (PPVs) and false-negative rates (FNRs) were calculated. McNemar tests were used to determine whether categorizations using shorter time periods differed from the gold standard. Statistical significance was defined as P < 0.05.ResultsWe identified 2770 T2DM cases and 21,005 controls when the algorithm was applied using 11-year data. Using 2007 data alone, PPVs and FNRs, respectively, were 70% and 25% for case identification and 59% and 67% for control identification. All time frames differed significantly from the gold standard, except for the 10-year period.ConclusionsThe accuracy of the algorithm reduced remarkably as data were limited to shorter observation periods. This impact should be considered carefully when designing/executing HTCP algorithms.     

葡萄籽原花青素通过Nrf2调节糖尿病大鼠肾组织GSTM的表达

目的: 研究葡萄籽原花青素(GSP)对糖尿病大鼠肾保护作用的分子生物学机制,为GSP治疗糖尿病肾病提供实验依据。方法: 雄性Wistar大鼠尾静脉注射0.1%链脲佐菌素(STZ)建立糖尿病大鼠模型,成模后随机分为糖尿病组(DM组)和糖尿病GSP治疗组(GSP组,GSP 250 mg·kg^-1·d^-1),另设正常对照组(C组)。观察24周后测量大鼠体重、收缩压、肾重/体重和24 h尿蛋白定量;采血测定空腹血糖(FPG)、尿素氮(BUN)、肌酐(SCr)和糖基化血红蛋白(HbA1c);观察糖尿病大鼠肾脏病理改变,并应用Western blotting和免疫组化法测定肾组织谷胱甘肽S-转移酶μ亚型(GSTM)和核因子E2相关因子2(Nrf2)的表达。结果: 实验开始时3组大鼠体重无明显差异(P>0.05),24周时DM组大鼠较C组大鼠体重显著下降(P<0.01),治疗后GSP组大鼠体重较DM组增加,但无显著差异(P>0.05)。第24周时DM组大鼠与C组相比较,收缩压、FPG、HbA1c、肾重/体重、24 h尿蛋白定量、BUN和SCr水平显著升高(P<0.01)。治疗后GSP组大鼠与DM组比较FPG和HbA1c水平降低,但无显著差异(P>0.05),收缩压、24 h尿蛋白定量和肾重/体重显著降低,(P<0.01),BUN和SCr水平显著降低(P<0.05)。GSP组肾组织病理改变较DM组改善。GSTM和Nrf2表达在DM组表达较C组上调,在GSP组治疗后回调(P<0.05)。结论: GSP可能通过Nrf2下调GSTM表达而起肾保护作用。