Dyphylline pancreatic cells of mice results in enhanced insulin secretion

to dyphylline that for placebo.Insulin resistance and impaired insulin secretion are major causes of the onset and development of type 2 diabetes (Muoio and Newgard, 2008). Drugs that enhance insulin secretion, such as sulfonylureas and meglitinides, are commonly used for the treatment of type 2 diabetes. However, these drugs enhance insulin secretion by direct closure of the KATP channel independent of blood glucose levels, thereby causing hypoglycemia (Doyle and Egan, 2003). Hence, patients with diabetes would benefit from the development of a novel antidiabetic drug that has a low hypoglycemic risk and effectively improves blood glucose control.

Secretion of insulin from pancreatic cells is stimulated by glucose and other nutrients, including Vinflunine  free fatty acids (FFAs) (Prentki et al 1997; Haber et al 2003). In isolated human and rodent islets, FFAs enhance insulin secretion in a manner that depends on glucose concentration.Plasma concentrations of FFAs are elevated in the fasted state, and they play a role in the enhancement of the postprandial insulin response in vivo (Stein et al 1996; Dobbins et al 1998). GPR40, a G protein-coupled receptor highly expressed in pancreatic cells, has been identified as a receptor for both saturated and unsaturated medium- and long-chain FFAs (Briscoe et al 2003; Itoh et al 2003; Kotarsky et al 2003). In addition, Itoh et al. (2003) demonstrated that the suppression of GPR40/FFA1 mRNA with small interfering RNA inhibited the enhancement of FFAinduced insulin secretion in mouse insulinoma MIN6 cells, indicating that GPR40/FFA1 is involved in the stimulation of acute insulin secretion by FFAs.

The role of GPR40/FFA1 in insulin secretion has also been confirmed by the use of  supplier flumazenil selective small-molecule GPR40/FFA1 agonists (Briscoe et al 2006; Tan et al 2008). In pancreatic cells, elevation of intracellular calcium triggers insulin secretion (Prentki et al 1997). Generally, activation of Gqprotein-coupled receptors results in phospholipase C activation, inositol 1,4,5-triphosphate (IP3) and diacylglycerol production, and increases in intracellular calcium concentration ([Ca2]i) (Taylor et al 1991). Studies have shown that GPR40/FFA1 is coupled mainly with Gqin rodent cell lines, and agonist stimulation of GPR40/FFA1 with FFAs enhances [Ca2]i and insulin secretion in these cells, which can be blocked by inhibitors of Gqsignaling (Fujiwara et al 2005; Shapiro et al 2005). Whereas FFAs acutely stimulate insulin secretion, chronic exposure to them causes cell dysfunction and/or cell death, so-called lipotoxicity (Haber et al 2003; Morgan, 2009).

Because endogenous ligands of GPR40/FFA1 are medium- and long-chain FFAs, it has price risedronate been suggested that GPR40/FFA1 might mediate chronic toxic effects of FFAs (Steneberg et al 2005). However, conflicting results obtained from GPR40/ FFA1-deficient mice have also been reported (Latour et al 2007; Kebede et al 2008; Lan et al 2008; Alquier et al 2009); these did not show the harmful effects of GPR40/FFA1 in pancreatic cells. Moreover, Nagasumi et al. (2009) have reported that the overexpression of GPR40/FFA1 in pancreatic cells of mice results in enhanced insulin secretion, improved glucose tolerance, and resistance to impairment of glucose tolerance induced by a high-fat diet. Therefore, it remains under debate whether GPR40/FFA1 agonism or antagonism foods would be more favorable for the treatment of type 2 diabetes and related disorders. [(3S)-6-({2 ,6 -dimethyl-4 -[(methylsulfonyl).

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