诺沙坦改善非胰岛素依赖型糖尿病大鼠胰岛素敏感性的作用机制

本文研究血管紧张素Ⅱ受体拮抗剂诺沙坦对非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus,NIDDM)大鼠胰岛素敏感性的改善作用,并探讨其作用机制。从饮水中给予正常或高脂喂养加小剂量链脲佐菌素(STZ)诱发的NIDDM大鼠诺沙坦(4 mg/kg),连续6周。分离骨骼肌,用免疫印迹法检测诺沙坦对胰岛素受体底物1(insulin receptor substrate 1,IRS-1)、蛋白激酶B(protein kinase B,PKB)和葡萄糖转运因子4(glucose transporter 4,GLUT4)的表达,以及IRS-1的磷酸化、IRS-1与磷脂酰肌醇3激酶(phosphatidylinositol(PI)3-kinase)的结合。口服葡萄糖耐量试验表明,口服诺沙坦可改善糖尿病大鼠胰岛素敏感性。在骨骼肌组织,NIDDM和正常大鼠的IRS-1、PKB和GLUT4蛋白表达无差异,且不受诺沙坦处理的影响。NIDDM大鼠胰岛素刺激后的骨骼肌IRS-1酪氨酸磷酸化水平、PI 3-kinase结合IRS-1的活性和PKB活性较对照组显著降低(P<0.01),且不能被诺沙坦改善。诺沙坦显著增加NIDDM大鼠肌细胞质膜(plasma membrane,PM)和T管(T-tubules,TT)胰岛素诱导的GLUT4的 含量(P<0.05)。与该结果一致的是,诺沙坦处理的NIDDM大鼠血糖水平较未处理NIDDM大鼠下降(P<0.05)。结果表明,诺沙坦可改善胰岛素抵抗状态,主要是通过非PI 3-kinase依赖的     

Coagulation inhibitors and glycaemic control in non-insulin-dependent diabetes mellitus

The relationship between long-term glycaemic control and the activity of coagulation inhibitors was investigated in 60 non-insulin-dependent diabetes mellitus (NIDDM) patients not on insulin therapy. Overall, the activities of antithrombin III (AT III) (median 96%, range 65–133%), protein C (127%, 24–190%) and protein S (130%, 54–163%) were not reduced. Patients in poor long-term glycaemic control as verified by increased glycated haemoglobin (HbA1c) demonstrated significantly decreased median AT III activity in comparison with patients in good glycaemic control (92% vs 101%,P=0.016). However, individual values for AT III activity were not below the critical limit of 60%. An inverse correlation between AT III activity and long-term glycaemic control (HbA1c) was calculated (r=–0.378,P=0.0029). As AT III concentrations were found to be normal, we propose that non-enzymatic glycation leads to reduced activity of AT III without affecting its concentration.     

Effect of long-term treatment with vanadate in drinking water on KK mice with genetic non-insulin-dependent diabetes mellitus

The glucose-lowering effect of vanadate, ammonium metavanadate (AMV), on diabetic KK mice was examined. Five-week-old male KK mice were administrated with a solution of AMV via drinking water at concentrations of vanadium (V) with 0.1, 1.0, 10 and 100 μg/mL for a period of 10 wk, respectively. Body weight, consumption of food and water, and blood glucose levels was measured every week for 10 wk. The results showed that food consumption and body weight in the experimental groups were similar to those in the control group. A statistically significant decrease of drinking water consumption and blood glucose levels in the group treated with 100 μg V/mL was observed. The glucose tolerance in the vanadate-treated mice with 10 and 100 μg V/mL was remarkably improved compared with the control group. Biochemical analyses at the end of experiments demonstrated that a distinct tendency for the glucose and hemoglobin A1c (HbA1c) levels to decrease with vanadate treatment in the blood was also observed. The glutamic pyruvic transaminase, glutamic oxaloacetate transaminase, blood urea nitrogen, triglyceride, high-density lipoprotein, and total cholesterol levels in plasma were lower in the higher vanadium groups than those in the control group. These results indicate that vanadium effectively produced the glucose-lowering effect at a higher dose than that at a low dose of vanadium in drinking water, without any overt signs of toxicity.     

Neurodegenerative changes in the hippocampus within the early period of experimental diabetes mellitus

We studied the dynamics of modifications of the structure and architectonics in different zones of the pyramidal layer of the rat hippocampus within the early periods (3, 7, and 14 days) after induction of diabetes mellitus by streptozotocin. Using confocal immunofluorescence microscopy, we found neurons containing a specific protein, NeuN; a fluorescence dye, Hoechst 33258, allowed us to visualize the cell nuclei. The density of localization of neurons in the CA2 area decreased significantly on the 3rd day of development of diabetes. In the CA1 and CA3 areas, a significant decrease in this index was observed beginning from the 7th day. Within this time interval, we observed neurons with clear condensation of chromatin in the nuclei of these cells. The obtained data indicate that formation of appreciable neurodegenerative changes in the hippocampus occurs within the initial stages of development of experimental diabetes mellitus; this phenomenon can be a factor in the development of diabetic encephalopathy. Neirofiziologiya/Neurophysiology, Vol. 40, No. 1, pp. 30–37, January–February, 2008.     

Streptozotocin-induced alterations in the levels of functional mitochondrial anion transport proteins

The effect of streptozotocin-induced diabetes on the levels of functional mitochondrial anion transport proteins has been determined. The experimental approach utilized for these studies consisted of the extraction of each of four mitochondrial anion transport proteins from rat liver mitoplasts (isolated from diabetic and control animals) with the nonionic detergent Triton X-114, followed by the functional reconstitution of each transporter in a liposomal system via the freeze-thaw-sonication technique. This approach permitted the quantification of transporter function without the complications that occur when such measurements are carried out with intact mitochondria (or mitoplasts). We found that experimental diabetes caused an increase in the extractable and reconstitutable specific (and total) transport activities of the pyruvate and dicarboxylate transporters, a decrease in the activity of the citrate transporter, and no significant change in the activity of the phosphate transporter relative to control values. An examination of the time course of the appearance of changes in the reconstitutable activities of the pyruvate and citrate transporters following the injection of streptozotocin revealed differences. Thus, whereas the activity of the pyruvate transporter displayed the most pronounced increase (193%) 1 week following streptozotocin injection and then subsequently declined from this peak and plateaued at later times (99% and 96% increases at 3 and 8 weeks, respectively), the activity of the citrate transporter progressively decreased with time (31-51% decreases at 1-8 weeks). We suggest that the observed diabetes-induced changes in mitochondrial anion transporter function are predictable on the basis of diabetes-induced alterations in the activities of enzymes that constitute metabolic pathways to which these transporters either supply substrate or remove product. Furthermore, we speculate that mitochondrial anion transport proteins may be regulated in coordination with the enzymes of such associated metabolic pathways.     

A shared comparison of diabetes mellitus and neurodegenerative disorders

Diabetes mellitus (DM), one of the most prevalent metabolic diseases in the world population, is associated with a number of comorbid conditions including obesity, pancreatic endocrine changes, and renal and cardio-cerebrovascular alterations, coupled with peripheral neuropathy and neurodegenerative disease, some of these disorders are bundled into metabolic syndrome. Type 1 DM (T1DM) is an autoimmune disease that destroys the insulin-secreting islet cells. Type 2 DM (T2DM) is diabetes that is associated with an imbalance in the glucagon/insulin homeostasis that leads to the formation of amyloid deposits in the brain, pancreatic islet cells, and possibly in the kidney glomerulus. There are several layers of molecular pathologic alterations that contribute to the DM metabolic pathophysiology and its associated neuropathic manifestations. In this review, we describe the general signature metabolic features of DM and the cross-talk with neurodegeneration. We will assess the underlying molecular key players associated with DM-induced neuropathic disorders that are associated with both T1DM and T2DM. In this context, we will highlight the role of tau and amyloid protein deposits in the brain as well in the pancreatic islet cells, and possibly in the kidney glomerulus. Furthermore, we will discuss the central role of mitochondria, oxidative stress, and the unfolded protein response in mediating the DM-associated neuropathic degeneration. This study will elucidate the relationship between DM and neurodegeneration which may account for the evolution of other neurodegenerative diseases, particularly Alzheimer's disease and Parkinson's disease as discussed later.     

Significance of platelet-activating factor acetylhydrolase in patients with non-insulin-dependent (type 2) diabetes mellitus

Background : Non-insulin dependent diabetes mellitus (NIDDM) represents an independent risk factor for cardiovascular diseases (CVD), being characterized by a continnous low-grade inflammation and endothelial activation state. Plasma platelet - activating factor - acetylhydrolases (PAF-AHs) are a subgroup of Ca²⁺ -independent phospholipase A₂ family (also known as lipoprotein-associated phospholipases A₂) that hydrolyze and inactivate the lipid mediator platelet-activating factor (PAF) and/or oxidized phospholipids. This enzyme is considered to play an important role in inflammatory diseases and atherosclerosis. The present study aims to investigate the relations between the levels of PAF-AH activity and LDL-cholesterol/HDL-cholesterol (LDL-ch/HDL-ch) ratio in NIDDM patients as compared to controls. Methods : serum PAF-AH activity was measured in 50 patients with dyslipidemia, in 50 NIDDM patients and in 50 controls (normal lipid and glucose levels). Total cholesterol, LDL-ch, HDL-ch, triglyceride and blood glucose were determined in all subjects. Results : All NIDDM patients display hiperlipidemia, with increased LDL-ch and triglyceride levels. There is a significant correlation between LDL-ch levels (especially LDL-ch / HDL-ch ratio) and PAF-AH activity in dyslipidemic and NIDDM patients. Conclusion : Diabetic and dyslipidemic patients have an increased plasma PAF-AH activity correlated with their LDL-ch levels and mainly with LDL-ch / HDL-ch ratio. Plasma PAF-AH high levels appear to be important as a risk marker for endothelial dysfunction in patients with NIDDM.     

膜转运蛋白ABCA1与2型糖尿病

胰岛β细胞机能失调是2型糖尿病发病机理的关键所在,而细胞内胆固醇积聚是2型糖尿病β细胞机能失调的发生机制.胆固醇转运体———三磷酸腺苷结合盒转运子A1(ABCA1)缺乏,导致胰岛内胆固醇增加及胰岛素分泌受损,这表明胆固醇流出受损导致β细胞发生功能障碍.     

Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery

ObjectiveIrisin has recently been introduced as a novel an exercise-inducible myokine which improves glucose metabolism in mice. However, regulation of circulating irisin in gestational diabetes mellitus (GDM) and in the peripartal period has not been assessed so far.MethodsCirculating irisin was quantified in 74 GDM patients and in 74 healthy, pregnant, gestational age-matched controls. In a subset of these patients (44 GDM, 41 controls), postpartum follow-up data were also available. In a second study population of 40 healthy women with singleton pregnancies undergoing elective Cesarean section, irisin was assessed in maternal serum before and within 24 h after delivery, as well as in umbilical cord blood and in placental tissue.ResultsIn the first study population, median [interquartile range] irisin levels were significantly higher in GDM patients as compared to controls after delivery (previous GDM: 446.3 [146.9] μg/l; controls: 378.0 [111.4] μg/l) but not during pregnancy (GDM: 482.1 [132.1] μg/l; controls: 466.6 [178.0] μg/l). Interestingly, fasting insulin (FI) was independently and positively associated with serum irisin in multivariate analysis during pregnancy. In agreement with these findings, relative changes (ratio) of FI independently and positively predicted relative changes of irisin (ratio) in the second study population.ConclusionsThe myokine irisin is independently associated with FI in pregnancy. The physiological significance of these findings needs to be assessed in future experiments.     

Chymotrypsin-reactive antibodies in insulin-dependent diabetes mellitus

In a previous study (Frazieret al., 1990), it was demonstrated that two patients with type 1 (insulin-dependent) diabetes mellitus had antibodies in their serum which reacted with four 29 kDa pancreas-specific proteins on two-dimensional immunoblots. This paper reports on the purification and identification of these pancreatic proteins. The protein with the pI closest to pH7 was purified through the use of ammonium sulfate fractionation and ion-exchange chromatography. Gel filtration chromatography established that the protein's molecular weight was closer to 25 kDa. Amino acid composition and sequence analyses demonstrated homology between the protein and chymotrypsin. It is suggested that an abnormal regulation of chymotrypsin activity might be related to antibodies formed in some diabetic patients.     

Mechanism of mitochondrial transport of thallous ions

Rat liver mitochondria were found to swell under nonenergized conditions when suspended in media containing 30–40 mM TINO₃. Respiration on succinate caused a rapid contraction of mitochondria swollen under nonenergized conditions. In the presence of thallous acetate, there was a rapid initial swelling under nonenergized conditions until a plateau was reached; respiration on succinate then caused a further swelling. Trace amounts of²⁰⁴Tl (less than 100 µM) equilibrated fairly rapidly across the mitochondrial membrane. The influx of Tl⁺ was able to promote the decay not only of a valinomycin-induced K⁺-diffusion potential but also of respiration-generated fields in the inner membrane in accordance with the electrophoretic nature of Tl⁺ movement. Efflux of Tl⁺ showed a half-time of about 10 sec at 20°C and was not affected appreciably by the energy state. Efflux was retarded by Mg²⁺ and by lowering the temperature. The data indicate that Tl⁺ when present at high concentrations, 30 mM or more, distributes across the mitochondrial inner membrane both in response to electrical fields and to pH. In energized mitochondria the uptake of Tl⁺ would occur electrophoretically, while Tl⁺/H⁺ exchange would constitute a leak. In the presence of NO ₃ ^– , the movements of Tl⁺ are determined by that of NO ₃ ^– , indicating short-range coupling of electrical forces. At low concentrations of Tl⁺, 5 mM or less, there was no indication of a Tl⁺/H⁺ exchange, which appears to be induced by high concentrations of Tl⁺.     

Mitochondrial dysfunction in diabetes and the regulatory roles of antidiabetic agents on the mitochondrial function

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with its associated morbidity and mortality. Many pathophysiological pathways such as oxidative stress, inflammatory responses, adipokines, obesity-induced insulin resistance, improper insulin signaling, and beta cell apoptosis are associated with the development of T2DM. There is increasing evidence of the role of mitochondrial dysfunction in the onset of T2DM, particularly in relation to the development of diabetic complications. Here, the role of mitochondrial dysfunction in T2DM is reviewed together with its modulation by antidiabetic therapeutic agents, an effect that may be independent of their hypoglycemic effect.     

Early-life background and the development of non-insulin-dependent diabetes mellitus

The relationship of early-life background factors to type 2, or non-insulin-dependent, diabetes mellitus (NIDDM) was examined with reference to family history of diabetes in two groups of Nisei (U.S. born/raised Japanese American) men from King County, Washington with identical mean (+/- S.E.M.) ages: 78 with NIDDM, 61.6 (+/- 0.7) years of age; and 79 with normal glucose tolerance (NGT), 61.6 (+/- 0.6) years of age. The early-life variables were birthplace, parents' education, father's occupation and mother's employment status during subject's childhood, sibship size, son birth order, physical activity and weight assessed for ages 15-20 years, and educational achievement. Multivariate logistic regression models were used to test for the effect of each variable on the risk for diabetes in the presence of other variables. Results are presented as odds ratios (OR) with 95% confidence intervals (CI). Significantly higher risk for NIDDM was found with urban birthplace (vs. rural, OR = 2.09, 95% CI = 1.37-3.19), parents' education above primary level (vs. primary level or less, OR = 1.64, 95% CI = 1.08-2.50), mother being employed (vs. housewife, OR = 2.17, 95% CI = 1.43-3.45), subject being less active-lean as a youth (vs. more active-lean, OR = 1.69, 95% CI = 1.11-2.63), and subject's not attaining a college degree (vs. college degree, OR = 2.17, 95% CI = 1.41-3.33). In separate analyses of the early-life variables by family history of diabetes, the interplay of environmental influences with familial predisposition to NIDDM is evident. The developmental background of NIDDM is discussed with reference to the concept of phenotype amplification within the context of the effects of westernization.     

Calcium transport sensitive to ruthenium red in cytochrome oxidase vesicles reconstituted with mitochondrial proteins

We describe a calcium transport that is sensitive to ruthenium red in liposomes reconstituted with mitochondrial extracts. This system is able to build an internally negative membrane potential, which allows the electrogenic influx of Ca²⁺ and Sr²⁺. Proteins with molecular weights higher than 35 kDa were incorporated to the vesicles, and enhanced the accumulation of the cation in an energy-dependent fashion.     

Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin

Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (30 mg/kg) administration in rat model of diabetes mellitus induced by alloxan (rat model of DMIA) or streptozotocin (rat model of DMIS) and their respective control male Sprague-Dawley rats. In rat models of DMIA and DMIS, the expressions and mRNA levels of CYP1A2, 2B1/2, and 3A1(23) increased, and oltipraz was metabolized mainly via CYP1A1/2, 2B1/2, 2C11, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, it would be expected that the AUC and CL values of oltipraz would be significantly smaller and faster, respectively, in rat models of diabetes. This was proven by the following results. After intravenous administration, the AUC values were significantly smaller in rat models of DMIA (40.1% decrease) and DMIS (26.0% decrease) than those in respective control rats, and this could be due to significantly faster CL values in rat models of DMIA (40.1% increase) and DMIS (26.0% increase). The faster CL could be due to increase in hepatic blood flow rate and significantly faster CL(int) in rat models of diabetes, since oltipraz is an intermediate hepatic extraction ratio drug in male Sprague-Dawley rats. After oral administration, the AUC values of oltipraz were also significantly smaller in rat models of DMIA (54.0% decrease) and DMIS (63.2% decrease). This could be due to increase in hepatic blood flow rate, significantly faster CL(int), and changes in the intestinal first-pass effect in rat models of diabetes. However, this was not due to decrease in absorption in rat models of diabetes.     

Effects of diabetes type and treatment on zinc status in diabetes mellitus

Zinc status was assessed in 53 diabetic patients: 18 insulin-dependent diabetic patients (IDDM), 22 noninsulin-dependent diabetic patients (NIDDM) treated with oral antidiabetic agents, and 13 insulin-treated, noninsulin-dependent diabetic patients (IRDM). Plasma zinc concentrations were in the usual range for healthy subjects in these three groups (15.3±0.9 μmol/L). Urinary zinc excretions were elevated in the IDDM group (18.3±4.1 μmol/24 h;p<0.01 vs normal) and in the NIDDM group (17.5±3.5 μmol/24 h;p<0.01 vs normal), but normal in the IRDM group (11.3±2.4 μmol/24 h). In 14 NIDDM patients treated with transient continuous sc insulin injections, urinary zinc decreased from 16.5±2.2 μmol/24 h before insulin treatment to 11.5±0.3 μmol/24 h after insulin treatment without any modification in plasma zinc concentrations.     

Streptozotocin-induced diabetes increases γ-glutamyltranspeptidase activity but not expression in rat liver

Earlier work describing increased biliary excretion of the acetaminophen-cysteine conjugate advanced the hypothesis that streptozotocin-induceddiabetes increases <γ > -glutamyltranspeptidase (GGT) expression in Sprague–Dawley rats. To test this hypothesis, rats were divided into control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by intravenous injection of 45 mg streptozotocin/kg body weight and was effectively controlled by insulin treatment in the appropriate group. Densitometric quantification demonstrated that hepatic GGT activity in diabetic rats was significantly increased when compared to normal and insulin-treated diabetic controls. Histochemical staining of liver was greater in female than in male rats, and staining increased in female rat liver as the duration of diabetes lengthened from 30 to 90 days. GGT activity was increased by diabetes in liver canalicular-enriched and basolateral-enriched membrane preparations, and it was unchanged in renal brush border-enriched membranes. Total mRNA isolated from diabetic and insulin-treated diabetic rat livers did not conclusively demonstrate an elevation of GGT mRNA relative to normal. Western blot analysis showed no differences in the amount of GGT in diabetic versus normal rat livers. These data indicate that streptozotocin-induced diabetes does not alter the expression of, but does increase the activity of, GGT in liver. © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 219–225, 1998     

Plasma levels of trace element status in early pregnancy and the risk of gestational diabetes mellitus: A nested case-control study

PurposeWe investigated the impacts of plasma levels of magnesium (Mg), zinc (Zn), calcium (Ca), iron (Fe), copper (Cu), selenium (Se), and chromium (Cr) on GDM risk and the potential mediation effect of blood glucose levels on the relationship between trace elements and GDM risk.MethodsThis nested case-control study was based on data from a birth cohort study conducted in Wuhan, China in 2013−2016. A total of 305 GDM cases and 305 individually-matched controls were included in the study. Conditional logistic regression models were used to estimate the associations between plasma trace element concentrations and GDM risk. A mediation analysis was conducted to explore whether blood glucose levels act as a mediator between trace element levels and GDM risk.ResultsAn IQR increment in plasma levels of Fe and Cu was associated with a significant increase in GDM risk [OR = 2.04 (95 % CI 1.62, 2.57) and OR = 1.52 (95 % CI 1.25, 1.82)], respectively. On the other hand, an IQR increment in plasma levels of Zn and Ca was associated with a significant decrease in GDM risk [OR = 0.55 (95 % CI 0.43, 0.71) and OR = 0.72 (95 % CI 0.56, 0.92)], respectively. The mediation analysis showed significant mediation of the association between Cu and GDM risk via the FBG (%mediated: 19.27 %), 1 h-PBG (12.64 %), 2h-PBG (28.44 %) pathways.ConclusionsPlasma levels of Zn and Ca were negatively associated with GDM risk, while Fe and Cu were positively associated. Blood glucose levels act as a mediator between plasma trace element exposures and GDM risk.