Synaptic adhesion molecules and PSD-95

Synaptic adhesion molecules are known to participate in various steps of synapse development including initial contacts between dendrites and axons, formation of early synapses, and their maturation and plastic changes. Notably, a significant subset of synaptic adhesion molecules associates with synaptic scaffolding proteins, suggesting that they may act in concert to couple trans-synaptic adhesion to molecular organization of synaptic proteins. Here, we describe an emerging group of synaptic adhesion molecules that directly interact with the abundant postsynaptic scaffold PSD-95, which include neuroligins, NGLs, SALMs, and ADAM22, and discuss how these proteins and PSD-95 act together to regulate synaptic development. PSD-95 may be one of the central organizers of synaptic adhesion that recruits diverse proteins to sites of synaptic adhesion, promotes trans-synaptic signaling, and couples neuronal activity with changes in synaptic adhesion.     

Beta-cell growth in the neonatal Goto-Kakisaki rat and regeneration after treatment with streptozotocin at birth

Aims/hypothesis. In the Goto-Kakisaki rat, a genetic model of non-insulin dependent diabetes, we have recently reported that as early as fetal age, there is a restriction of the beta-cell mass which is maintained in the adult animal and is detectable before the onset of hyperglycaemia. It is therefore important to investigate the beta-cell growth potential in young Goto-Kakisaki rats. Methods. We have studied in 4 and 7-day-old Goto-Kakisaki neonates: 1. the in vivo replication rate of the beta cell; 2. the occurrence of beta-cell apoptosis; 3. the effectiveness of beta-cell regeneration after damage caused by neonatal treatment with streptozotocin. Results. The replication rate in vivo of beta cells and the beta-cell apoptosis were similar in untreated Wistar and Goto-Kakisaki neonates on days 4 and 7 whereas the total beta-cell masses were reduced to 50 % in the Goto-Kakisaki groups. Treatment with streptozotocin reduced the total beta-cell mass to the same extent in both Wistar and Goto-Kakisaki rats on day 4 compared with the corresponding normal values in Wistar and Goto-Kakisaki neonates. From day 4 to day 7, spontaneous beta-cell regeneration was manifest in both groups. Compared with the Wistar streptozotocin group, the net value of the beta-cell mass added during this period was more limited in the Goto-Kakisaki streptozotocin group, despite the replication activity of the residual beta cells being increased in this group to the same extent as in the Wistar streptozotocin group. Conclusion/interpretation. We therefore suggest: 1. that the reduced beta-cell mass in the untreated neonatal Goto-Kakisaki rat does not appear to reflect a reduction in the rate of beta-cell replication or an increased beta-cell death by apoptosis but is potentially due to an impaired rate of beta-cell neogenesis, and 2. that beta-cell regeneration can be reactivated after streptozotocin insult in the neonatal Goto-Kakisaki rat, although to a lesser extent compared with that in streptozotocin-treated Wistar neonates. [Diabetologia (1999) 42: 1098–1106] Received: 8 January 1999 and in revised form: 26 February 1999     

Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats

The impact of diabetes and especially hyperglycemia on brain glucose utilization and insulin binding are still not clear. This is probably due to the fact that most studies have been performed in streptozotocin treated rats that are highly hyperglycemia and that could have an effect per se on the brain. The aim of the present work was to measure, in vivo, glucose utilization and insulin binding in different areas of the brain of the spontaneously diabetic GK rats that present a moderate hyperglycemia. Brain insulin receptors number was not changed in the brain of GK rats. By contrast, an increased glucose utilization was present in the external plexiform and the intergranular layers of the olfactory bulbs, as well as in the amygdaloid of the GK rats. These structures are involved in conditioned taste aversion, which was found to be greatly altered in the diabetic rats. These results sustain the hypothesis of impaired neuropsychological functions in diabetic patients particularly in term of learning and memory.     

Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats

Background and aimIn type 2 diabetes, the interplay between cells and inflammatory mediators up-regulates CD36 expression in macrophages. The aim of this work was to investigate advanced glycation end products (AGE)-induced CD36 expression and its regulation by insulin in aortic vascular smooth muscle cells (VSMCs) from Goto–Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. The context of overexpression of CD36 in aortas was also evaluated.Methods and resultsVSMCs were isolated and cultured from the aortas of GK rats and non-diabetic rats. The expression of proteins was evaluated by Western blot. The aortic production of superoxide anion (O₂^·−) was measured by luminescence on isolated tissue. AGEs and advanced oxidation protein products (AOPPs) were determined in plasma by fluorescence spectroscopy and spectrophotometry, respectively.AGE receptor (RAGE), NF-κB, and CD36 protein expression as well as O₂^·− production were higher in GK aortas than in control aortas, and AGEs and AOPPs were higher in GK plasma. In VSMCs from non-diabetic rats, insulin was able to reduce (10 nM) or suppress (100 nM) the protein overexpression of CD36 induced by AGEs–BSA. In contrast, in VSMCs from GK rats, insulin was unable to reduce AGEs–BSA-induced CD36 overexpression.ConclusionsThe results suggest an overexpression of CD36 in VSMCs from GK rats and impaired control by insulin. In the context of increased plasma AGEs, aortic RAGE overexpression and increased oxidative stress markers, the data are compatible with an AGEs induced CD36 overexpression in diabetes.     

Exercise training and selenium or a combined treatment ameliorates aberrant expression of glucose and lactate metabolic proteins in skeletal muscle in a rodent model of diabetes

Exercise training (ET) and selenium (SEL) were evaluated either individually or in combination (COMBI) for their effects on expression of glucose (AMPK, PGC-1α, GLUT-4) and lactate metabolic proteins (LDH, MCT-1, MCT-4, COX-IV) in heart and skeletal muscles in a rodent model (Goto-Kakisaki, GK) of diabetes. Forty GK rats either remained sedentary (SED), performed ET, received SEL, (5 µmol·kg body wt^-1·day^-1) or underwent both ET and SEL treatment for 6 wk. ET alone, SEL alone, or COMBI resulted in a significant lowering of lactate, glucose, and insulin levels as well as a reduction in HOMA-IR and AUC for glucose relative to SED. Additionally, ET alone, SEL alone, or COMBI increased glycogen content and citrate synthase (CS) activities in liver and muscles. However, their effects on glycogen content and CS activity were tissue-specific. In particular, ET alone, SEL alone, or COMBI induced upregulation of glucose (AMPK, PGC-1α, GLUT-4) and lactate (LDH, MCT-1, MCT-4, COX-IV) metabolic proteins relative to SED. However, their effects on glucose and lactate metabolic proteins also appeared to be tissue-specific. It seemed that glucose and lactate metabolic protein expression was not further enhanced with COMBI compared to that of ET alone or SEL alone. These data suggest that ET alone or SEL alone or COMBI represent a practical strategy for ameliorating aberrant expression of glucose and lactate metabolic proteins in diabetic GK rats.     

自发性2型糖尿病动物模型GK大鼠的发病特征研究

目的: 研究自发性2型糖尿病动物模型(GK)大鼠的发病特征。 方法: 以Wistar大鼠(n=12)为对照,从第13周龄起连续监测GK大鼠(n=61)的基础血糖值、体重、摄食量和饮水量。第32周龄时,开展糖耐量试验,进行大便常规和肝肾指数检查,检测血浆中血脂、肾功能和糖化血红蛋白(HbA1c)的水平,取胰腺和肾脏进行病理检查。 结果: GK大鼠在第24周龄时开始发病,血糖稳定地维持在11.0 mmol·L^-1以上的高血糖水平,HbA1c水平亦明显升高,至少可以维持到第32周龄;期间还出现类似于糖尿病病人"消瘦"、"多食"、"多饮"等临床症状;死亡率相对较低,仅为11.47%左右。GK大鼠对糖负荷的代谢能力降低,胰腺和肝脏组织病理改变明显加重。 结论: GK大鼠在第24～32周龄期间发病,具有明显的、稳定的糖尿病发病特征,且死亡率低,有利于开展糖尿病的发病机制和药物的有效性评价研究。     

Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism

Ghrelin, a hormone whose levels increase during food deprivation, plays a pivotal role in the regulation of food intake, energy metabolism and storage, as well as in insulin sensitivity. Here, we investigated the effects of acyl-ghrelin neutralization with the acyl-ghrelin-binding compound NOX-B11(2) during the fasting-refeeding cycle. Our data demonstrate that ghrelin neutralization with NOX-B11(2) impairs recuperation of lost body weight after food deprivation. Analysis of enzymes involved in glucose and lipid metabolism in liver of fed, fasted and refed rats revealed that neutralization of acyl-ghrelin resulted in minor decreases in the enzymes of glycolytic and lipogenic pathways during fasting. However, during refeeding these enzymes as well as glycogen levels recovered more slowly when acyl-ghrelin was blocked. The high levels of ghrelin in response to food deprivation may contribute to an adequate decrease in hepatic glycolytic and lipogenic enzymes and aid in the recovery of body weight and energetic reserves once food becomes available after the fasting period.     

Genetic Regulation of Bone Traits Is Influenced by Sex and Reciprocal Cross in F2 Progeny From GK and F344 Rats

A genome‐wide linkage analysis to identify quantitative trait loci (QTLs) for bone phenotypes was performed in an F₂ intercross of inbred spontaneously type 2 diabetic GK and normoglycemic F344 rats (108 males and 98 females). The aim of the study was to locate genome regions with candidate genes affecting trabecular and cortical bone and to investigate the effects of sex and reciprocal cross. pQCT was used to determine tibial bone phenotypes in the F₂ rats, comprising reciprocal crosses with divergent mitochondrial (mt) DNA. Sex and reciprocal cross‐separated QTL analyses were performed followed by assessment of specific interactions. Four genome‐wide significant QTLs linked to either cortical vBMD, tibia length, body length, or metaphyseal area were identified in males on chromosomes (chr) 1, 8, and 15. In females, three significant QTLs linked to cortical BMC or metaphyseal total vBMD were identified on chr 1 and 2. Several additional suggestive loci for trabecular and cortical traits were detected in both males and females. Four female‐specific QTLs on chr 2, 3, 5, and 10 and four reciprocal cross‐specific QTLs on chr 1, 10, and 18 were identified, suggesting that both sex and mt genotype influence the expression of bone phenotypes.