Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas

Abstract

Objective: Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts. Methods: The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA. Results: Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC 50 : 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr 6 ]UII(4 -11). In contrast, [Ala 8 ]UII(4 -11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII.Conclusions: Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only ]UII(4 -11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.European Journal of Endocrinology 151 803-809

Human Urotensin II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages

“…6 Plasma U-II levels are known to be high in patients with diabetes mellitus. 8 Animal experiments have shown that U-II inhibits glucose-induced insulin release from pancreatic ␤-cells, 29 and stimulates hyperlipidemia by channeling glucose to free fatty acid synthesis. 30 These findings suggest that U-II may be associated with metabolic syndrome.…”

Role of urotensin II in health and disease

“…At high concentrations (100 nmol/l) frog UII inhibits glucose-and arginine-induced insulin responses in the rat pancreas (112). When synthetic rat UII was used on the same model, a dose-dependent inhibition of glucose-induced insulin release was observed once again (IC 50 ϭ 0.12 nmol/l) (111). This insulinostatic pathway of inhibition is independent of the somatostatin pathway (86).…”

“…In humans, single nucleotide polymorphism analysis in the Hong-Kong Chinese population confirmed that certain UTS2 gene haplotypes are associated with insulin resistance and pancreatic ␤-cell function (92). Thus, UII likely plays an important and direct inhibitory role on ␤-cell insulin secretion in an autocrine/paracrine manner, and may contribute to insulin resistance in pathological settings (111).…”

“…Hyperglycemia and insulin resistance are two interrelated components of the metabolic syndrome, and both are related to UII. UII and the UT receptor are both expressed in the pancreatic islets (111). In salmon, UII increases glucose-6-phosphatase activity and reduces liver glycogen content (107).…”

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…The UII gene is also expressed in the human and rat pancreas (Coulouarn et al, 1998;Ames et al, 1999;Sugo et al, 2003), and the evidence of the presence of the UII peptide has been found in a rat pancreas extract by reversed-phase HPLC analysis combined with radioimmunoassay detection (Silvestre et al, 2004), suggesting that UII may control pancreatic activity. The effect of UII on the endocrine pancreas has been studied using an in situ perfused rat pancreas model (Silvestre et al, 1986).…”