Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Abstract

explored and provide evidence supporting this concept. This includes inactivation of hormone sensitive lipase (HSL) ( 5, 6 ) and A 1 -adenosine receptor agonists ( 7 ). In addition, several other G protein-coupled receptors (GPRs) are involved in controlling adipocyte FFA release, including GPR43, GPR81, and GPR109A ( 8-10 ).The GPR109A agonist nicotinic acid (NiAc) has been used clinically ever since its antidyslipidemic effects (HDL elevation and reductions of total cholesterol, LDL-cholesterol, and TG) were discovered more than 50 years ago ( 11-15 ). Although NiAc potently lowers FFA acutely, large-scale clinical studies, with repeated oral NiAc administration, often report increased levels of fasting glycemia ( 16-19 ). NiAc has not been optimized to achieve durable and therapeutically meaningful FFA lowering. By this, we specifi cally mean reducing around-the-clock FFA area under the curve (AUC). In theory, this might be achieved by sustained NiAc exposure; however, the FFA-lowering effect seen initially appears to be lost over time despite maintained NiAc exposure (tolerance development) ( 20 ). Time-dependent loss of both FFA lowering and glucose control improvement also occur in patients with type 2 diabetes, treated with the NiAc analog acipimox ( 21,22 ). To avoid tolerance development, drug holidays are needed. However, at the end of each NiAc exposure period, there is the risk of FFA rebound (here referring to the situation where FFA overshoots pretreatment levels in connection with NiAc decline) due to the short NiAc plasma half-life ( 23 ). FFA rebound is associated with impaired glucose control ( 24, 25 ). The question of whether there might be an optimal balance between periods of continuous exposure (which would minimize rebound) and drug holidays (which would minimize tolerance) in order to achieve maximal FFA lowering has not been addressed. Lipid overload in nonadipose tissues has been linked to the pathogenesis of insulin resistance and atherogenesis ( 1-4 ). A potential means for reversing peripheral lipid overload is to restrict the release of FFAs from adipose tissues. A number of independent mechanisms have been N.D. Oakes, P. Thalén, and A. Kjellstedt Abbreviations: ATGL, adipocyte triglyceride lipase; AUC, area under the curve; ER, extended release; GIR, glucose infusion rate; GPR, G protein-coupled receptor; HOMA-IR, homeostasis model assessment for insulin resistance; HSL, hormone sensitive lipase; NiAc, nicotinic acid; PDE-3B, phosphodiesterase-3B .

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

“…Recently we tried to reduce tolerance by interspacing abruptly terminated NiAc exposures with drug holidays. This approach was partially successful, retaining acute NiAc-induced FFA lowering and insulin sensitivity but without delivering significant peripheral tissue lipid unloading (10). This absence of tissue lipid lowering may have reflected a failure to lower average FFA levels over the 24 h period due to a combination of FFA rebound and insufficient containment of tolerance.…”

“…In the morning of day 5, to enable blood sampling in unrestrained animals, the jugular catheter was unplugged and connected to a swivel system as previously described (10). After a 2.5-h adaptation period, blood sampling was initiated at 13:00.…”

“…Surgical procedures were performed as previously described (10). In brief, for subcutaneous NiAc/saline administration, a programmable mini-pump (iPrecio SMP200 Micro Infusion Pump; Primetech Corporation, Tokyo, Japan) was implanted subcutaneously via a dorsal skin incision.…”

“…1 (top panel). The day before the acute study, food was removed at 17:00, and at 01:00 the preprogrammed implanted pump began infusing NiAc at a constant rate (170 nmol/min/kg, corresponding to 29.1 µl/ hr/kg) for 12 h. At 09:30 animals were anesthetized and surgically prepared with jugular and carotid catheters as previously described (10).…”

“…Fresh NiAc (pyridine-3-carboxylic acid; Sigma-Aldrich, St. Louis, MO) infusion solution was prepared to a concentration of 350 mM using procedures described in (10). Vehicle, for control animals, consisted of sodium chloride solutions at equimolar concentrations.…”