Philip Duncanson

Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose

Summary The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.

The reactions of trialkylsilyl-containing phosphites with electrophilic organic compounds

The reactions of silyl-containing phosphites with electrophilic alkynes and various carbonyl compounds have been investigated. The higher nucleophilicity of silyl phosphites, relative to the analogous trialkyl phosphites, and the ease with which transfer of a silyl group occurs from the initially formed quasi-phosphonium intermediates, has a significant impact both on the nature of the products formed and the conditions needed to bring about the reaction.

Novel ylidic phosphoryl compounds from halogenated furan-2,5-diones with trivalent phosphorus esters: Application of this approach to new trisphosphonates containing a geminal bisphosphonate unit

Abstract The reactions of trivalent phosphorus esters, including trialkyl phosphites, dialkyl phosphonites, and alkyl phosphinites, with 3-halo- and 3,4-dihalo-furan-2,5-diones has been shown to lead to the formation of novel phosphorus ylides possessing additional phosphoryl-containing groups. For the reaction of 3,4-dihalo-furan-2,5-diones with trialkyl phosphites, the products are trialkoxyphosphonium ylides containing an adjacent geminal bisphosphonate unit. These can be used to provide a convenient route to novel 2,3,3-tris(dialkoxyphosphoryl)-substituted propionate esters which can be hydrolyzed to give the corresponding novel trisphosphonic monocarboxylic acid. GRAPHICAL ABSTRACT