Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide

Glucose dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with therapeutic potential for type 2 diabetes due to its insulin-releasing and antihyperglycaemic actions. However, development of GIP-based therapies is limited by N-terminal degradation by DPP IV resulting in a very short circulating half-life. Numerous GIP analogues have now been generated exhibiting DPP IV resistance and extended bioactivity profiles. In this study, we report a direct comparison of the long-term antidiabetic actions of three such GIP molecules, N-AcGIP, GIP(LyS(37)PAL) and N-AcGIP(LyS(37)PAL) in obese diabetic (ob/ob) mice. An extended duration of action of each GIP analogue was demonstrated prior to examining the effects of once daily injections (25 nmol kg(-1) body weight) over a 14-day period. Administration of either N-AcGIP, GIP(LyS(37)PAL) or N-AcGIP(LyS37PAL) significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to saline treated controls. All three analogues significantly enhanced glucose and nutrient-induced insulin release, and improved insulin sensitivity. The metabolic and insulin secretory responses to native GIP were also enhanced in 14-day analogue treated mice, revealing no evidence of GIP-receptor desensitization. These effects were accompanied by significantly enhanced pancreatic insulin following N-AcGIP(Lys(37)PAL) and increased islet number and islet size in all three groups. Body weight, food intake and circulating glucagon were unchanged. These data demonstrate the therapeutic potential of once daily injection of enzyme resistant GIP analogues and indicate that N-AcGIP is equally as effective as related palmitate derivatised analogues of GIP. (c) 2006 Elsevier Inc. All rights reserved.

Network[ed] Listening – towards a de-centering of beings

In this paper, I question modes of listening in network music performance environments, and specifically draw on my experience as a performer listening in these scenarios. I situate network listening within the context of current music making, and refer to changes in compositional practices that draw specific attention to listening. I argue that some of these compositional developments play a determining role in articulating a new discourse of listening. Eric Satie's concept of Furniture Music, Schaeffer's ideas on reduced listening, Oliveros' deep listening practices as well as digital music platforms all serve to show a development towards a proliferation in listening experiences. I expand this narrative to listening practices in network performance environments, and identify a specific bodily fragility in listening in and to the network. This fragile state of listening and de-centered kind of performative being allow me to draw parallels to the Japanese art form Butoh and Elaine Scarry's metaphor of beauty. My own performance experiences, set within the context of several critical texts, allow me to see network[ed] listening as an ideal corporeal state, which offers a rethinking of linear conceptions of the other and a subject's own relation with her world. Ultimately, network[ed] listening posits listening as a corporeal and multi-dimensional experience that is continuously being re-shaped by technological, socio-political and cultural concerns.