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  • In addition to these effects on metabolic function in


    In addition to these effects on metabolic function in cardiac cells, this study also demonstrates changes in the expression of hypertrophic genes and proteins subsequent to GPR119 activation. Again this occurred in a distinct pattern dependent on palmitate exposure. Of interest SOCS3 mRNAs were decreased basally but increased after palmitate exposure. SOCS3, in addition to its roles in regulating insulin signalling, also has a role in controlling cardiac hypertrophy and left ventricular function (Yasukawa et al., 2012). Cardiac-specific loss of SOCS3 is associated with deleterious increases in dilated cardiomyopathies, cardiac hypertrophy and left ventricular dysfunction and mortality (Yajima et al, 2011, Yasukawa et al, 2001). Basally, the reduction of SOCS3 occurred concurrently with reductions in the mRNA expression of TGFβ1, its downstream target CTGF, and the activation ERK 1/2 protein, all of which are considered pro-hypertrophic and pro-fibrotic (Bueno, Molkentin, 2002, Chen et al, 2000, Rosenkranz, 2004, Ulm et al, 2014), to suggest that it would be unlikely that GPR119 would increase hypertrophy basally. In conditions of temporary palmitate treatment the GPR119 agonist increased the expression of phosphorylated JNK protein and the mRNA expression of TGFβ1. Like TGFβ1, increases in JNK activity are pro-hypertrophic (Wang, 2007). In our hands, 5 µM palmitate induced cell hypertrophy without affecting cell viability. Wang et al. (2009) also demonstrated palmitate-induced hypertrophy in H9c2 cells however this study utilised a higher dose of palmitate which was associated with reduced cell viability. Despite the changes in pro-hypertrophic markers in response to GPR119 agonism seen in the current study, when we measured functional hypertrophic growth GPR119 activation produced no change under any condition of palmitate exposure in the timeframe measured. Consistent with the known effects of GPR119 on glucose control and GLP-1 secretion (Chu et al, 2007, Chu et al, 2008, Gao et al, 2011a, Gao et al, 2011b, Lauffer et al, 2009, Overton et al, 2006), we considered it more likely that GPR119 is a regulator of cardiomyocyte energetics. Given that GLP-1 promotes glucose stimulated insulin secretion, Nourseothricin sulfate glucose uptake and has been shown to be cardioprotective (Chai et al, 2012, Liu et al, 2010, Zhao et al, 2006), the indirect effects of GPR119 agonism secondary to increased plasma GLP-1 may improve cardiac muscle metabolism of glucose and fatty acids and thus agonists which selectively target the gastrointestinal tract may prevent any detrimental effects of direct activation of Nourseothricin sulfate myocardial GPR119.
    Acknowledgements LMC was supported by a scholarship (PB 10M 5472) from the National Heart Foundation of Australia. AJM was supported through the Australian Government's Collaborative Research Networks (CRN) program.
    Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by elevated blood glucose levels in the context of insulin resistance and relative insulin deficiency. Impairments in both insulin production and insulin sensitivity result in a chronic demand for greater β-cell insulin production, which ultimately leads to the gradual loss of pancreatic β-cell function as diabetes progresses. Currently we are in an unprecedented era of explosive increases of diabetes population, from approximately 285million in 2010 to a projection of over 330million diabetics worldwide by 2030. Despite current available treatments such as insulin, metformin, thiazolidinones (TZDs), sulfonylurea derivatives, and dipeptidyl peptidase 4 (DPP-IV) inhibitors, glycemic control represents a significant unmet medical need, due to both the increasing patient population and the ineffectiveness of the above antidiabetic agents over years of treatment. G protein-coupled receptor 119 (GPR119) is a rhodopsin-like, class A G-coupled GPCR, which is predominately expressed in human pancreatic β-cells, where it mediates insulin secretion, and in gastrointestinal L-cells, where it mediates GLP-1 release. The activation of GPR119 increases the intracellular accumulation of cyclic adenosine monophosphate (cAMP), leading to enhanced glucose-dependent insulin secretion from pancreatic β-cells and increased release of the gut hormones such as GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY) from enteroendocrine cells. This dual mechanism of action might produce favorable effects on glucose homeostasis and β-cell preservation, along with other beneficial effects such as reduced food intake and body weight., Scientific evidence has been published by various laboratories demonstrating the capability of small synthetic GPR119 agonists to lower glucose in a variety of animal models. In addition, Overton et al. reported that OEA (oleoylethanolamide, an endogenous agonist of GPR119) and PSN632408 (a synthetic GPR119 agonist) reduced body weight, white adipose tissue depots, and food intake in diet-induced obese rats. Several pharmaceutical companies have entered clinical trials with small molecule GPR119 agonists. This includes: Johnson & Johnson/Arena JNJ-38431055,, Metabolex/Sanofi-Aventis MBX-2982,, GlaxoSmithKline GSK1292263,, and Astellas Pharma PSN821, (). The available clinical data demonstrate the ability of GPR119 agonists to promote incretin release and reduce postprandial glucose excursion. All these results have made GPR119 an attractive drug target for treating diabetes and possibly obesity, with a low propensity to cause hypoglycemia.