Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR,PKA and MEK signalling pathways

AIMS/HYPOTHESIS: Prolonged exposure of rat beta cells to the insulin secretagogue glibenclamide has been found to induce a sustained increase in basal insulin synthesis. This effect was calcium-dependent and localised in cells that had been degranulated by the drug. Since it was blocked by the translation inhibitor cycloheximide, we examined whether sustained exposure to glibenclamide activates translational factors by calcium-dependent signalling pathways. METHODS: Purified rat beta cells were cultured with and without glibenclamide in the presence or absence of inhibitors of calcium-dependent signalling pathways before measurement of basal and stimulated protein and insulin synthesis, and assessment of abundance of (phosphorylated) translation factors. RESULTS: A 24 h exposure to glibenclamide induced activation of four translation factors, i.e. phosphorylation of eukaryotic initiation factor (eIF) 4e binding protein 1 and ribosomal protein S6 (rpS6), and dephosphorylation of eIF-2alpha and eukaryotic elongation factor 2. The rise in phospho-rpS6 intensity was localised to a subpopulation of beta cells with low insulin content. This activation of translational factors and the associated elevation of insulin synthesis were completely blocked by the calcium channel blocker verapamil and partially blocked by the mammalian target of rapamycin (mTOR) inhibitor rapamycin, the protein kinase A (PKA) inhibitor Rp-8-Br-cAMPs and the mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (MEK) inhibitor U0126; a combination of inhibitors exhibited additive effects. CONCLUSIONS/INTERPRETATION: Prolonged exposure to glibenclamide activates protein translation in pancreatic beta cells through the calcium-regulated mTOR, PKA and MEK signalling pathways. The observed intercellular differences in translation activation are proposed as underlying mechanism for functional heterogeneity in the pancreatic beta cell population.     

Fasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study

Background and aims

Existing literature in individuals without diabetes has not demonstrated a relationship between IR and incident AF; however, data are limited and only fasting glucose measures of IR were assessed. We evaluated the relationship of both fasting and post-glucose load IR measures with the development of atrial fibrillation in nondiabetic older adults.

RS 10767664 gene variant in Brain Derived Neurotrophic Factor (BDNF) affect metabolic changes and insulin resistance after a standard hypocaloric diet

Background

Role of BDNF variants on change in body weight and cardiovascular risk factors after weight loss remains unclear in obese patients.

Long-acting insulin analogs and cancer

Aims

Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial.

胰岛素泵治疗围手术期妊娠糖尿病的护理

目的：探讨胰岛素泵治疗围手术期妊娠糖尿病患者的护理。方法：回顾性分析62例围手术期妊娠糖尿病患者应用胰岛素泵的治疗和护理。结果：使用胰岛索泵患者血糖控制满意,未发生使用故障,未发生低血糖反应,术后切口愈合时间短,无并发症发生。结论：围手术期妊娠糖尿病应用胰岛素泵是最符合生理的方法,通过全面、细致的观察和护理,达到最佳效果,快速平稳降低血糖。     

老年糖尿病并骨质疏松血IGF-1、骨钙素与胰岛素抵抗的相关性研究

目的：探讨老年糖尿病并骨质疏松血清胰岛素样生长因子-1（IGF-1）、骨钙素（BGP）的水平变化与胰岛素抵抗及骨密度（BMD）的关系。方法：选取2012年10月-2013年5月在本院老年病科住院治疗的108例糖尿病患者,年龄≥60岁,根据骨密度测定结果及骨质疏松症诊断标准分为观察组62例和对照组46例,比较两组间的空腹血糖（FBG）、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）、低密度脂蛋白（LDL-C）、高密度脂蛋白（HDL-C）、IGF-1、BGP及BMD水平,分析血清IGF-1、BGP水平与各项指标的相关性。结果：观察组的FBG、FINS、HOMR-IR、LDL-C水平均明显高于对照组,而HDL-C、BGP及BMD水平均明显低于对照组（P〈0.01或P〈0.05）;两组患者血清游离IGF-1、BGP水平与年龄、FBG、FINS、HOMA-IR、LDL-C水平呈负相关, IGF-1与BGP及BMD水平呈正相关（P〈0.01或P〈0.05）。结论：低血清IGF-I水平、低血清BGP水平及胰岛素抵抗是糖尿病并骨质疏松症发生发展的危险因素。     

The interaction between Toll-like receptor 4 signaling pathway and hypoxia-inducible factor 1α in lung ischemia–reperfusion injury

Background

Lung ischemia–reperfusion injury (LIRI) is the life-threatening complication occurring after lung transplantation. Toll-like receptor 4 (TLR4) signaling pathway and hypoxia-inducible factor-1α (HIF-1α) are intimately involved in the development and progression of various inflammatory and hypoxia diseases; however, the relationship of them in LIRI in vivo is still far from clear.

Materials and methods

Forty-five Sprague–Dawley rats were randomly distributed in nine groups: (1) Sham group, (2) LIRI group, (3) LIRI + saline control group, (4) LIRI + dimethyl Sulfoxide control group, (5) LIRI + lipopolysaccharide group, (6) LIRI + TAK-242 group (TAK-242 is a TLR4 inhibitor, ethyl (6R)-6- [N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate), (7) LIRI + thioredoxin group (thioredoxin is an apoptosis signal–regulating kinase 1 (ASK1) inhibitor), (8) LIRI + SB203580 group (SB203580 is a p38 inhibitor), and (9) LIRI + chetomin group (chetomin is a HIF-1α inhibitor). The interaction between TLR4 signaling pathway (including TLR4, myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), ASK1, and p38) and HIF-1α and the role of TLR4-dependent HIF-1α were analyzed.

Results

In LIRI, HIF-1α accumulation was induced in a TLR4-dependent fashion, and MyD88, but not TRIF, and activation of ASK1 and p38 were found to be critical for TLR4-mediated HIF-1α accumulation. HIF-1α protein played a critical role in TLR4-mediated lung injury of LIRI (including inflammation, cell apoptosis, and lung damage). HIF-1α protein upregulated TLR4 expression of LIRI in a positive feedback manner.

Conclusions

We identify that the TLR4-HIF-1 loop may be existed in LIRI. Therefore, we suggest that the interaction between them may represent a novel therapeutic target for the development of novel target-based therapies of LIRI.     

The role of DJ-1 in the oxidative stress cell death cascade after stroke

Oxidative stress is closely associated with secondary cell death in many disorders of the central nervous system including stroke,Parkinson’s disease,Alzheimer’s disease.Among many aberrant oxidative stress-associated proteins,DJ-1 has been associated with the oxidative stress cell death cascade primarily in Parkinson’s disease.Although principally expressed in the cytoplasm and nucleus,DJ-1 can be secreted into the serum under pathological condition.Recently,a close pathological association between DJ-1 and oxidative stress in stroke has been implicated.To this end,we and others have demonstrated the important role of mitochondria in neuroprotection for stroke by demonstrating that the translocation of DJ-1 in the mitochondria could potentially mitigate mitochondrial injury.Here,we discuss our recent findings testing the hypothesis that DJ-1 not only functions as a form of intracellular protection from oxidative stress,but that it also utilizes paracrine and/or autocrine cues in order to accomplish extracellular signaling between neighboring neuronal cells,resulting in neuroprotection.This article highlights recent evidence supporting the status of DJ-1 as key anti-oxidative stress therapeutic target for stroke.     

Store-operated calcium entry in neuroglia

Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca²⁺ signals that define the “Ca²⁺ excitability” of glia. In mammalian glial cells the major source of Ca²⁺ for this excitability is the lumen of the endoplasmic reticulum (ER), which is ultimately (re)filled from the extracellular space. This occurs via store-operated Ca²⁺ entry (SOCE) which is supported by a specific signaling system connecting the ER with plasmalemmal Ca²⁺ entry. Here, emptying of the ER Ca²⁺ store is necessary and sufficient for the activation of SOCE, and without Ca²⁺ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca²⁺ sensors, such as stromal interaction molecule, and possibly ER Ca²⁺ pumps (of the SERCA type). There are at least two sets of plasmalemmal channels mediating SOCE, the Ca²⁺-release activated channels, Orai, and transient receptor potential (TRP) channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca²⁺ signal observed following stimulation of metabotropic receptors on glial cells.