The joint analysis of both genes by means of tagging SNPs and haplotypic association analyses showed a modest association for insulin and HOMA, although for glucose values we only observed a trend toward association. Analysing both genes independently we found that PER3 region is strongly associated with fasting insulin and UTS2 with fasting glucose. However, the integration of both regions in a single model in which the effect of one of them is controlled for the effect of the other region indicates that the observed associations at both loci are not independent, but they are related to the same causal site. In our study, we have a poor coverage of the UTS2 region coding for GDC-0941 the two short transcripts. The rs228652 analysed by our group is located only 849 bp from the S89A polymorphism but it is not associated with any of the traits analysed in our population. By contrast, we have extended our study to UTS2 region encoding the long transcript and flanking regions and have found that the region associated with T2DM related traits exceeds the UTS2 region and include the PER3 gene. PER3 is one of the period clock genes implicated in the circadian clock function. Alterations of the internal clock function is related to the development of obesity and other metabolic age-related diseases, including abnormal glucose metabolism. PER3 mRNA levels have been shown to be lower in T2DM subjects and to Gefitinib negatively correlate with glycosylated haemoglobin and fasting glucose levels. In addition, a polymorphic 54-bp repeat length variant was associated with higher serum levels of IGF-I and IGF-I to IGFBP3 ratios. This polymorphism has also been associated with IL-6 serum levels. IL-6 is an adipokine, a class of cytokine which includes molecules such as TNFa or PAI that play a central role in body homeostasis, including the regulation of food intake and energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodelling, regulation of blood pressure and coagulation. Moreover, downstream UTS2 is located in the TNFRSF9 gene, which encodes a receptor for tumor necrosis factor, another adipokine. In our analysis, we have only included two polymorphisms at the TNFRSF9 gene region that are not associated with any of the traits analysed. These two SNPs are in the same block of UTS2 and the three polymorphisms that modulate UTS2 mRNA levels. The role of UII in glucose homeostasis is well established. Plasma UII levels have been reported to be almost twice as high in diabetic patients compared with healthy subjects. This increase in UII level does not seem to be a consequence of hyperglycemia, but UII itself may be responsible for hyperglyce- mia. UII and the UTR are both expressed in the pancreatic islets, where it inhibits insulin release without affecting glucagon or somatostatin levels. A recent report has, however, suggested that inhibition of glucose-induced insulin secretion in beta cells is mediated by the UII receptor and PKC pathway, as well as the somatostatin receptor, which could be activated by high dose of UII. Other proposed mechanisms include activation of L-type Ca2+ channels, increase in the phospholipid turnover, activation of the adenylate cyclase/cAMP system or blockage of ATP- dependent K+ channels. In cardiomyocytes, UII also increases phosphorylation of Akt and its downstream target GSK-3b, a serine/threonine protein kinase discovered for its property to inhibit glycogen synthase that has been implicated in many disease states, among others tumorigenesis, diabetes or neurodegenerative diseases. In salmon, UII increases glucose- 6-phosphatase activity and reduces liver glycogen content.