Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects

Kelly, John J.; Lawson, J A; Campbell, Lesley V.; Storlien, Leonard H; Jenkins, A. B.; Whitworth, Judith A.; O’Sullivan, Anthony J

doi:10.1038/sj.jhh.1001099

Cited by 57 publications

(44 citation statements)

References 34 publications

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“…Consistent with this idea, fasting plasma FFA levels decreased in healthy subjects during the first week of NA treatment but rebounded to control levels after 2 wk (2), and increased fasting FFA levels have been observed after 2 wk or more of NA treatment (32,33). Because FFA rebound may offset some of the lipid-lowering effects of NA and/or cause insulin resistance (2,22,32,42), it is important to understand the underlying mechanisms.…”

mentioning

confidence: 80%

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Choi

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue. Am J Physiol Endocrinol Metab 300: E1012-E1021, 2011. First published March 8, 2011; doi:10.1152/ajpendo.00650.2010.-Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipidlowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (Ͼ60%, P Ͻ 0.01), and this effect was maintained for Ն5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P Ͻ 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment. hypolipidemic drug; free fatty acids; perilipin; phosphodiesterase; triglyceride synthesis; insulin resistance; nicotinic acid receptor; microarray analysis NICOTINIC ACID (NA; or niacin) is a B-group vitamin. In addition to its function as a vitamin, NA, in high doses, has been used as a lipid drug for five decades (6, 21); it produces very desirable effects such as decreasing plasma triglycerides (TG), VLDL, and LDL-cholesterol levels and increasing HDL-cholesterol levels (14,38). Major clinical trials have demonstrated that NA treatment reduces the progression of atherosclerotic cardiovascular disease (9, 18). The lipid-lowering effects of NA have traditionally been attributed to its antilipolytic effect in adipocytes (10). NA binds to and stimulates a G proteincoupled receptor [i.e., GPR109A or HM74A (37, 41)] in the plasma membrane of adipo...

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confidence: 80%

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Choi

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…The suppression of lipolysis by nicotinic acid is followed by a rebound in FFA release, such that the levels of FFA rise above the baseline upon washout of the effect (Pereira, 1967;Blackard and Heidingsfelder, 1969). The rebound has been suggested to be responsible for the paradoxical decrease in insulin sensitivity observed when using large doses of nicotinic acid (Kelly et al, 2000;Poynten et al, 2003). The mechanism of FFA rebound with nicotinic acid remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Dhalla

Santikul²,

Smith³

et al. 2007

J Pharmacol Exp Ther

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Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A 1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619, a novel partial A 1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p Ͻ 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A 1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

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“…Nicotinic acid, an alternative agent suggested for addition to statin therapy for management of combined dyslipidaemia, appears to decrease insulin sensitivity by about 15-20%. [26][27][28] Clinical studies show that whereas acute treatment with nicotinic acid inhibits hormone-sensitive lipase, prolonged administration (for at least three months) resulted in a rebound deleterious increase in free fatty acid levels. 29 There was no rebound increase in free fatty acid levels in another study in individuals with metabolic syndrome who were treated with fenofibrate for three months.…”

Section: Reduction Of Cardiovascular Risk Beyond Statin Therapymentioning

confidence: 99%

The role of fenofibrate in clinical practice

Zambón

Cusi

2007

Diabetes and Vascular Disease Research

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PPARα is critical to lipid metabolism in the liver. Recent findings which showed that pioglitazone, a PPARγ agonist with weak PPARα activity, improved fatty liver disease in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome or type 2 diabetes have prompted interest in whether more potent PPARα agonists, such as fenofibrate, may have a role in the management of non-alcoholic fatty liver disease (NAFLD). The combination of fenofibrate and a statin is well tolerated, with no apparent increase in the risk of myopathy, unlike gemfibrozil-statin combination therapy.In overview, the available evidence indicates that the combination of fenofibrate with a statin is a useful approach for optimising reduction in the risk of cardiovascular disease in patients with type 2 diabetes and metabolic syndrome, as well as delaying the progression of diabetes-related microvascular complications. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the outcome benefits of this approach. Diabetes Vasc Dis Res 2007;4(suppl 3):S15-S20

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Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects

Cited by 57 publications

References 34 publications

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

The role of fenofibrate in clinical practice

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Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects

Cited by 57 publications

References 34 publications

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

The role of fenofibrate in clinical practice

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Antilipolytic Activity of a Novel Partial A₁Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid