title: Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats.
abstract: Acute nicotinic acid (NiAc) administration results in rapid reduction of plasma FFA concentrations. However, sustained NiAc exposure is associated with tolerance development resulting in return of FFA to pretreatment levels. The aim of this study was to determine whether a 12 h rectangular exposure profile (intermittent dose group) could avoid tolerance development and thereby reverse insulin resistance induced by lipid overload. FFA lowering was assessed in male Sprague Dawley (lean) and obese Zucker rats (obese) in response to a 5 h NiAc infusion, in either NiAc-naïve animals or after 5 days of continuous (24 h/day) or intermittent (12 h/day) NiAc dosing (via implantable, programmable minipump). We found that intermittent dosing over 5 days preserved NiAc-induced FFA lowering, comparable to dosing in NiAc-naïve animals. By contrast, following 5 days continuous administration, NiAc-induced FFA lowering was lost. The effect of intermittent NiAc infusion on insulin sensitivity was assessed in obese Zucker rats using hyperinsulinemic-isoglycemic clamps. The acute effect of NiAc to elevate glucose infusion rate (vs. saline control) was indeed preserved with intermittent dosing, while being lost upon continuous infusion. In conclusion, an intermittent but not continuous NiAc dosing strategy succeeded in retaining NiAc's ability to lower FFA and improve insulin sensitivity in obese Zucker rats.-Kroon, T., A. Kjellstedt, P. Thalén, J. Gabrielsson, and N. D. Oakes.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kroon
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Kjellstedt
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Thalén
authors.affiliation: Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gabrielsson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Oakes
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000235:genetics; D009525:Niacin / Q000008:administration & dosage*; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D009525:Niacin; D005947:Glucose
keywords: GPR109A; adipose tissue; diabetes; drug therapy/hypolipidemic drugs; insulin; lipolysis and fatty acid metabolism; niacin; tachyphylaxis