During the last five years, within the EU FP6 Integrated Project XENOME (LSHB-CT-2006-037377), we have convincingly demonstrated in primates that a complete control of induced type 1 diabetes is routinely obtained for 6/8 months after transplantation of subcutaneous alginate macroencapsulated porcine islets xenograft without the use of any immunosuppression. In order to improve the function of pig islets, we have produced with AVANTEA a transgenic pig expressing GLP-1 at the level of the pig islets. In fact, GLP1 is not only able to (i) increase the insulin gene expression and insulin biosynthesis, but also to (ii) induce the replication of islet cells and promotes islet-cell neogenesis and (iii) protect islets cells from apoptosis. GLP-1 has already demonstrated its in vivo potential to improve insulin secretion in subjects with impaired glucose tolerance and type 2 diabetes. New vectors (GLP1/M3Rr) containing both GLP1 sequence and muscarinic receptor mutation (M3R) will also be tested. The main objectives of this four-year project will therefore be (1) to evaluate in vitro the effect of GLP1/M3R transgene expression in pig islets after hyperglycaemic challenge; (2) to continue to produce double transgenic pigs specifically expressing GLP-1/M3R in pig islets under insulin promoter, and (3) finally to test these modified pig islets in our well characterized pig-to-diabetic primates model in vivo. However, in order to use islets from newborn unmodified or transgenic pigs, we will also set up (4) the pig islets isolation and cell maturation technique for Neonates Pancreatic Pig Cluster cells since neonates pig islets have prolonged survival and would also render possible the use of Designed Pathogen Free (DPF) neonates pigs which will represent a key point to reach clinical studies. BIOT will be mainly involved in this part of the work which is in vitro purification, amplification of NPCCS. GCU and AVIDIN Ltd will together develop arrays and a set of molecular testing for pig cell pathogens.A pilot study for safety will be achieved whether all the prerequisite are achieved at the end of the fourth year project.