Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.     

Cover Image,Volume 69, Issue 3

The cover image is based on the Mini‐Review Well‐defined, environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications by Takeshi Endo et al., https://doi.org/10.1002/pi.5952 . Cover image © Takeshi Endo Images.

     

Prediction of spectral reflectance factor distribution of automotive paint finishes

It is necessary to determine the accurate reflectance of painted surfaces for the review of paint finishes by computer graphics (CG) before actual painting of the exterior color of automobiles, and for quality control during production and inspection processes. We have optimized a method for measuring reflectance by using a statistical technique. We have found that the reflectance of a painted surface is best measured at an incident angle of 60° and at five aspecular angles of 10°, 18°, 28°, 40°, and 90°. Our method makes it possible to accurately reproduce reflection characteristics of paint finishes containing special flake pigments, such as pearl mica. Also it was proved that our method can apply not only to solid and metallic coatings but to all painted surfaces. © 2005 Wiley Periodicals, Inc. Col Res Appl, 30, 275–282, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20125     

Percutaneous lumbar nucleotomy

The nature of the events whereby the reactive intermediates resulting from the bioactivation of bromobenzene and furosemide induce hepatotoxicity is unknown. To examine a role for disturbances in intracellular calcium homeostasis, secondary to a depletion in cellular reduced glutathione (GSH) and reduced protein thiols (PSHs), isolated mouse hepatocytes were exposed to cytotoxic concentrations of bromobenzene or furosemide. Cytosolic calcium concentration, as well as thiol status, was determined. The incubation of hepatocytes with 3.0 mM bromobenzene, and subsequent additions (1.2 mM) of the agent every hour, resulted in significant GSH depletion. The loss of plasma membrane integrity at 1.5 h preceded both a rise in the cytosolic Ca2+ concentration and depletion of total PSH content. Furosemide (1.0 mM) produced a 70% depletion in cellular GSH content in isolated hepatocytes. The initiation of cell damage occurred concurrently with both a rise in the cytosolic Ca2+ concentration and a depletion of total PSH content 4 h following furosemide addition. Since the increase in cytosolic Ca2+ did not precede cytotoxicity, these results do not support an initiating role for Ca2+ deregulation in bromobenzene and furosemide hepatotoxicities. In addition, depletion of PSH content did not correlate with bromobenzene- or furosemide-induced cytotoxicity.     

Development of 170 GHz/500 kW gyrotron

A development of 170GHz/500kW level gyrotron was carried out as R&D work of ITER. The oscillation mode is TE_31,8. In a short pulse experiment, the maximum power of 750kW was achieved at 85kV/40A. The efficiency was 22%. In the depressed collector operation, 500kW/36%/50ms was obtained. The maximum efficiency of 40% was obtained at P_RF=470kW whereas the power decrease by the electron trapping was observed. Pulse extension was done up to 10s at P_RF=170kW with the depressed collector operation. The power was limited by the temperature increase of the output window.     

Inter- and intra-molecular ionic interactions of polyampholyte: Carboxymethyl-2-diethylaminoethylcellulose

Carboxymethyl-2-diethylaminoethylcellulose (CM-DEAE cellulose) was prepared by etherification of carboxymethylcellulose with diethylaminoethyl chloride in a NaOH solution. The behaviour of CM-DEAE cellulose in aqueous solution was studied by viscosity and GPC measurements. The degree of substitution (DS) and existing states of DEAE substituents were examined by the use of proton NMR, and those of the CM substituents were observed with FT-IR. The results reveal that the reduced viscosity and apparent molecular size of CM-DEAE cellulose vary with the concentration of sodium chloride and changes in pH and DS. These phenomena can be explained in terms of inter- and intra-molecular ionic interactions.     

Damage tolerance of glass mat/epoxy laminates hybridized with flexible resin under static and impact loading

This study deals with the impact property and damage tolerance of matrix hybrid composite laminates with different laminate constitution. The matrix hybrid composite laminates consisted of the laminae with a conventional epoxy resin and the laminae with a flexible epoxy resin modified from the conventional resin to avoid the interlaminar delamination. The impact energy absorption ratio greatly depended on the matrix resin placed at the impact face. The energy absorption was almost constant if the conventional resin was placed at the impact surface layer, while it increased exponentially with the increasing fraction of the flexible resin if the flexible resin was placed at the impact face. The impact energy was absorbed by the damage development and propagation in the laminate with conventional resin laminae as the impacted face, while it was absorbed by both the recoverable deformation of the flexible resin and the damage propagation in the laminate with flexible resin laminae as the impacted face.     

Improvements of the T-Ω method for 3-D eddy currentanalysis

An improved T-Ω method that can analyze magnetic fields produced not only by eddy currents but also by magnetizing currents is proposed. The method is applied to the analysis of 3-D eddy-current models with holes. The usefulness of the method is investigated by comparing calculated results with measured results and with results obtained by the A-Φ method. The T-Ω method has the advantage that the CPU time can be considerably reduced when most of the analyzed region is current-free and the eddy current flows two-dimensionally. The method is especially effective when the shape of the winding is simple and the distribution of magnetizing current is known beforehand. It is not effective when most of the analyzed region is current-carrying     

A 64-Mb DRAM with meshed power line

A 64-Mb dynamic RAM (DRAM) has been developed with a meshed power line (MPL) and a quasi-distributed sense-amplifier driver (qDSAD) scheme. It realizes high speed, t_RAS=50 ns (typical) at V_cc=3.3 V, and 16-b input/output (I/O). This MPL+qDSAD scheme can reduce sensing delay caused by the metal layer resistance. Furthermore, to suppress crosstalk noise, a V_SS shield peripheral layout scheme has been introduced, which also widens power line widths. This 64-Mb DRAM was fabricated with 0.4-μm CMOS technology using KrF excimer laser lithography. A newly developed memory cell structure, the tunnel-shaped stacked-capacitor cell (TSSC), was adapted to this 64-Mb DRAM