Niacin Treatment Research Articles

Niacin ameliorates ulcerative colitis via prostaglandin D2‐mediated D prostanoid receptor 1 activation

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.

Effects of niacin and betaine on bovine mammary and uterine cells exposed to thermal shock in vitro

The objective of this study was to investigate the direct effects of feed supplements niacin and betaine on the heat shock responses of in vitro cultured cells derived from bovine mammary and uterine tissues. First, we determined the mRNA expression profiles of the niacin receptor (GPR109A) in bovine tissues (liver, skin, uterus, udder, and ovary) and in cells derived from bovine mammary epithelium (mammary alveolar cells, MAC-T; bovine mammary epithelial cells, BMEC) and endometrium (bovine endometrial cells, BEND). We found that GPR109A was distributed in all examined tissues and cells, and the highest expression was in cells from skin and udder. Second, we evaluated the effects of niacin treatment on the mRNA abundance of heat shock proteins 70 and 27 (HSP70 and HSP27) in MAC-T, BMEC, and BEND under thermoneutral conditions and heat stress, and whether these effects were associated with alterations in the mRNA expression of prostaglandin E2 synthesis-related genes, including cyclooxygenase 1 and 2 (COX-1 and COX-2) and microsomal prostaglandin E synthase 1 and 2 (mPGES-1 and mPGES-2). Quantitative PCR data indicated that niacin suppressed HSP70 mRNA expression in BMEC and both HSP70 and HSP27 in BEND under thermoneutral conditions. Only COX-2 expression was downregulated by niacin in BMEC; other prostaglandin E2 synthesis-related genes stayed unaltered in BMEC and BEND. The mRNA abundance of HSP70, COX-1, COX-2, and mPGES-1 were elevated in niacin-treated MAC-T. During heat stress, niacin increased mRNA levels of HSP70 and HSP27 in MAC-T and HSP27 in BEND, but decreased HSP70 in BMEC. Although mPGES-2 was stimulated by niacin in BEND, the mRNA expression of prostaglandin E2 synthesis-related genes were consistent with neither HSP70 nor HSP27 expression patterns in niacin-treated BMEC and MAC-T. These data suggest that the effects of niacin on heat shock protein expression and prostaglandin E2 synthesis were not well coupled in these cells. Finally, we tested the effects of betaine treatment on viability and apoptosis in BMEC. Compared with control cultures, viability was higher in betaine-treated cells at 8 h under thermoneutral conditions and at 16 h in heat stress, and apoptotic rates were lower at 8 h. Our data support a dual role for niacin in regulating heat shock protein expression in normal and heat-shocked cells derived from mammary and uterine tissues, and positive effects of betaine in regulating mammary cell viability during heat stress.

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1.

Niacin is a well established drug used to lower cholesterol and prevent cardiovascular disease events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin D2 (PGD2). Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant [a PGD2 receptor subtype 1 (DP1) blocker] to statin-based therapies does not significantly decrease the risk of cardiovascular disease events, but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects on myocardial ischemia require the activation of the PGD2/DP1 axis. Myocardial infarction (MI) was reproduced by ligation of the left anterior descending branch of the coronary artery in mice. We found that niacin increased PGD2 release in macrophages and shifted macrophages to M2 polarization both in vitro and in vivo by activation of DP1 and accelerated inflammation resolution in zymosan-induced peritonitis in mice. Moreover, niacin treatment facilitated wound healing and improved cardiac function after MI through DP1-mediated M2 bias and timely resolution of inflammation in infarcted hearts. In addition, we found that niacin intake also stimulated M2 polarization of peripheral monocytes in humans. Collectively, niacin promoted cardiac functional recovery after ischemic myocardial infarction through DP1-mediated M2 polarization and timely resolution of inflammation in hearts. These results indicated that DP1 inhibition may attenuate the cardiovascular benefits of niacin.

Recent explanatory trials of the mode of action of drug therapies on lipoprotein metabolism.

Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.

Functionality of High-Density Lipoprotein as Antiatherosclerotic Therapeutic Target.

A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease.1,2 Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease.1 Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%.3 However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk.2,4 Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is …

Role of Niacin in Current Clinical Practice: A Systematic Review

BackgroundNiacin, a potent high-density lipoprotein cholesterol-raising drug, seems an attractive approach to reduce cardiac events in patients with or at risk of atherosclerotic cardiovascular disease. However, previous evidence for niacin has been challenged recently by negative outcomes in 2 large, randomized, controlled trials comparing niacin to placebo with background statin therapy. We studied the currently available evidence for the role of niacin treatment for reducing the risk of cardiovascular events in current practice. MethodsA systematic review of randomized controlled trials in the MEDLINE, EMBASE, CINAHL, and Cochrane databases comparing niacin alone or combined with statin therapy was performed. We extracted trial level data, including basic characteristics and number of patients enrolled, duration of follow up, occurrence of adverse events, and cardiovascular-related outcomes. Random effects meta-analysis was conducted to estimate the risk ratio (RR) for individual trial endpoints. ResultsThirteen trials (N = 35,206) were selected for final analysis. The mean follow-up duration was 32.8 months. Overall, niacin led to significant increases in serum high-density lipoprotein cholesterol levels from baseline trial enrolment by 21.4%, 9.31 (95% confidence interval [CI] 5.11-13.51) mg/dL. However, we did not observe any differences in all-cause mortality rates (RR 0.99; 95% CI 0.88-1.12) between niacin and control arms. Further, niacin treatment was associated with a trend toward lower risk of cardiovascular mortality (RR 0.91; 95% CI 0.81-1.02), coronary death (RR 0.93; 95% CI 0.78-1.10), nonfatal myocardial infarction (RR 0.85; 95% CI 0.73-1.0), revascularization (coronary and noncoronary) (RR 0.83; 95% CI 0.65-1.06), and stroke (RR 0.89; 95% CI 0.72-1.10), compared with control. ConclusionNiacin therapy does not lead to significant reductions in total or cause-specific mortality or recurrent cardiovascular events among persons with or at risk of atherosclerotic cardiovascular disease.

Effect of niacin on lipoprotein subfractions concentration in patients with elevated lipoprotein(a)

Objectives: To investigate changes of lipoprotein subfractions concentrations in patients with elevated level of lipoprotein(a) [Lp(a)] on niacin treatment.

Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials

AimLipoprotein(a) (Lp(a)) is a proatherogenic and prothrombotic lipoprotein. Our aim was to quantify the extended-release nicotinic acid Lp(a) reducing effect with a meta-analysis of the available randomized clinical trials. MethodsA meta-analysis and random-effects meta-regression were performed on data pooled from 14 randomized placebo-controlled clinical trials published between 1998 and 2015, comprising 17 treatment arms, which included 9013 subjects, with 5362 in the niacin arm. ResultsThe impact of ER niacin on plasma Lp(a) concentrations was reported in 17 treatment arms. Meta-analysis suggested a significant reduction of Lp(a) levels following ER niacin treatment (weighted mean difference – WMD: −22.90%, 95% CI: −27.32, −18.48, p<0.001).Results also remained similar when the meta-analysis was repeated with standardized mean difference as summary statistic (WMD: −0.66, 95% CI: −0.82, −0.50, p<0.001). When the studies were categorized according to the administered dose, there was a comparable effect between the subsets of studies with administered doses of <2000mg/day (WMD: −21.85%, 95% CI: −30.61, −13.10, p<0.001) and ≥2000mg/day (WMD: −23.21%, 95% CI: −28.41, −18.01, p<0.001).The results of the random-effects meta-regression did not suggest any significant association between the changes in plasma concentrations of Lp(a) with dose (slope: −0.0001; 95% CI: −0.01, 0.01; p=0.983), treatment duration (slope: −0.40; 95% CI: −0.97, 0.17; p=0.166), and percentage change in plasma HDL-C concentrations (slope: 0.44; 95% CI: −0.48, 1.36; p=0.350). ConclusionIn this meta-analysis of randomized placebo-controlled clinical trials, treatment with nicotinic acid was associated with a significant reduction in Lp(a) levels.

Dietary Niacin Supplementation Suppressed Hepatic Lipid Accumulation in Rabbits.

An experiment was conducted to investigate the effect of niacin supplementation on hepatic lipid metabolism in rabbits. Rex Rabbits (90 d, n = 32) were allocated to two equal treatment groups: Fed basal diet (control) or fed basal diet with additional 200 mg/kg niacin supplementation (niacin). The results show that niacin significantly increased the levels of plasma adiponectin, hepatic apoprotein B and hepatic leptin receptors mRNA (p<0.05), but significantly decreased the hepatic fatty acid synthase activity and adiponectin receptor 2, insulin receptor and acetyl-CoA carboxylase mRNA levels (p<0.05). Plasma insulin had a decreasing tendency in the niacin treatment group compared with control (p = 0.067). Plasma very low density lipoproteins, leptin levels and the hepatic adiponectin receptor 1 and carnitine palmitoyl transferase 1 genes expression were not significantly altered with niacin addition to the diet (p>0.05). However, niacin treatment significantly inhibited the hepatocytes lipid accumulation compared with the control group (p<0.05). In conclusion, niacin treatment can decrease hepatic fatty acids synthesis, but does not alter fatty acids oxidation and triacylglycerol export. And this whole process attenuates lipid accumulation in liver. Besides, the hormones of insulin, leptin and adiponectin are associated with the regulation of niacin in hepatic lipid metabolism in rabbits.

Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation.

Niacin, also known as vitamin B3 or nicotinamide is a water-soluble vitamin that is present in black beans and rice among other foods. Niacin is well known as an inhibitor of metastasis in human breast carcinoma cells but the effect of niacin treatment on TRAIL-mediated apoptosis is unknown. Here, we show that niacin plays an important role in the regulation of autophagic flux and protects tumor cells against TRAIL-mediated apoptosis. Our results indicated that niacin activated autophagic flux in human colon cancer cells and the autophagic flux activation protected tumor cells from TRAIL-induced dysfunction of mitochondrial membrane potential and tumor cell death. We also demonstrated that ATG5 siRNA and autophagy inhibitor blocked the niacin-mediated inhibition of TRAIL-induced apoptosis. Taken together, our study is the first report demonstrating that niacin inhibits TRAIL-induced apoptosis through activation of autophagic flux in human colon cancer cells. And our results also suggest that autophagy inhibitors including genetic and pharmacological tools may be a successful therapeutics during anticancer therapy using TRAIL.

GW26-e0196 Effects of Niacin on ApoE-/- Mice’ Adipose Tissue, Serum Lipid and Atherosclerosis

To investigate the effects of Niacin on ApoE-/- mice' adipose tissue, serum lipid and atherosclerosis, and furthermore to explore the potential relation among them. Total 28 male ApoE-/- mice were randomly divided into 3 groups: control group (n =8), model group (n =10), Niacin treatment group (n

Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials

ObjectivePrevious studies have suggested that niacin treatment raises glucose levels in patients with diabetes and may increase the risk of developing diabetes. We undertook a meta-analysis of published and unpublished...

Blood Lipids and Type 2 Diabetes Risk: Can Genetics Help Untangle the Web?

Emerging data from randomized trials have shown that a growing number of lipid-lowering drugs appear to influence glycemic control in addition to their hypolipidemic effects. Statins have been shown conclusively in large meta-analyses of randomized trials to increase, albeit modestly, the risk of new-onset type 2 diabetes (T2D) in an apparently dose-dependent manner (1–3). In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, treatment with torcetrapib, a CETP inhibitor that raised HDL cholesterol (HDL-C) concentrations, improved glycemic control (4), but in the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study, niacin treatment, which also raised HDL-C, raised blood glucose and T2D risk (5). In a recent intriguing observational study, notwithstanding the inevitable limitations of its design, patients with familial hypercholesterolemia (FH) appeared less likely to develop T2D (6). Evidence is therefore emerging for a relationship between circulating lipid concentrations and/or their therapeutic/genetic modulators and alterations in glycemia. The mechanisms underlying such relationships remain uncertain and are the subject of much research, not least because they may reveal new drug targets for diabetes or help in the mitigation of dysglycemia risks with specific therapies. In this issue of Diabetes , Fall et al. (7 …

Extended-Release Niacin Versus Fenofibrate in HIV-Infected Participants With Low High-Density Lipoprotein Cholesterol: Effects on Endothelial Function, Lipoproteins, and Inflammation.

Low levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with increased cardiovascular disease (CVD) risk. Virologically controlled participants without CVD on stable ART with low HDL-C (men <40 mg/dL, women <50 mg/dL) and triglycerides >150 mg/dL were randomized to receive open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks. The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in participants with complete follow-up scans. Of 99 participants, 74 had complete data (35 niacin, 39 fenofibrate). Median age was 45 years, 77% were male, median CD4(+) count was 561 cells/µL, and brachial FMD was 4.2%. Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the median (interquartile range) change was +0.6% (-1.6 to 2.3) with niacin (P = .28) and +0.5% (-1.0 to 3.0) with fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels. Despite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or inflammatory markers in participants with well-controlled HIV infection and low HDL-C. NCT01426438.

Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype

BackgroundLipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. MethodsFor this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 ± 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5–2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin–antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. ResultsAt baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. ConclusionHigh-dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype.

Niacin Ameliorates Kidney Warm Ischemia and Reperfusion Injury–Induced Ventricular Dysfunction and Oxidative Stress and Disturbance in Mitochondrial Metabolism in Rats

ObjectiveKidney ischemia and reperfusion (I/R) injury–associated acute and chronic kidney injury often leads to cardiac dysfunction, which may involve depletion of intracellular NAD+ (the oxidized form of the nicotinamide adenine dinucleotide coenzyme) and reduction in intracellular adenosine triphosphate (ATP) levels, resulting in mitochondrial dysfunction. We examined whether treatment with niacin, an antioxidant and a component of NAD+, protects cardiac function and improves myocardial mitochondrial metabolism during kidney I/R injury. MethodsStudies were performed in Sprague-Dawley male rats divided into sham-operated, kidney I/R, and niacin-treated kidney I/R groups. Niacin was administered 3 days before the ischemia through 7 days of reperfusion. Kidney ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. After 7 days of reperfusion, we measured the cardiac function using a simultaneous pressure-volume catheter, cardiac biomarker (troponin T; cTnT), and kidney injury marker (creatinine and blood urea nitrogen). Myocardial malondialdehyde level and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α mRNA expression also were measured. ResultsKidney I/R injury impairs cardiac function, induces myocardial and kidney injury, and markedly increases myocardial PGC-1α mRNA expression, suggesting utilizing more free fatty acid for ATP production. Niacin treatment improved cardiac function, reduced oxidative stress, and sustained PGC-1α expression (P < .05). ConclusionsKidney I/R-associated cardiac dysfunction is likely associated with increases in myocardial lipid peroxidation and utilizing more free fatty acid for ATP production. Niacin improves mitochondrial metabolism and reduced myocardial oxidative stress.

A Pilot Trial to Examine the Effect of High-Dose Niacin on Arterial Wall Inflammation Using Fluorodeoxyglucose Positron Emission Tomography

Although studies have reported direct inhibition of inflammatory pathways with niacin, the effect of niacin on arterial wall inflammation remains unknown. We examined the effect of niacin on arterial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). Nine statin-treated patients with coronary disease were randomized to niacin 6000 mg/day or placebo. FDG-PET/CT and lipids were assessed at baseline and at 12 weeks. FDG was quantified in the aorta, right carotid artery, and left carotid artery as the target-to-background ratio (TBR) and target-to-background difference (TBD). Eight patients completed the study. No significant changes in FDG measured by aortic, left carotid, or right carotid TBR or TBD were seen in either group. Compared to baseline, niacin-treated subjects exhibited a significant 29% reduction in low-density lipoprotein cholesterol (LDL-C; 95% confidence interval [CI], -50% to 8%; P = .01) and a nonsignificant 29% reduction in LDL particle number (LDL-P; 95% CI, -58% to 0.2%; P = .07). A nonsignificant 11% increase in HDL-C (95% CI, -15% to 37%; P = .30) and 8% decrease in HDL-P (95% CI, -44% to 28%; P = .51) were observed with niacin treatment. In a pooled analysis, changes in LDL-P were positively correlated with FDG uptake in the aorta (TBR r = 0.66, P = .08; TBD r = 0.75, P = .03), left carotid (TBR r = 0.65, P = .08; TBD r = 0.74, P = .03), and right carotid (TBR r = 0.54, P = .17; TBD r = 0.61, P = .11). In this pilot study, adding niacin to statin therapy did not affect arterial wall inflammation measured by FDG-PET/CT. However, an association between changes in arterial FDG uptake and LDL-P was observed. Larger studies are needed to definitively examine the effect of niacin on arterial wall inflammation.

Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets

The widely used lipid-lowering drug niacin is reported to induce hyperglycemia during chronic and high-dose treatments, but the mechanism is poorly understood. Recently, the niacin receptor [G-protein-coupled receptor, (GPR) 109a], has been localized to islet cells while its potential role therein remains unclear. We, therefore, aimed at investigating how GPR109a regulates islet beta-cell function and its downstream signaling using high-fat diet-induced obese mice and INS-1E beta cells. Eight-week niacin treatment elevated blood glucose concentration in obese mice with increased areas under the curve at oral glucose and intraperitoneal insulin tolerance tests. Additionally, niacin treatment significantly decreased glucose-stimulated insulin secretion (GSIS) but induced peroxisome proliferator-activated receptor gamma (Pparg) and GPR109a expression in isolated pancreatic islets; concomitantly, reactive oxygen species (ROS) were transiently increased, with decreases in GSIS, intracellular cyclic adenosine monophosphate (cAMP) accumulation and mitochondrial membrane potential (ΔΨm), but with increased expression of uncoupling protein 2 (Ucp2), Pparg and Gpr109a in INS-1E cells. Corroborating these findings, the decreases in GSIS, ΔΨm and cAMP production and increases in ROS, Pparg and GPR109a expression were abolished in INS-1E cells by GPR109a knockdown. Our data indicate that niacin-induced pancreatic islet dysfunction is probably modulated through activation of the islet beta-cell GPR109a-induced ROS-PPARγ-UCP2 pathways.

Niacin in the Treatment of Hyperlipidemias in Light of New Clinical Trials: Has Niacin Lost its Place?

Niacin is considered to be a powerful drug for the treatment of lipid and lipoprotein abnormalities connected with “residual cardiovascular risk”, which persist in high-risk patients even when the target goals of LDL-C are achieved with statin therapy. Recent large randomized clinical studies – AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides) and HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) – delivered some disappointing results, leading to the conclusion that no further benefit (decreased parameters of cardiovascular risk) is achieved by adding niacin to existing statin therapy in patients with high cardiovascular risk. Moreover, in these studies, several adverse effects of the treatment were observed; therefore, niacin treatment for hypolipidemias is not recommended. In this paper, we analyze the mechanisms underlying the hypolipidemic and antiatherogenic effects of niacin as well as some limitations of the designs of the AIM HIGH and HP2-THRIVE studies. We also provide the possibilities of rational usage of niacin for specific types of dyslipidemias.

Niacin reverses migratory macrophage foam cell arrest mediated by oxLDL in vitro.

IntroductionNiacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress. Here, we evaluate whether Niacin reverses the redox sensitive migratory arrest of macrophages in response to oxidised(ox) LDL uptake.Material and MethodsMigration of RAW264.7 cells, a murine macrophage cell line and bone marrow derived macrophages from wildtype and iNOS knockout mice was quantified using a modified Boyden chamber. Unstimulated cells or cells preincubated with oxLDL or non-oxidised (n)LDL were treated with Nicotinic acid or Nicotinamide. Nitric oxide, peroxynitrite and ROS production were assessed using electron paramagnetic resonance (ESR). Additionally, flow cytometry analysis of apoptosis, fokal adhesion kinase (FAK), phalloidin, CD36, F4/80 macrophage marker and iNOS gene expression (PCR) were assessed.ResultsMigration of Nicotinic acid, Nicotinamide treated cells or unstimulated cells did not differ (P>0.05). oxLDL treatment significantly reduced migration vs. unstimulated cells (p<0.05). In contrast, migratory arrest in response to oxLDL treatment was reversed by co-incubation with Nicotinic acid and Nicotinamide. The oxLDL-induced peroxynitrite formation in RAW264.7 cells was abolished by Niacin and glutathion (GSH) oxidation was significantly reduced. However, nitric oxide (NO)- and reactive oxygen species (ROS) production induced by oxLDL were not affected by Niacin treatment of RAW264.7 cells. In addition, Nicotinic acid and Nicotinamide reduced actin polymerization, a marker for migratory arrest.DiscussionOur data shows that oxLDL induced inhibition of macrophage migration in vitro can be reversed by Niacin. Furthermore, Niacin reduces peroxynitite formation and improves antioxidant GSH.