Highlights d Human b cell dysfunction induced by metabolic stress may be persistent or transient d Specific transcriptomic changes associate with durable or reversible damage d Type 2 diabetes (T2D) b cells have several functional and molecular alterations d T2D and irreversibly or temporarily impaired b cells share key transcriptome traits

Main Text (excl abstract, refs, figure legends, acknows) = 3992 words 2 Abbreviations, BCI, BCM, -cell imaging and mass, respectively; IMIDIA, Innovative Medicines Initiative in DIAbetes; MRI, magnetic resonance imaging; OPT, optical projection tomography; PET, positron emission tomography; SPECT, single photon emission computed tomography; VMAT, vesicular monoamine transporter; GLP1, glucagon-like peptide-1; PSA-NCAM, polysialylated neural cell adhesion molecule; SUR 1, sulfonylurea receptor 1; STZ, streptozotocin; T1D type 1 diabetes; T2D, type 2 diabetes; TMEM27, transmembrane protein 27; USPIO, ultrasmall superparamagnetic iron oxide 3 AbstractDiabetes mellitus is a growing worldwide epidemic currently affecting 1 in 12 adults.Treatment of disease complications typically consumes ~10% of healthcare budgets in developed societies. Whilst immune-mediated destruction of insulin-secreting pancreatic -cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underlies the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aiming at -cell restoration is still hampered by the absence of means to measure -cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. Here, we describe progress towards this goal achieved by the Innovative Medicines Initiative in DIAbetes (IMIDIA), a collaborative public-private consortium supported by the European Commission and dedicated resources of pharmaceutical companies. We compare several of the available imaging modalities and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches and furthermore we discuss the simultaneous development of animal models that can be used to measure subtle changes in -cell mass, a prerequisite for validating the clinical potential of the different imaging tracers.4

Blockade of the N-methyl-D-aspartate receptor by uncompetitive antagonists has implications for symptomatic and neuroprotective therapy of various neuropsychiatric diseases. Since the three-dimensional (3D) structure of this ion channel is unknown, the structural requirements for uncompetitive inhibition were investigated by application of a three-step strategy: At first, Ki values were measured for a number of structurally diverse compounds at the phencyclidine (PCP) binding site in postmortem human frontal cortex. Second, a pharmacophore model was developed for this set of molecules employing a mathematical method called graph theory. The resulting pharmacophore provided a very good explanation for the ability of structurally diverse compounds to bind to the same binding site. Using the experimental data and the pharmacophore as a basis for the third step, a three-dimensional quantitative structure-activity relationship (3D-QSAR) applying comparative molecular field analysis (CoMFA) was performed. The QSAR proved to be highly consistent and showed good predictiveness for several additional molecules. The results give a deeper insight into the structural requirements for effective NMDA receptor antagonism and offer the opportunity for improved drug design. The study represents the first quantitative 3D-QSAR model for NMDA receptor blockade, and it comprises structurally very different molecules. That the alignment for a highly consistent CoMFA is based on an automated 3D pharmacophore analysis has important methodological implications.