Activation of the UII system was also proposed to be associated with the development of metabolic syndrome. Although UII doesn’t seem to be implicated in the initiation of the individual factors comprising the metabolic syndrome, there is evidence that UII plays a role in the development of each factor. UII plays a role in hypertension, in both dyslipidemia and obesity, and in hyperglycemia. Increased plasma UII levels in patients with T2DM was recently associated with the metabolic syndrome phenotype. The primary clinical outcomes of the metabolic syndrome are cardiovascular diseases, such as coronary heart diseases or stroke. Several reports have shown that plasma UII levels are increased in cardiovascular diseases such as congestive heart failure and other cardiac diseases. Expression of both UII and UT receptors are increased in the heart of patients after myocardial infarction, suggesting a possible pathological role in cardiac remodeling. Indeed, UII was shown to be involved in cardiac fibrosis, hypertrophy and remodeling. Interestingly, several studies have linked hyperglycaemia, at the time of hospital admission,GSK1120212 with higher mortality in patients with acute coronary syndrome. The effect of admission hyperglycaemia on mortality seems to be independent of a previous diagnosis of diabetes mellitus; indeed, some studies have suggested that mortality may be higher in patients with hyperglycaemia without a previous history of diabetes, compared to those with known history of ICG-001 diabetes. This last study showed that given the same degree of hyperglycemia on admission, known diabetes has a protective influence on short-term outcomes in hospitalized ACS patients. The mechanism by means chronic diabetes mitigates the effect of hyperglycemia in acute cardiovascular event is unknown. Given that UII has been proven to be a potent insulinostatic peptide, urotensin II receptor antagonists have been proposed as potential drugs for treating the impaired insulin secretion characteristic of T2DM patients. In a follow-up study, Clozel et al. observed that chronic oral treatment with palosuran, a potent and selective UTR antagonist, improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. Other authors have reported that, in the absence of exogenous UII, palosuran potentiated glucose-induced insulin release in perfused rat pancreas and decreased 24- hour urinary albumin excretion rate in diabetic patients with renal failure with regard to their disease progression. However, other studies have reported that palosuran has no effect on the first-phase insulin response, insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score of diabetic patients in diet- treated patients with T2DM. Furthermore palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly in hypertensive patients with type 2 diabetic nephropathy. In conclusion, our results are compatible with a role for UII in glucose homeostasis and diabetes. Although we have not examined previously associated polymorphisms such as S89A, we have studied highly linked SNPs in UTS2 gene region with positive results. However, we cannot rule out the possibility that PER3 gene underlies the reported associations, although the biological relevance of PER3 in glucose metabolism is not well established.