Effects of the reactive metabolite methylglyoxal on cellular signalling, insulin action and metabolism – What we know in mammals and what we can learn from yeast.

Levels of reactive metabolites such as reactive carbonyl and oxygen species are increased in patients with diabetes mellitus. The most important reactive dicarbonyl species, methylglyoxal (MG), formed as by-product during glucose metabolism, is more and more recognized as a trigger for the development and progression of diabetic complications. Although it is clear that MG provokes toxic effects, it is currently not well understood what cellular changes MG induces on a molecular level that may lead to pathophysiological conditions found in long-term diabetic complications. Here we review the current knowledge about the molecular effects that MG can induce in a cell. Within the mammalian system, we will focus mostly on the metabolic effects MG exerts when applied systemically to rodents or when applied in vitro to pancreatic beta-cells and adipocytes. Due to the common limitations associated with complex model organisms, we then summarize how yeast as a very simple model organism can help to gain valuable comprehensive information on general defence pathways cells exert in response to MG stress. Pioneering studies in additional rather simple eukaryotic model organisms suggest that many cellular reactions in response to MG are highly conserved throughout evolution

Hormesis enables cells to handle accumulating toxic metabolites during increased energy flux.

Energy production is inevitably linked to the generation of toxic metabolites, such as reactive oxygen and carbonyl species, known as major contributors to ageing and degenerative diseases. It remains unclear how cells can adapt to elevated energy flux accompanied by accumulating harmful by-products without taking any damage. Therefore, effects of a sudden rise in glucose concentrations were studied in yeast cells. This revealed a feedback mechanism initiated by the reactive dicarbonyl methylglyoxal, which is formed non-enzymatically during glycolysis. Low levels of methylglyoxal activate a multi-layered defence response against toxic metabolites composed of prevention, detoxification and damage remission. The latter is mediated by the protein quality control system and requires inducible Hsp70 and Btn2, the aggregase that sequesters misfolded proteins. This glycohormetic mechanism enables cells to pre-adapt to rising energy flux and directly links metabolic to proteotoxic stress. Further data suggest the existence of a similar response in endothelial cells

Neuronal overexpression of insulin receptor substrate 2 leads to increased fat mass, insulin resistance, and glucose intolerance during aging

The insulin receptor substrates (IRS) are adapter proteins mediating insulin's and IGF1's intracellular effects. Recent data suggest that IRS2 in the central nervous system (CNS) is involved in regulating fuel metabolism as well as memory formation. The present study aims to specifically define the role of chronically increased IRS2-mediated signal transduction in the CNS. We generated transgenic mice overexpressing IRS2 specifically in neurons (nIRS2 (tg)) and analyzed these in respect to energy metabolism, learning, and memory. Western blot (WB) analysis of nIRS2 (tg) brain lysates revealed increased IRS2 downstream signaling. Histopathological investigation of nIRS2 (tg) mice proved unaltered brain development and structure. Interestingly, nIRS2 (tg) mice showed decreased voluntary locomotoric activity during dark phase accompanied with decreased energy expenditure (EE) leading to increased fat mass. Accordingly, nIRS2 (tg) mice develop insulin resistance and glucose intolerance during aging. Exploratory behavior, motor function as well as food and water intake were unchanged in nIRS2 (tg) mice. Surprisingly, increased IRS2-mediated signals did not change spatial working memory in the T-maze task. Since FoxO1 is a key mediator of IRS2-transmitted signals, we additionally generated mice expressing a dominant negative mutant of FoxO1 (FoxO1DN) specifically in neurons. This mutant mimics the effect of increased IRS2 signaling on FoxO-mediated transcription. Interestingly, the phenotype observed in nIRS2 (tg) mice was not present in FoxO1DN mice. Therefore, increased neuronal IRS2 signaling causes decreased locomotoric activity in the presence of unaltered exploratory behavior and motor coordination that might lead to increased fat mass, insulin resistance, and glucose intolerance during aging independent of FoxO1-mediated transcription

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease

© 2011 American Aging Association

39K NMR and EPR study of multiferroic K3Fe5F15

39K NMR spectra and relaxation times of polycrystalline K3Fe5F15 have been used as a microscopic detector of the local magnetic fields at the magnetic transition at TN = 123 K. The NMR lineshape widens abruptly upon crossing TN due to the onset of internal magnetic fields, while we find no significant lineshift. The paraelectric to ferroelectric transition at Tc = 490 K and the magnetic transition at TN have also been studied using X-band EPR (electron paramagnetic resonance). An increase and subsequent decrease in the EPR susceptibilities is observed on approaching TN from above. There is also a significant increase in the linewidth. At the same time the g-factor first decreases and then increases with decreasing temperature. The local magnetic field is different at different K sites and is much smaller than the magnetic field around the Fe sites. This seems to be consistent with the behaviour of a weak ferrimagnet. The ferrimagnetism does not seem to be due to spin canting as the lattice is disordered, but may arise from thermal blocking of superparamagnetic percolation clusters. The ferroelectric transition at Tc shows no electronic anomaly, demonstrating that we are dealing with a classical phonon anomaly as found in conventional oxides rather than an electronic transition

Magnetic properties of multiferroic K3Cr2Fe3F15

The local electronic and structural as well as the macroscopic magnetic properties of K3Cr2Fe3F15 have been studied between room temperature and 4 K. The system has been found to be isostructural with ferroelectric and weakly ferrimagnetic K3Fe5F15 above the ferroelectric transition temperature T-c. The X-band and 216 GHz Cr3+ electron paramagnetic resonance (EPR) spectra as well as the magnetic susceptibility and Moumlssbauer data show the existence of two magnetic relaxor type transitions around 37 and 17 K. The K-39 magic angle sample spinning NMR, EPR, and the Moumlssbauer data further demonstrate the existence of two nonequivalent Fe, Cr, and K sites in the unit cell as well as the presence of rapid exchange at higher temperatures. The observation of the Fe2+ EPR and Moumlssbauer spectra shows that the Fe2+ ion is in a high spin state

Cell cycle arrest and cell death correlate with the extent of ischaemia and reperfusion injury in patients following kidney transplantation – results of an observational pilot study.

Steunstichting ESOT A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors