Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Charakterisierung des Ionentransporters NKCC1 in der Chemosensorik

Die olfaktorische Wahrnehmung wird hauptsächlich durch einen cAMP-vermittelten Signalweg gesteuert, welcher zu einem Ausstrom an Chloridionen führt und in der Depolarisation eines Neurons resultiert. Der Natrium-Kalium-Chlorid-Kotransporter NKCC1 gilt als potentieller Kandidat für die notwendige Akkumulation von Chloridionen in Neuronen. Ziel dieser Arbeit war es, den Einfluss von NKCC1 auf die Chloridakkumulation von Neuronen mithilfe NKCC1-gendefizienter Mäuse zu untersuchen. Hierzu wurde erstmalig eine Transkriptom-Analyse des olfaktorischen Epithels (OEs) von NKCC1-gendefizienten Mäusen und wildtypischen Geschwistertieren angefertigt. NKCC1 ist der am höchsten exprimierte Transporter in Neuronen. Sein Fehlen erzeugt jedoch eine verringerte Neuronenzahl im OE, was vermuten lässt, dass NKCC1 an der kontinuierlichen Neurogenese des OE beteiligt ist. Analysen des Proteingehalts von neuronalen Markern wiesen zudem auf eine Inhibierung der Reifung von Vorläuferzellen im OE hin

Identification and functional characterization of claudin subunits as new transmembrane AMPA receptor regulatory proteins

Das Ziel dieser Arbeit war es, weitere AMPA-Rezeptor-Hilfsproteine zu identifizieren und zu charakterisieren. Mitglieder der Claudin-Proteinfamilie wurden aufgrund ihrer hohen Sequenzhomologien und strukturellen Ähnlichkeiten zu TARPs als mögliche AMPA-Rezeptor-modulierende Proteine untersucht. Alle Claudine welche aus Ratten-Gesamthirn-RNA kloniert werden konnten, wurden mit dem AMPA-Rezeptor GluA1(Q)flip koexprimiert. Die Proteine Claudin-20 und Claudin-24 wurden dabei als mögliche modulierende Proteine identifiziert und ihren modulierenden Eigenschaften weiter untersucht. Die beiden Proteine, insbesondere Claudin-24, modulieren viele Eigenschaften der AMPA Rezeptoren, wie zum Beispiel erhöhte Desensitisierung, die reduzierte Glutamat-Affinität und die stark erhöhten glutamatinduzierten Gleichgewichtsströme der Ca$^{2+}$-undurchlässigen Rezeptoren. Durch funktionelle Ähnlichkeiten zu dem TARP $\gamma$5 wurde Claudin-24 im Laufe dieser Arbeit erstmals als Typ-II TARP klassifiziert

Identification of a novel gnao-mediated alternate olfactory signaling pathway in murine OSNs

It is generally agreed that in olfactory sensory neurons (OSNs), the binding of odorant molecules to their specific olfactory receptor (OR) triggers a cAMP-dependent signaling cascade, activating cyclic-nucleotide gated (CNG) channels. However, considerable controversy dating back more than 20 years has surrounded the question of whether alternate signaling plays a role in mammalian olfactory transduction. In this study, we demonstrate a specific alternate signaling pathway in Olfr73-expressing OSNs. Methylisoeugenol (MIEG) and at least one other known weak Olfr73 agonist (Raspberry Ketone) trigger a signaling cascade independent from the canonical pathway, leading to the depolarization of the cell. Interestingly, this pathway is mediated by Gnao activation, leading to $Cl^{-}$ efflux; however, the activation of adenylyl cyclase III (ACIII), the recruitment of $Ca^{2+}$ from extra-or intracellular stores, and phosphatidylinositol 3-kinase-dependent signaling (PI signaling) are not involved. Furthermore, we demonstrated that our newly identified pathway coexists with the canonical olfactory cAMP pathway in the same OSN and can be triggered by the same OR in a ligand-selective manner. We suggest that this pathway might reflect a mechanism for odor recognition predominantly used in early developmental stages before olfactory cAMP signaling is fully developed. Taken together, our findings support the existence of at least one odor-induced alternate signal transduction pathway in native OSNs mediated by Olfr73 in a ligand-selective manner

The time course of intentional binding

Environmental stimuli caused by actions (i.e., effects) are perceived earlier than stimuli not caused by actions. Thisphenomenon is termed intentional binding (IB), and serves as implicit measure of sense of agency. We investigated the influenceof effect delay and temporal predictability on IB, measured with the classic clock procedure as the bias to perceive the effectas temporally shifted towards the action. For short delays, IB increased with delay (Experiment 1: 200 ms, 250 ms, 300 ms)and this initial increase declined for longer delays (Experiment 2: 100 ms, 250 ms, 400 ms). These results extend previousfindings showing IB to decrease with increasing delays for delay ranges of 250 ms to 650 ms. Further, the indication that IB,that is, sense of agency, might be maximal for different delays depending on the specific characteristics and context of actionand effect, has important implications for human-machine interfaces

RAD50, an SMC family member with multiple roles in DNA break repair: How does ATP affect function?

The protein complex including Mre11, Rad50, and Nbs1 (MRN) functions in DNA double-strand break repair to recognize and process DNA ends as well as signal for cell cycle arrest. Amino acid sequence similarity and overall architecture make Rad50 a member of the structural maintenance of chromosome (SMC) protein family. Like SMC proteins, Rad50 function depends on ATP binding and hydrolysis. All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA. In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined. Here we review the data on the ATP-dependent activities of MRN and their possible mechanistic significance. We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin

Structural conservation of RecF and Rad50: implications for DNA recognition and RecF function

RecF, together with RecO and RecR, belongs to a ubiquitous group of recombination mediators (RMs) that includes eukaryotic proteins such as Rad52 and BRCA2. RMs help maintain genome stability in the presence of DNA damage by loading RecA-like recombinases and displacing single-stranded DNA-binding proteins. Here, we present the crystal structure of RecF from Deinococcus radiodurans. RecF exhibits a high degree of structural similarity with the head domain of Rad50, but lacks its long coiled-coil region. The structural homology between RecF and Rad50 is extensive, encompassing the ATPase subdomain and the so-called ‘Lobe II' subdomain of Rad50. The pronounced structural conservation between bacterial RecF and evolutionarily diverged eukaryotic Rad50 implies a conserved mechanism of DNA binding and recognition of the boundaries of double-stranded DNA regions. The RecF structure, mutagenesis of conserved motifs and ATP-dependent dimerization of RecF are discussed with respect to its role in promoting presynaptic complex formation at DNA damage sites