Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes – a review

Type 2 diabetes mellitus is a metabolic disease associated with low quality of life and early death. The goal in diabetes treatment is to prevent these outcomes by tight glycemic control and minimizing vascular risk factors. So far, even intensified combination regimen with the traditional antidiabetes agents have failed to obtain these goals. Incretin mimetics are a new class of antidiabetes drugs which involve modulation of the incretin system. They bind to and activate glucagon-like peptide-1 (GLP-1) receptors on pancreatic beta-cells following which insulin secretion and synthesis are initiated. Since the compounds have no insulinotropic activity at lower glucose concentrations the risk of hypoglycemia – a well-known shortcoming of existing antidiabetes treatments – is low. Additionally, incretin mimetics have been shown to be associated with beneficial effects on cardiovascular risk factors such as weight loss, decrease in blood pressure and changes in lipid profile. Current clinical data on the two available incretin mimetics, exenatide and liraglutide, are evaluated in this review, focusing on pharmacology, efficacy, safety and tolerability. The review is built on a systematic PubMed and Medline search for publications with the key words GLP-1 receptor agonist, exenatide, liraglutide and type 2 diabetes mellitus up to January 2009

Study of Magnetic Excitation in Singlet-Ground-State Magnets CsFeCl3_3 and RbFeCl3_3 by Nuclear Magnetic Relaxation

The temperature dependences of spin-lattice relaxation time $T_1$ of $^{133}$Cs in CsFeCl$_3$ and $^{87}$Rb in RbFeCl$_3$ were measured in the temperature range between 1.5 K and 22 K, at various fields up to 7 T applied parallel (or perpendicular) to the c-axis, and the analysis was made on the basis of the DCEFA. The mechanism of the nuclear magnetic relaxation is interpreted in terms of the magnetic fluctuations which are characterized by the singlet ground state system. In the field region where the phase transition occurs, $T_1^{-1}$ exhibited the tendency of divergence near $T_{\rm N}$, and this feature was ascribed to the transverse spin fluctuation associated with the mode softening at the $K$-point. It was found that the damping constant of the soft mode is remarkably affected by the occurrence of the magnetic ordering at lower temperature, and increases largely in the field region where the phase transition occurs.Comment: 12 pages, 18 figures, submitted to J. Phys. Soc. Jp

ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast

ER-phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER-phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro-ER-phagy has been discovered, the molecules and mechanisms mediating micro-ER-phagy remain unknown. Here, we first show that micro-ER-phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1-Spo7 phosphatase complex and the ESCRT machinery as key components for micro-ER-phagy. Third, we demonstrate that macro- and micro-ER-phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that the ESCRT machinery directly functions in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro-ER-phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis

The dielectric clad axial slot antenna

Dieletric clad axial slot antenna

Expansion, Geometry, and Gravity

In general-relativistic cosmological models, the expansion history, matter content, and geometry are closely intertwined. In this brief paper, we clarify the distinction between the effects of geometry and expansion history on the luminosity distance. We show that the cubic correction to the Hubble law, measured recently with high-redshift supernovae, is the first cosmological measurement, apart from the cosmic microwave background, that probes directly the effects of spatial curvature. We illustrate the distinction between geometry and expansion with a toy model for which the supernova results already indicate a curvature radius larger than the Hubble distance.Comment: 4 pages, 1 color figur

Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD

Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD