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    • Our data for glucose and insulin

    2022-06-28

    Our data for glucose and insulin tolerance tests indicate that niacin-induced hyperglycemia is proportional to the degree of insulin resistance induced, implying that there is deterioration in islet function with niacin treatment (McCulloch et al., 1991). In this regard, we have demonstrated, for the first time, chronic adverse effects of niacin on pancreatic islet function as evidenced by reduced GSIS, despite the fact that islet architecture was unchanged (Fig. 2, Fig. 3). These data appear contradictory to our further finding, that cAMP levels are decreased by niacin which should, in turn, promote cell death, since it is reported that cAMP promotes pancreatic beta-cell survival (Jhala et al., 2003). In examining other potentially relevant factors with important roles in regulating beta-cell energy metabolism and survival, however, we found a notable induction of Pparg and Ucp2 mRNA in vivo and in vitro, providing a possible mechanistic explanation for niacin-induced attenuation of GSIS in beta cc-5013 (Ravnskjaer et al, 2005, Zhang et al, 2001). This mechanism also helps explain the increase in beta cell survival, since UCP2 can be protective for beta cells, while PPARγ activation can enhance beta cell proliferation as well as protecting beta cells from apoptosis (Han et al, 2008, Kanda et al, 2009). In addition, induction of UCP2 may also be indirectly controlled by PPARγ activation (Bugge et al, 2010, Medvedev et al, 2002) and previous work has shown UCP2-knockout mice not to become insulin resistant on long-term high-fat diets (Joseph et al., 2002). Together, these data suggest that enhancement of UCP2 production could contribute to deterioration in insulin resistance with niacin. Our further study using UCP2-specific inhibitors showed that they abolished the effect of niacin on cell viability (Fig. S2A); we suggest that this is because niacin induces a defensive response in INS-1E cells, mediated via UCP2, since with inhibition of UCP2, niacin-induced ROS and other damage cannot be salvaged, which would lead to beta cell death; findings that provide further evidence to suggest that UCP2 may provide a protective mechanism preventing niacin-induced beta-cell death. Our present studies on ROS and ΔΨm suggests a further novel modulatory action of niacin on islet beta cells, which differs from previous findings in other cell types, in that niacin can decrease, but not increase, ROS levels (Benavente and Jacobson, 2008); these data also suggest that ROS generation may occur exclusively in the cytoplasm, through NAD(P)H oxidase (Fig. 5A and B), which is closely associated with NAD+ and NAD(P)H levels (Ying, 2008), and we also found that niacin had a unique action in reducing NAD+ and NAD/NADH ratios in INS-1E cells (unpublished data, not shown), which could itself contribute to increasing the generation of cytosolic ROS. However, how niacin decreases NAD+ in beta cells remains unclear and requires elucidation. The present study is the first, we believe, to demonstrate clearly the significant role of GPR109a in regulating islet beta-cell function. Remarkably, we found that niacin blunted first phase insulin secretion during OGTT (Fig. 2D), indicative of progression from normal glucose tolerance to impaired glucose tolerance and likely to be relevant to the enhanced postprandial plasma glucose seen in humans (Del Prato et al., 2002), since siRNA-knockdown of GPR109a, specifically in INS-1E cells, confirmed its novel function in beta cells (Fig. 6). It is noteworthy that the reduction of niacin-induced GSIS in GPR109a-knockdown cells supports the existence of a modulatory role of GPR109a, as does the fact that niacin-induced suppression of intracellular cAMP level was abolished in GPR109a knock-down cells. A signaling cascade governs normal insulin release in beta cells, including cytoplasmic Ca2+ and cAMP concentrations, the latter being known to amplify Ca2+-triggered exocytosis (secretion) of insulin granules (Grapengiesser et al, 1988, Landa et al, 2005). In regard to our findings, one important issue still to be addressed is the relationship between PPARγ and cAMP signaling (McQuaid et al., 2006). Substantive studies in other cell types have shown that PPARγ can be activated by niacin through its receptor GPR109a, and cAMP is also reported to be directly regulated by this receptor (Knowles et al, 2006, Rubic et al, 2004). Our current findings make a preliminary start on identifying the signaling pathway(s) of GPR109a, and its downstream effects on beta cells. As shown in Fig. 7, intracellular cAMP is regulated by GPR109a directly. Though PPARγ is a putative downstream signal from GPR109a, conveying the effects of niacin on the regulation of insulin secretion in beta cells, it is possible that this signaling is itself affected by UCP2 through its crosstalk with PPARγ.