br Conclusion br Acknowledgment This study was supported by

Conclusion
Acknowledgment This study was supported by grants from the Excellence Initiative of the German federal and state governments, the Else Kröner-Fresenius Foundation and the German Society for Cardiology (DGK) to F.K. and grants from the Deutsche Forschungsgemeinschaft (SFB TRR 219 M-03) and the Marga und Walter Boll-Stiftung, to M.L.
Introduction Reduced incretin secretion and action are hallmarks of Type 2 Diabetes (T2D) (Holst et al., 2011; Rask et al., 2001). It is well established that the insulinotropic effect of glucose-dependent insulinotropic polypeptide (GIP) is reduced in T2D subjects, while obesity is associated with increased GIP levels. Glucagon-like peptide-1 (GLP-1) plasma levels are lower in T2D patients, but its insulinotropic effect is retained in T2D (Holst et al., 2011; Nauck et al., 1993a, 1993b; Vilsboll et al., 2003). This is the basis for the success of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors in the treatment of T2D patients (Rask et al., 2001; Nauck et al., 1993a). Cocaine- and amphetamine-regulated transcript (CART) is a brain-gut peptide with a wide range of biological effects as a neurotransmitter and as a hormone (Rogge et al., 2008; Ekblad et al., 2003). Post-translational processing of CART may differ in central and peripheral tissues (Thim et al., 1999) resulting in two major biologically active fragments CART 55–102 and CART 62–102 (Thim et al., 1999; Dey et al., 2003). Importantly, the carboxy-termini (exon 3) is found in all CART peptides and contains six cysteine residues forming disulphide bonds that are crucial for the biological activity of CART (Thim et al., 1998). Both major CART forms have been shown to be biologically active, however activity differences were also reported (reviewed in (Dylag et al., 2006)). CART expression has been demonstrated in the central, peripheral and enteric nervous systems (Ekblad et al., 2003; Kristensen et al., 1998; Kuhar et al., 2000), in adipose tissue (Banke et al., 2013), as well as in endocrine A-803467 sale in the pancreatic islets (Wierup and Sundler, 2006; Wierup et al., 2004a), the thyroid (Wierup et al., 2007) and the adrenal medulla (Wierup et al., 2007; Koylu et al., 1997). CART has been demonstrated in blood (Bech et al., 2008; Ramachandran et al., 2015; Vicentic et al., 2004; Yilmaz et al., 2014), however information on the regulation of CART secretion and about the main sources of circulating CART is limited (Rogge et al., 2008; Bech et al., 2008; Vicentic et al., 2004). In appetite-regulating nuclei of the hypothalamus CART acts as an inhibitor of food intake (Rogge et al., 2008; Kristensen et al., 1998), and Cart−/− mice develop obesity (Wierup et al., 2005; Asnicar et al., 2001). Cart−/− mice also exhibit impaired glucose tolerance due to insufficient insulin release, prior to the onset of obesity (Wierup et al., 2005). Furthermore, CART increases insulin secretion from isolated human and mouse islets, as well as in vivo in mice (Abels et al., 2015). In addition, CART further potentiates GLP-1-enhanced glucose-stimulated insulin secretion (Abels et al., 2015; Wierup et al., 2006). Similar to the incretin hormones, the effect of CART on insulin secretion is glucose-dependent (Abels et al., 2015). However, the mechanisms behind the action of CART are difficult to dissect as specific CART receptor(s) has not been identified. The effect of CART on ERK activation in neuronal cell lines (Lakatos et al., 2005) and inhibition of voltage-gated Ca2+ channels in neurons (Yermolaieva et al., 2001) has been shown to be pertussis toxin-sensitive, suggesting that CART binds to a Gi/o GPCR. On the other hand, in beta-cells, we have shown that CART increases cAMP levels (Sathanoori et al., 2013) and potentiates insulin secretion in a cAMP/PKA-dependent manner in vitro (Wierup et al., 2006), indicating the involvement of Gαs in the mediation of the effects of CART in beta-cells. Furthermore, alike GLP-1, CART decreases glucagon secretion in mouse and human islets and in vivo in mice (Abels et al., 2015) and protects beta-cells from glucotoxicity-induced cell death in vitro in rats (Sathanoori et al., 2013).