Pressure pain precedes development of type 2 disease in Zucker rat model of diabetes

Decreased hind limb pressure pain threshold (PPT) is an early indicator of insulinopenia and neuropathy developing in STZ-rat models of type 1 diabetes and pre-diabetes. To test if pain on pressure is also a hallmark of compensated insulin resistance and type 2 diabetes in this work we measured PPT of Zucker lean (ZL), Zucker fatty (ZF) and Zucker fatty diabetic rats (ZDF; 8 animals per group). Using clinically accepted cut-off values for diagnosis of human diabetes and pre-diabetes, at 6th week of age (the study entry), all animals maintained random blood glucose within a normal range (< 7.9 mM). Over the following 4 weeks, the random glucose remained normal in lean and ZF rats; it however crossed 11 mM cut-off for the diagnosis of diabetes in all ZDF rats. With no detectable relation to blood glucose levels or changes throughout the study, lean, ZF and ZDF rats maintained respectively highest, intermediate and lowest PPT levels (83+/-1, 70+/-1 and 59+/-1 g; mean values for all tests per group). Thus in Zucker rat model, type 2 diabetes-associated impairment of nerve function precedes the development of hyperglycemia. Furthermore, since normoglycemic, but displaying decreased PPT, ZF rats were strongly hyperinsulinemic (plasma insulin concentration 30+/-4 ng/ml vs. 2.4+/-0.3 ng/ml in lean rats) these data suggest that hyperinsulinemia compensating for glucose metabolism might not restore compromised nerve function.     

A high-sucrose diet induces fatty liver, but not deterioration of diabetes mellitus in Zucker diabetic fatty rats

A high-sucrose diet induces insulin resistance and dyslipidemia in normal rats. The purpose of the present study was to investigate effects of a high-sucrose diet to glycolipid metabolism in Zucker Diabetic Fatty (ZDF) rat. Male ZDF rats were fed with a high-sucrose (68%) diet from 6 to 18 weeks of age. In biochemical analyses, the glucose levels did not change as compared with those in standard diet-fed rats, but the total cholesterol levels were elevated during the experimental period. In pathological analyses, the relative liver weight increased by about 2-fold as compared with that in standard diet-fed rats, and severe fatty change was observed by high-sucrose feeding. A high-sucrose diet induces fatty liver, but not deterioration of diabetes mellitus in ZDF rats. High sucrose-fed rats are considered to be very useful to determine the relationship between hepatic insulin resistance and diabetes mellitus.     

Preserved LTP and water maze learning in hyperglycaemic-hyperinsulinemic ZDF rats

Previous investigations have demonstrated that cognitive deficits as well as hippocampal dysfunctions are generated in animals presenting manifestations of Type 1 diabetes (T1D) mellitus. The present study examined whether such deficits can also be reproduced in the Zucker Diabetic Fatty (ZDF) rats after they developed symptoms of Type 2 diabetes (T2D). Learning and memory assessments were performed using the Morris water maze 5 weeks after the animals presented symptoms of Type 1 diabetes for Experiment 1 (Exp 1) and after 8 weeks for Experiment 2 (Exp 2). Testing in the water maze revealed that ZDF rats learned the task normally, although control rats were found to swim significantly faster after 5 or 8 weeks of untreated diabetes. From an electrophysiological perspective, we observed that the integrity of synaptic function was also preserved in ZDF rats as no alterations in long-term potentiation (LTP) were observed in the area CA1 of hippocampal slices. It is concluded that hyperglycaemia is not the only factor influencing water maze learning and LTP in this animal model of Type 2 diabetes (T2D). The experiments suggest that the resistance of ZDF rats to cognitive and electrophysiological dysfunctions might be related to the protective action of hyperinsulinemia. Indeed, measurements of the plasma insulin level at the end of testing were significantly superior in ZDF rats in comparison to control rats.     

Assessment of erythrocyte morphology in patients with type 2 diabetes mellitus: a pilot study of electron microscopy-based analysis in relation to healthy controls

Background/aim The present study aimed to assess erythrocyte morphology in newly diagnosed type 2 diabetes mellitus patients using scanning electron microscopy.Materials and methods In total, 30 patients admitted to endocrine outpatient clinics were included in the study. The patients were divided into two groups according to their fasting blood glucose levels: type 2 diabetes mellitus (n = 15, fasting blood glucose levels ≥ 126 mg/dL) and control (n = 15, fasting blood glucose levels < 99 mg/dL). The patient’s demographic characteristics, haemoglobin A1c levels, and scanning electron microscopy findings regarding erythrocyte morphology were recorded.ResultsThere was no significant difference between the control and type 2 diabetes mellitus group in terms of the participants’ age (51.13 ± 8.53 vs. 50.33 ± 8.72 years, p = 0.8) and the male/female ratio (9/6 vs. 9/6). In the control group, discocytes were abundant, echinocytes were rare, and spherocytes were absent. On the other hand, discocytes were less common and echinocyte-shaped erythrocytes were more common in the type 2 diabetes mellitus group than in the control group. In addition, spherocytes were detected in the type 2 diabetes mellitus group. Moreover, the diameter of discocytes was significantly lower (p = 0.014), and blood glucose and haemoglobin A1c levels were significantly higher (p < 0.05 for both) in the type 2 diabetes mellitus group than in the control group. ConclusionOur findings indicate that high glucose levels in type 2 diabetes mellitus patients lead to significant alterations in erythrocyte morphology, including decreased erythrocyte deformability and the formation of echinocytes and spherocytes due to eryptosis. The possibility of decreased erythrocyte deformability due to excessive eryptosis may disturb microcirculation in newly diagnosed, treatment-naïve type 2 diabetes mellitus patients who do not have any complications.     

Mechanisms of hyperkalemia associated with hyporeninemic hypoaldosteronism in streptozotocin-induced diabetic rats.

This study was aimed at investigating the mechanisms of clinically important overt hyperkalemia in diabetes mellitus with underlying hyporeninemic hypoaldosteronism known as a classic model of the syndrome of hyporeninemic hypoaldosteronism (SHH). Rats (Sprague-Dawley, male) were streptozotocin-treated (60 mg/kg, ip) and used after 60 days. Rats with plasma glucose levels higher than 300 mg/dL (mean +/- SEM, 423 +/- 20 mg/dL, n = 8) were selected as the diabetic group. Age-matched normal rats served as control (mean plasma glucose, 88 +/- 2, mg/dL, n = 8). Serum potassium concentrations and osmolalities as well as serum creatinine levels were significantly higher in the diabetic than in the control group (5.07 +/- 0.09 vs. 4.68 +/- 0.11 mEq/L; 330 +/- 14 vs 290 +/- 3 mOsm/L; 0.40 +/- 0.03 vs 0.31 +/- 0.02 mg/dL, p < 0.05). Plasma renin activity (PRA) in the diabetic group was significantly lower than that in the control group (6.0 +/- 1.0 vs 12.1 +/- 1.1 ng Al/ml/h, p < 0.001). Plasma aldosterone concentration (PAC) was also significantly lower in the former than in the latter (368 +/- 30 vs 761 +/- 57 pg/ml, p < 0.001). Renomegaly, abnormal distal tubular cells with few organelles, and increased lipid droplets with pyknotic nucleus in zona glomerulosa of the adrenal glands were noted in the diabetic group. In conclusion, multifactorial causes including insulinopenia, hyperosmolality, elevated serum creatinine level and hypoaldosteronism with possible contribution of altered distal tubular response to aldosterone may have interacted to develop hyperkalemia in these diabetic rats.     

Down-Regulation of Renal Gluconeogenesis in Type II Diabetic Rats Following Roux-en-Y Gastric Bypass Surgery: A Potential Mechanism in Hypoglycemic Effect

ObjectiveThis study was initiated to evaluate the effects of Roux-en-Y gastric bypass surgery on renal gluconeogenesis in type 2 diabetic rats and its relationship with hormonal parameters.MethodsDiabetic rats were induced by intraperitoneal injection of streptozotocin (STZ; 35 mg/kg) combined with a high-fat diet. They were then randomly divided into three groups: diabetes model group (DM group, n = 8), sham Roux-en-Y gastric bypass group (SRYGB group, n = 8), and Roux-en-Y gastric bypass group (RYGB group, n = 14). Another 8 normal rats comprised the normal control group (NC group, n = 8). Body weight, glucose, serum lipid, insulin, glucagon-like peptide-1 (GLP-1), leptin, and adiponectin were measured pre- and postoperatively. Glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor-α (IR-α), insulin receptor-β (IR-β), and glycogen synthase kinase 3 beta (Gsk3b) were measured in renal cortex by using RT-PCR and Western immune-blot analyses on the 4th week after operation.ResultsFollowing RYGB surgery, surgery-treated rats showed significantly improved oral glucose tolerance, dyslipidemia and insulin resistance as well as increased post-gavage insulin levels and serum circulating levels of GLP-1 and adiponectin. RT-PCR and Western immune-blot analyses showed PEPCK and G6Pase protein and mRNA to be significantly decreased in the renal cortex in the RYGB group (p < 0.05 vs. DM or SRYGB group); in addition, IR-α and Gsk3b phosphorylation levels increased in the RYGB group (p < 0.05 vs. DM or SRYGB group).ConclusionDown-regulation of renal gluconeogenic enzymes might be a potential mechanism in hypoglycemia. An improved insulin signal pathway in the renal cortex and increased circulating adiponectin concentrations may contribute to the decline of renal gluconeogenesis following RYGB surgery.Key Words: Type 2 diabetes mellitus, Gluconeogenesis, Gastric bypass surgery, Insulin, Adiponectin     

2型糖尿病大鼠心室肌细胞离子通道功能和表达变化

目的:探讨2型糖尿病大鼠心室肌细胞离子通道电流及其相关蛋白表达的改变。方法:采用Zucker糖尿病肥胖(Zucker diabetic fatty,ZDF)大鼠建立2型糖尿病大鼠模型,Zucker瘦型(Zucker lean,ZL)大鼠为对照组。采用急性酶解法分离大鼠单个心室肌细胞,采用全细胞膜片钳技术记录其动作电位、L型钙通道电流(I_Ca-L)及瞬时外向钾电流(I_to)的变化;提取大鼠心肌组织蛋白,采用Western blot检测心肌细胞肥大标志物β-肌球蛋白重链(β-myosin heavy chain,β-MHC)和心房钠尿肽(atrial natriuretic peptide,ANP),以及L型钙通道(Cav1.2)和钾通道(Kv4.3)的蛋白表达水平。结果:用高脂饮食诱导ZDF大鼠成功建立2型糖尿病模型;与ZL大鼠相比,ZDF大鼠心室肌细胞的动作电位时程显著延长,I_Ca-L和I_to密度显著降低[峰值分别为(?5.96±0.37)pA/pF vs(?4.92±0.30)pA/pF,(12.43±0.86)pA/pF vs(7.48±0.58)pA/pF,均P<0.05];与ZL大鼠相比,ZDF大鼠心肌组织中β-MHC和ANP的表达水平明显增加,伴有Cav1.2和Kv4.3蛋白表达下降(P<0.05)。结论:与ZL大鼠相比,2型糖尿病大鼠心肌细胞肥大,心室肌细胞动作电位时程延长,I_Ca-L和I_to密度及其相关蛋白表达水平降低,提示糖尿病大鼠心室肌细胞发生电生理重构。     

Stereological assessment of pancreatic beta-cell mass development in male Zucker Diabetic Fatty (ZDF) rats: correlation with pancreatic beta-cell function

The present study was initiated to improve our understanding of pancreatic beta‐cell dynamics in male Zucker Diabetic Fatty (ZDF) rats and hence provide a framework for future diabetes studies in this animal model. Male ZDF rats from 6, 8, 10, 12, 14, 16, 20 and 26 weeks of age were subjected to an oral glucose tolerance test (OGTT). The animals were then euthanized and pancreases were removed for morphometric analyses of pancreatic beta‐cell mass. As evident by a marked fourfold increase in insulin secretion, insulin resistance developed rapidly from 6 to 8 weeks of age. Simultaneously, the pancreatic beta‐cell mass expanded from 6.17 ± 0.41 mg at 6 weeks of age, reaching a maximum of 16.5 ± 2.5 mg at 16 weeks of age, at which time pancreatic beta‐cell mass gradually declined. The corresponding changes in glucose/insulin homeostasis were analysed using a standard insulin sensitivity index (ISI), an area under the curve (AUC) glucose‐insulin index, or simple semi‐fasted glucose levels. The study demonstrated that male ZDF rats underwent rapid changes in pancreatic beta‐cell mass from the onset of insulin resistance to frank diabetes coupled directly to marked alterations in glucose/insulin homeostasis. The study underscores the need for a critical co‐examination of glucose homeostatic parameters in studies investigating the effects of novel anti‐diabetic compounds on pancreatic beta‐cell mass in the male ZDF rat. A simple assessment of fasting glucose levels coupled with information about age can provide a correct indication of the actual pancreatic beta‐cell mass and the physiological state of the animal.     

Association of a F479L variant in the cytosolic phospholipase A2 gene (PLA2G4A) with decreased glucose turnover and oxidation rates in Pima Indians

Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids. AA and AA metabolites play key roles in glucose disposal and insulin secretion. PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus. We have screened the PLA2G4A gene and identified a C-->G variant, which predicts a phenylalanine to leucine substitution. In logistic regression analyses adjusted for age, sex, ethnicity, and birth year, we found a trend toward association between this SNP and diabetes [OR=1.53 (0.97-2.40); p=0.06]. Individuals with the variant genotype had lower mean basal endogenous glucose output (1.8+/-0.03 vs. 1.9+/-0.01 mg/kgEMBS/min; p=0.04) and lower mean basal glucose oxidation (1.2+/-0.11 vs. 1.4+/-0.03 mg/kgEMBS/min; p=0.005) compared to individuals with the wild-type genotype. During a low dose insulin infusion, non-diabetic individuals with the variant genotype had a lower mean glucose oxidation (1.9+/-0.11 vs. 2.0+/-0.03 mg/kgEMBS/min; p=0.04) and total glucose turnover rate (2.5+/-0.22 vs. 2.6+/-0.06 mg/kgEMBS/min; p=0.01) compared to subjects with the wild-type genotype. In addition, under basal conditions, individuals with the variant genotype had a higher mean lipid oxidation rate compared to individuals with the wild-type genotype (0.77+/-0.25 vs. 0.67+/-0.23 mg/kgEMBS/min; p=0.02). These results provide evidence supporting a role for the eicosanoid biosynthesis pathway in type 2 diabetes mellitus pathophysiology.     

脐带间充质干细胞移植治疗大鼠糖尿病

背景：脐血间充质干细胞具有很强的增殖能力和分化能力,在趋向分化作用下可以分化成胰岛β细胞,进而起到治疗糖尿病的作用。 目的：观察移植脐带间充质干细胞对大鼠糖尿病的治疗效果。 方法：30只雄性SD大鼠中随机取6只作为对照组,注射生理盐水;其中24只按45 mg/kg的剂量注射链脲霉素建立糖尿病模型后,随机等分为移植组和糖尿病组,移植组大鼠尾静脉注射移植脐带间充质干细胞。 结果与结论：造模后30 d,糖尿病组大鼠空腹血糖维持在较高水平,且高于对照组(P < 0.05)。造模后,与糖尿病组相比,移植组大鼠空腹血糖水平显著下降(P < 0.05),体质量显著增加(P < 0.01),45 d时移植组大鼠空腹血糖水平与体质量接近对照组水平(P > 0.05),而糖尿病组大鼠空腹血糖维持较高水平,且体质量持续下降。提示脐带间充质干细胞移植能有效治疗大鼠糖尿病。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

T cell reactivity to human insulinoma cell line (CM) antigens in patients with type 1 diabetes.

Autoimmune (type 1) diabetes mellitus results from a progressive destruction of insulin secreting beta cells operated by T lymphocytes in pancreatic islets. Circulating autoreactive T cells to specific beta cell antigens are detected in patients with type 1 diabetes. To date, several beta cell autoantigens have been identified in this disease (GAD, IA-2, 38kD secretory protein, insulin, ICA69 etc.), however, it is possible that also other unidentified self molecules contribute to trigger beta cell autoimmunity. In this study we used the human insulinoma cell line CM as source of beta cell antigens to detect reactive T lymphocytes in patients with type 1 diabetes mellitus. This cell line has been previously shown to express a number of recognized beta cell antigens. Since the expression of several beta cell antigens is affected by glucose stimulation we tested two preparations of CM cells cultured under different conditions containing low (0.8 mM) and high glucose concentration (11 mM). T cell proliferation was measured using cells from 32 patients with type 1 diabetes (19 of recent onset and 13 at 3 to 22 months from diagnosis) and 27 age-matched control subjects. A significant increase in T cell proliferation to CM cells grown in high glucose conditions (11 mM) (p < 0.05) was found in type 1 diabetic patients compared to controls. No significant differences were observed when using CM cells cultured at the low glucose concentration. Furthermore, the response to both extracts of CM cells was independent of disease duration (p = 0.6 for both CM cells cultured at 0.8 and 11 mM glucose). These data indicate that T cell reactivity to homogenates of CM cells is detectable in patients with type 1 diabetes and suggest that this human insulinoma cell line is an interesting potential source of beta cell material for immunological studies of autoimmune diabetes.     

Effect of aerobic training on diabetic nephropathy in a rat model of type 2 diabetes mellitus

The effect of aerobic exercise intervention on the renal functional and ultrastructural changes associated with diabetes mellitus were studied in the obese Zucker rat, a rat model of type 2 diabetes. The obese Zucker rats began training at 18 wk of age (n=8) and were compared to obese sedentary controls (n=12) and lean sedentary nondiseased littermates (n=10). Body weight, kidney weight, serum creatinine, urine creatinine, creatinine clearance, urine IgG, urine IgG/creatinine ratio, urine total protein, urine albumin, urine albumin/creatinine ratio, glycated hemoglobin, serum fructosamine, fasting serum glucose, serum insulin, serum total cholesterol, serum triglycerides, blood pressure, and morphometric analyses of cortical glomeruli by light microscopy and electron microscopy were performed to evaluate renal function, structure, and metabolic control. The exercise training consisted of treadmill running, 5 da/wk for 1 hr/da. Exercise intervention lowered the body weight (p <0.05), reduced the percentage of glycated hemoglobin (p <0.05), and diminished the urine albumin concentration (p <0.05), compared to the obese sedentary controls. Exercise intervention did not significantly affect morphometric indices of renal ultrastructure. This study shows that aerobic exercise intervention significantly improved metabolic control and reduced albuminuria in a rat model of type 2 diabetes.     

Directionality index of neural information flow as a measure of synaptic plasticity in chronic unpredictable stress rats

Type 2 diabetes and chronic heavy alcohol consumption each have been known to be associated with the impairment of hippocampus-dependent cognitive functions. Although both conditions often coexist clinically and there is accumulated evidence of a relationship between the two, the combined effect on hippocampal long-term potentiation (LTP) has not yet been investigated. We compared the effect of type 2 diabetes itself with that of type 2 diabetes with chronic heavy alcohol consumption on the hippocampal LTP using Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, which resembles the characteristics of human type 2 diabetes. Ten of 16-week-old male OLETF rats were randomized into two treatment groups according to weight: the OLETF-Alcohol (O-A, n=5) and the OLETF-Control (O-C, n=5). The rats in the O-A group were fed Lieber-DeCarli Regular EtOH over a 10-week period and the amount of alcohol consumption was 8.42±2.52g/kg/day. To ensure the effect of poor glycemic control on LTP, intraperitoneal glucose tolerance test was performed after a 10-week treatment. The hippocampal LTP was measured by extracellular field excitatory post-synaptic potentials at Shaffer collateral (SC) synapses in the CA1 region. Although the O-A group showed significantly lower fasting and postprandial glucose (P<0.01 and P=0.02, respectively), the hippocampal LTP was more significantly attenuated in the O-A group than the O-C group (P=0.032). The results of this study suggested that chronic heavy alcohol consumption could potentiate the impairment of hippocampal LTP in individuals with impaired glucose tolerance or early type 2 diabetes, even though it did not aggravate, but did improve glycemic control. Clinical attention to chronic heavy drinking will be required in preventing cognitive impairment in individuals with type 2 diabetes.     

Corticosterone disrupts glucose-, but not lactate-supported hippocampal PS-LTP

We previously reported that acute exposure of rat hippocampal brain slices to stress levels of corticosterone aggravated ischemic neuronal damage. The present study examined whether or not an acute stress level corticosterone exposure interferes with expression of rat hippocampal CA1 population spike long-term potentiation (PS-LTP) in slices supplemented either with glucose or lactate. Exposure of glucose-supplemented (5mM) slices to corticosterone (1microM) for 90min significantly diminished their ability to generate and maintain PS-LTP compared to equicaloric lactate-supplemented (10mM) slices (p<0.05). Moreover, this diminished expression of LTP in glucose-supplemented slices was ameliorated by either treatment with RU38486 (5microM), a potent corticosterone receptor antagonist or with10mM glucose. These results suggest that lactate may serve as an effective alternate energy substrate during exposure to elevated levels of corticosterone, allowing maintenance of glucocorticoid-sensitive neuronal functions such as synaptic potentiation during metabolically critical periods when glucose utilization is compromised.     

丝胶对2型糖尿病大鼠海马蛋白激酶B信号转导通路的作用

目的探讨丝胶(彩色蚕茧经浸泡、水煎、浓缩获得)对2型糖尿病大鼠海马蛋白激酶B(Akt)信号转导通路的作用。方法 36只雄性SD大鼠随机分为3组(n=12):正常对照组、糖尿病模型组和丝胶治疗组。小剂量链脲佐菌素(25mg/kg)连续腹腔注射(1次/d,3d)建立2型糖尿病大鼠模型。丝胶治疗组大鼠给予丝胶灌胃[2.4g/(kg·d),35d]。TUNEL法检测海马CA1区神经元凋亡,Western blotting法和RT-PCR法检测海马Akt信号转导通路相关因子Akt、核转录因子kappa B(NF-κB)和前凋亡因子Bad蛋白和mRNA的表达。结果与正常对照组比较,糖尿病模型大鼠海马CA1区神经元的凋亡指数明显升高(P0.01);海马Akt、NF-κB的表达明显降低,Bad的表达明显升高(P0.01)。与糖尿病模型组比较,丝胶治疗组大鼠海马CA1区神经元的凋亡指数明显降低(P0.05);海马Akt、NF-κB的表达明显升高,Bad的表达明显降低(P0.01,P0.05)。结论丝胶可通过调节糖尿病模型大鼠海马Akt信号通路的异常变化减少海马神经元凋亡,对糖尿病海马损伤具有一定的拮抗作用。     

Prevalence of islet cell antibodies and its correlation with glucose and insulin response to oral glucose tolerance test in 1st degree relatives of insulin dependent diabetes mellitus probands

93 first degree relatives (1st DR) of insulin dependent diabetes mellitus (IDDM) patients were investigated for detection of islet cell antibodies (ICA) and beta cell functional status. ICA were detected in 26.9% Ist DR subjects (25/93), equally in parents, siblings and offspring. Normal (n = 16), impaired (n = 5) and diabetic (n = 4), glucose curves were seen in 1st DR. Low insulin levels were observed in parents and siblings with normal glucose tolerance test (N-GTT) at 90 min (p < 0.05), and (p < 0.0005) relatives with impaired glucose tolerance and diabetes. Insulin release to glucose (IRG-insulinogenic index) in control group was 352 +/- 42 mu U/mg. From the group of 25 ICA positive cases, 4 had mean IRG of 394 +/- 70 mu U/mg (group A) comparable to control, and had N-GTT; 12 had mean IRG of 107 +/- 15.9 mu U/mg (group B) significantly low (P < 0.005) compared to controls and group A and 9 showed IRG of 75 +/- 29.3 mu U/mg, lower than group B (NS) with abnormal response to glucose load. Loss of insulin secretory ability thus can precede hyperglycemia by years. The ICA positive relatives were grouped based on the immunological status with their probands. ICA status in probands does not give an idea about ICA status in their relatives. This indepth study leads to understand the correlation of genetic, metabolic and immunological parameters for early detection of IDDM in first degree relatives.     

Atorvastatin improves peritoneal sclerosis induced by hypertonic PD solution in rats

BACKGROUND: Peritoneal sclerosis is a complication of peritoneal dialysis and results in ultrafiltration failure. It is related to chronic peritoneal injury due to dialysis solution content and recurrent peritonitis. Statins have anti-inflammatory properties which may be of value in modulating responses to injury. We evaluated the capacity of atorvastatin to modify peritoneal alterations secondary to hypertonic glucose. METHODS: Thirty-two non-uremic rats were divided into three groups: group I (Sham) rats received no treatment (n=11), group II received hypertonic (3.86%, 10 ml/day) PD solution (n=10) and group III received hypertonic PD solution (10 ml/day) plus 80 mg/L atorvastatin in drinking water (n=11). After four weeks, a one-hour peritoneal equilibration test (PET) was performed with 3.86% PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D 1 /D 0 glucose), ultrafiltration volume (UF), dialysate protein, TGF-beta 1 and VEGF levels were determined. RESULTS: Administration of atorvastatin resulted in preserved UF (4.9+/-0.8 vs 7.5+/-0.6 mL, p <0.01), protein loss (2.2+/-0.2 vs 2.1+/-0.1 g/L, p >0.05), and peritoneal thickness (53+/-3 vs 26+/-4 microm, p <0.01). D 1 /D 0 glucose was significantly reduced in the dextrose group (0.70+/-0.02 vs 0.56+/-0.04, p <0.01). Both higher levels of TGF-ss 1 (206+/-40 vs 474+/-120 pg/mL, p<0.05), and VEGF in dialysate effluent (4+/-0.4 vs 7.9+/-3 pg/mL, p>0.05), was determined in the dextrose group. CONCLUSION: Exposure to hypertonic glucose solution resulted in alterations in peritoneal transport manifested by a rapid dissipation of the glucose gradient and resultant impaired UF response. Administration of atorvastatin led to prevention of these alterations. We suggest that the anti-inflammatory properties of statins are useful in providing protection of the peritoneal membrane from the effects of hypertonic glucose.     

2型糖尿病患者红细胞免疫功能与血糖、胰岛素水平的相关性探讨

目的 :探讨了 2型糖尿病患者红细胞免疫功能的变化及其与血糖和胰岛素的相关性。方法 :应用免疫法测定 5 2例 2型糖尿病患者红细胞免疫功能 ,酶法测定血糖 ,放免法测定胰岛素含量并与 35名正常人作对照。结果 :2型糖尿病患者RBC -C3bRR水平明显降低 (p <0 0 1)与血糖和胰岛素水平呈负相关 (r=-0 32 5 1、- 0 3312 ,p<0 0 5 ) ,RBC -ICRRR水平明显高于正常人 (p <0 0 1) ,与血糖和胰岛素水平呈正相关 (r=0 35 12、0 346 4 ,p <0 0 5 )。结论 :2型糖尿病患者存在有红细胞免疫调节的紊乱 ,其免疫功能的低下与血糖和胰岛素升高有相关性。     

Effects of diabetes duration and glycemic control on free radicals in children with type 1 diabetes mellitus

Parameters of lipid peroxidation, protein oxidation, and antioxidant defense systems were measured in blood samples from 47 children with type 1 diabetes mellitus and from 51 healthy controls, matched for age and sex. In the diabetic children, chemiluminescent assay of plasma superoxide anion gave photoemission (counts x 10(3), mean +/- SD) of 674 +/- 412, which were significantly higher than those in the controls (452 +/- 185; p <0.05). Plasma vitamin A levels in the diabetic children (243 +/- 90 microg/dl) were also higher than those in the controls (207 +/- 59 microg/dl, p <0.05). In a subgroup of 24 diabetic children with blood HbA1C levels >or=8.5%, plasma lipoperoxide (LPO) and vitamin E levels were higher (p <0.05) than those in 23 diabetic children with blood HbA1C levels <8.5%. In a subgroup of 26 children with diabetes duration >or=5 yr, plasma LPO levels were higher (p <0.05) than those in 21 children with diabetes duration <5 yr. These findings confirm the presence of oxidant stress in children with type 1 diabetes mellitus and demonstrate that certain indices of oxidant stress are influenced by the duration of diabetes and by the efficacy of glycemic control. These observations suggest that supportive therapy aimed at oxidative stress may help to prevent clinical complications in children with type 1 diabetes mellitus.     

Progressive decrease of proinsulin secretion in sulphonylurea-treated type 2 diabetes

Progressive deterioration of beta-cell function is proposed as a disease-related factor of sulphonylurea (SU) failure in type 2 diabetes. If it gradually worsens over time then disease duration may mirror the progressive beta-cell deterioration. The aim of the present study is to assess whether or not disease duration is influential in remodelling the secretion pattern of insulin-like molecules and in glucose control of SU-treated type 2 diabetes. A research model is used to investigate proinsulin secreting capacity over time, using two groups of patients: i) disease duration <5 years (n=62), comprising SU responders (SUr; n=48) and SU failures (SUf; n=14); and ii) disease duration > or = 5 years (n= 37), comprising an SUr group (n=17) and an SUf group (n=20). Blood samples are taken at 0 h, 0.5 h 1 h, 2 h and 3 h during a standard oral glucose tolerance test and measured for glucose, total proinsulin (TPI), intact proinsulin (IPI) and specific insulin (SI) concentrations. Pairwise comparison of estimated marginal means of blood glucose, SI, IPI and TPI levels at each time point are carried out between groups and subgroups. (SUr vs. SUf). Homa insulin resistance index (IR index) is applied to analyse IR between the groups. It was found that patients with shorter disease duration had higher proinsulin (TPI and IPI) levels at all time points (P<0.05), together with a lower glucose level at 2 h and 3 h (P<0.05). Homa insulin index analysis showed no difference between the two groups (P=0.26). Results also showed that the SUr group had a significantly lower glucose level at Oh and 3h (P<0.05), although no significant difference in insulin and proinsulin levels was found between the SUr and SUf groups. In conclusion, proinsulin may play an important role in glucose control in SU-treated type 2 diabetes, but the effect is reduced in SUf patients.