It is well known that the expression of

It is well known that the expression of GPR109A is regulated under physiological and pathological conditions. We previously found that GPR109A expression in islet beta-cells increased with age and was up-regulated by interferon-γ (Li et al., 2011). GPR109A levels in Min6 and INS-1E islet beta-cells increased significantly in the presence of high glucose and niacin, respectively (Chen et al., 2015, Yang et al., 2015). Further, diabetic retina epithelial NAD/NADH Quantitation Colorimetric Kit express higher levels of GPR109A (Gambhir et al., 2012). In contrast, we found that GPR109A in islet beta-cells was down-regulated dramatically in type 2 diabetic patients as well as in diabetic db/db mice (Fig. 4, Fig. 5), suggesting that GPR109A might play an important role in the prevention of diabetes. However, the molecular mechanism leading to the down-regulation of GPR109A in T2DM is puzzling, since inflammatory cytokines in islets presumably should have stimulated GPR109A expression. Recently, Bardhan et al. reported that IFNγ secreted by activated T cells, could activate GPR109A transcription in colon cancer cells via promoting hyperacetylation of the GPR109A promoter (Bardhan et al., 2015). Therefore, it will be tempting to postulate that genetic factor(s) in T2DM prevent the induction of GPR109A. Alternatively, long-term hyperglycemia may stimulate proliferation and de-differentiation of islet beta-cells (Jonas et al., 1999), leading to reduced GPR109A expression. Furthermore, the expression of GPR109A in insulinoma was severely down-regulated (Fig. 6). Consistently, transcripts of GPR109A in INS-1 and NIT-1, which were derived from rodent insulinoma, were 100-fold lower than that of freshly isolated murine islets (Fig. 7). Similar observation has been reported in colon epithelial cells, that GPR109A expression is silenced in colon cancer cells, and that transgenic expression and stimulation with niacin induced apoptosis in colon cancer cells by blocking NF-κB activation (Singh et al., 2014), showing that GPR109A has the tumor-suppressive effects on colon cancer. However, when GPR109A was over-expressed in INS-1 cells, apparently, we did not notice significant cell death in the presence of niacin stimulation. Therefore, the role of GPR109A in the development of insulinoma is not clear. One technical explanation is that the concentration of niacin used in this study was much lower than that used for colon cancer cells (Singh et al., 2014). Consistent with our previous report, intracellular cAMP induced by IBMX/forskolin was inhibited in INS-1 cells in the presence of niacin (Fig. 8). Of note, without the expression of a transgenic GPR109A, intracellular cAMP reduced only subtly, probably reflecting the fact that endogenous expression of GPR109A in INS-1 cells was extremely low (Fig. 7). In any event, over-expression of GPR109A of either mouse or human origin in INS-1 cells conferred a significantly greater reduction of cAMP accumulation, which was abrogated completely by the pretreatment of PTX, suggesting that GPR109A signaling via Gi is functional in both murine and human islets. Consistent with the inhibition of cAMP accumulation, GSIS from INS-1 cells, especially when transfected with GPR109A, was significantly suppressed in the presence of niacin (Fig. 9). The result might provide part of the reasons that glycemic control was aggravated in diabetic patients under chronic niacin medication.
Conflict of interest
Acknowledgments The authors would like to thank Youhong Cui and Miao Chen for their valuable advices. This research was supported by the Li Ka Shing Foundation; the Natural Science Foundation of China (http://www.nsfc.gov.cn/ Grant Nos. 30971665, 81172894, 81370925); and the Education Department of Guangdong (http://www.gdhed.edu.cn/ Grant No. cxzd1123). Informed consent was obtained from all individual participants included in the study.
Introduction Nicotinic acid has been used clinically for more than 50 years [1] since it has anti-atherogenic effects, including the ability to reduce triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), and elevate high-density lipoprotein cholesterol (HDL-C) [2]. Nicotinic acid administration rapidly lowers non-esterified fatty acid (NEFA) levels, many literature described this was the core mechanism by which nicotinic acid provides its effect on lipids metabolism. In particular, a lowering of the NEFA substrate limits hepatic TG synthesis and TG secretion as very low density lipoprotein (VLDL) from the liver [[1], [2], [3], [4]]. Although the proposed mechanism requires further investigation, reduced VLDL production is believed to be one of the mechanism to cause other anti-dyslipidemic effects, including LDL-C reduction and HDL-C elevation [2,4].