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  • While CART increased circulating levels


    While CART increased circulating levels of GIP and GLP-1 in vivo, we were unable to detect any effect of exogenous CART on GIP and GLP-1 mRNA expression or GLP-1 secretion in vitro. There is no ready explanation for this discrepancy. The CART doses used (both in vivo and in vitro) have been shown to stimulate insulin secretion in parallel experiments (Abels et al., 2015). This shows that the peptide is biologically active, but we cannot exclude that other doses of CART would affect GLP-1 and GIP secretion or expression in the cell lines employed. A potential explanation, could be that the stimulatory effect of CART on GIP and GLP-1 observed in vivo is indirect, e.g. via another hormone or via the enteric- or central nervous system. We also studied how L- and K-cell CART is regulated by known stimulators of incretin expression and secretion. Our data show that CART mRNA expression in GLUTag and STC-1 cells was inert to ambient glucose concentration. This is different from the situation in rat pancreatic beta-cells, in which CART expression is increased by glucose (Sathanoori et al., 2013; Abels et al., 2016; Xu et al., 2016). On the other hand, CART expression was increased after culture with palmitate or oleate, depending on cell type. The doses of FFAs were at the higher end and the possibility that CART expression is increased, as part of a stress response cannot be excluded. We also tested whether CART is regulated by GIP and GLP-1. Whereas GLP-1 was without effect, GIP increased CART expression in both cell lines. Whether CART is secreted as a consequence of elevated GIP levels remains to be established. Assessment of CART secretion into the cell media is difficult due to the rather low CART expression levels in the 2-Chlorotrityl Chloride Resin and not enough sensitivity of the available CART assays, thus the use of in vivo models would be preferable. In summary, CART is expressed in K-cells and L-cells in the human upper small intestine, CART increases glucose-stimulated GIP and GLP-1 secretion in vivo in mice, and endogenous CART regulates GLP-1 and GIP expression and GLP-1 secretion in clonal cells. We conclude that CART is a regulator of incretin synthesis and secretion. The therapeutic potential for CART-based agents to improve incretin secretion needs further investigation.
    Author contributions LS performed experiments, drafted and edited the manuscript; AL performed CART EIA and edited the manuscript; AHTF performed in vivo experiments; EA edited and reviewed the manuscript; EZ performed confocal microscopy experiments; SEF provided human specimens and performed histological analyses; ER edited and reviewed the manuscript; JK and HH performed OGTT and MMT; NW conceived the study, drafted and edited the manuscript.
    Conflicts of interest
    Acknowledgements We thank Prof. Pirjo Nuutila (University of Turku, Turku, Finland) for OGTT and MMT studies, and Prof. Claes B. Wollheim (Université de Genève, University Medical Centre, Geneva, Switzerland) for constructive suggestions and discussions. This work was supported by the Swedish Research Council (Project grants: 521-2012-2119, 522-2008-4216, K2009-55X 21111-01-4, 2017-00862), Linneaeus grant to Lund University Diabetes Centre349-2008-6589, SFO EXODIAB 2009-1039), The Novo Nordisk Foundation, The Royal Physiographic Society in Lund, The medical faculty at Lund University, and Crafoord and Albert Påhlsson Foundations.
    Introduction The global prevalence of both type 2 diabetes (T2D) and obesity has steadily increased over the last three decades (Ng et al., 2014, World Health Organization, 2016). Successful management of T2D frequently requires that hyperglycemia and excess body weight are simultaneously addressed. The glucagon-like peptide 1 receptor agonists (GLP-1RAs) are a class of pharmacological agents that address both conditions. GLP-1RAs are therapeutically effective and achieve significant decreases in hyperglycemia and body weight, though the magnitude of body weight reduction is limited and tends to plateau over time (Klonoff et al., 2008, le Roux et al., 2017, Lorenz et al., 2013, Neff and Kushner, 2010). Novel treatments that recruit additional mechanisms of biological action constitute one of the more promising early-phase approaches to safely enhance efficacy when current therapy no longer delivers progressive improvements in disease management (Tschöp et al., 2016).