Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney

Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate whether short duration of combined hyperglycemia and hyperinsulinemia, mimicking the metabolic environment of prediabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n = 4) or 7 h of combined hyperglycemic- hyperinsulinemic clamp (HG+HI clamp; n = 6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical transforming growth factor-β (TGF-β) and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mammalian target of rapamycin (mTOR) complexes, and ERK signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of Toll-like receptor 4 (TLR4) and infiltration of CD68-positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation, and oxidative stress in the kidney. This finding could have implications for the control of short-term rises in blood glucose in diabetic individuals at risk of developing kidney disease. © 2014 the American Physiological Society

Coupling and propagation of normal and dysrhythmic gastric slow waves during acute hyperglycaemia in healthy humans

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72187/1/j.1365-2982.2008.01235.x.pd

Clique-based data mining for related genes in a biomedical database

<p>Abstract</p> <p>Background</p> <p>Progress in the life sciences cannot be made without integrating biomedical knowledge on numerous genes in order to help formulate hypotheses on the genetic mechanisms behind various biological phenomena, including diseases. There is thus a strong need for a way to automatically and comprehensively search from biomedical databases for related genes, such as genes in the same families and genes encoding components of the same pathways. Here we address the extraction of related genes by searching for densely-connected subgraphs, which are modeled as cliques, in a biomedical relational graph.</p> <p>Results</p> <p>We constructed a graph whose nodes were gene or disease pages, and edges were the hyperlink connections between those pages in the Online Mendelian Inheritance in Man (OMIM) database. We obtained over 20,000 sets of related genes (called 'gene modules') by enumerating cliques computationally. The modules included genes in the same family, genes for proteins that form a complex, and genes for components of the same signaling pathway. The results of experiments using 'metabolic syndrome'-related gene modules show that the gene modules can be used to get a coherent holistic picture helpful for interpreting relations among genes.</p> <p>Conclusion</p> <p>We presented a data mining approach extracting related genes by enumerating cliques. The extracted gene sets provide a holistic picture useful for comprehending complex disease mechanisms.</p

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers from elderly women

The predictive role of tumour proliferative rate and expression of p53, bcl-2 and bax proteins, alone and in association with tumour size, nodal involvement and oestrogen receptors (ER), was analysed on 145 elderly patients (≥70 years of age) with histologically assessed node-positive breast cancers treated with radical or conservative surgery plus radiotherapy followed by adjuvant tamoxifen for at least 1 year. The 7-year probability of relapse was significantly higher for patients with tumours rapidly proliferating (hazard ratio (HR) = 2.0, P = 0.01), overexpressing p53 (HR = 4.4, P = 0.0001), weakly or not exhibiting bcl-2 (HR = 1.9, P = 0.02), without ERs (HR = 3.4, P = 0.0001) or with ≥ 4 positive lymph nodes (HR = 2.3, P = 0.003) than for patients with tumours expressing the opposite patho-biological profile. Conversely, tumour size and bax expression failed to influence relapse-free survival. Adjustment for the duration of tamoxifen treatment did not change these findings. Oestrogen receptors, cell proliferation, p53 accumulation and bcl-2 expression were also predictive for overall survival. Within ER-positive tumours, cell proliferation, p53 accumulation, bcl-2 expression and lymph node involvement provided significant and independent information for relapse and, in association, identified subgroups of patients with relapse probabilities of 20% (low-risk group, exhibiting only one unfavourable factor) to 90% (high-risk group, exhibiting three unfavourable factors). Such data could represent the initial framework for a biologically tailored therapy even for elderly patients and highlight the importance of a patho-biological characterization of their breast cancers. © 2000 Cancer Research Campaig