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Optimizing nicotinic acid delivery for durable antilipolysis and improved metabolic control

Kroon, Tobias (2016). Optimizing nicotinic acid delivery for durable antilipolysis and improved metabolic control. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2016:31
ISBN 978-91-576-8564-3
eISBN 978-91-576-8565-0
[Doctoral thesis]

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Abstract

Type 2 diabetes is a devastating disease affecting hundreds of millions worldwide. Lipid accumulation in peripheral non-adipose tissues is a major driver of insulin resistance, a central pathophysiological defect of this disease. Plasma free fatty acids (FFA), derived from adipose tissue lipolysis, are an important source of the intracellular lipid pools. Hence, adipose tissue antilipolysis may be an approach for reversing peripheral tissue lipid overload and the down-stream negative consequences, including insulin resistance.

Nicotinic acid (NiAc) is a potent inhibitor of adipose lipolysis, acutely reducing plasma FFA concentrations. However, a major FFA rebound occurs upon abrupt NiAc washout and sustained exposures are associated with tolerance development, with FFA returning to pre-dose levels. A key principle of this work was the use of precisely defined plasma NiAc exposure profiles, produced using a programmable, implantable mini-pump. Metabolic consequences of NiAc-induced FFA lowering were assessed in a translationally relevant preclinical model of the metabolic syndrome, the obese Zucker rat.

A feedback turnover model adequately described acute FFA responses to NiAc. This model aided in designing a gradual NiAc termination protocol which minimized FFA rebound. The strategy of around-the-clock exposure failed to deliver sustained FFA lowering, due to tolerance development. By contrast, an intermittent strategy succeeded in preserving acute FFA lowering and insulin sensitizing effects. A more complex model was required in order to capture the development of complete tolerance in response to sustained NiAc exposure. Further experiments revealed that NiAc timed to feeding decreased triglycerides in liver and heart and reduced plasma fructosamine. During an oral glucose tolerance test, plasma FFA levels were reduced with amelio¬ration of hyperglycemia and hypertriglyceridemia. By contrast, NiAc timed to fasting did not reduce tissue lipids, ameliorate glucose intolerance or dyslipidemia.

In conclusion, the NiAc exposure profile has a major influence on metabolic control. A macro-pharmacologic approach succeed in identifying a rational NiAc delivery profile that suppressed rebound and tolerance and profoundly improved metabolic control in obese Zucker rats. The work shows the power of a multi-disciplinary drug discovery approach, using a comprehensive understanding of the relationship between pharmacokinetics and pharmacodynamics combined with knowledge of metabolic physiology.

Authors/Creators:Kroon, Tobias
Title:Optimizing nicotinic acid delivery for durable antilipolysis and improved metabolic control
Series/Journal:Acta Universitatis agriculturae Sueciae (1652-6880)
Year of publishing :2016
Depositing date:29 April 2016
Volume:2016:31
Number of Pages:84
Papers/manuscripts:
NumberReferences
IAhlström, C., T. Kroon, L. A. Peletier, J. Gabrielsson (2013). Feedback modelling of non-esterified fatty acids in obese Zucker rats after nicotinic acid infusions. J Pharmacokinet Pharmacodyn 40(6), 623-638.
IIKroon, T., A. Kjellstedt, P. Thalén, J. Gabrielsson, N. D. Oakes (2015). Dosing profile profoundly influences nicotinic acid’s ability to improve metabolic control in rats. J. Lipid Res. 56(9), 1679-1690.
IIIKroon, T., T. Baccega, A. Olsén, J. Gabrielsson, N. D. Oakes. Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats. (Submitted manuscript).
IVAndersson, R., T. Kroon, J. Almquist, M. Jirstrand, N. D. Oakes, J. Gabrielsson. Third generation turnover model – Nicotinic acid-induced tolerance of insulin and free fatty acids. (In manuscript).
Place of Publication:Uppsala
Publisher:Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences
ISBN for printed version:978-91-576-8564-3
ISBN for electronic version:978-91-576-8565-0
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agris subject categories.:X Agricola extesions > X38 Human medicine, health, and safety
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Pharmacology and Toxicology
(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 302 Clinical Medicine > Endocrinology and Diabetes
Agrovoc terms:nicotinic acid, diabetes, metabolic disorders, fatty acids, insulin, resistance, metabolism, pharmacokinetics, pharmacodynamics, animal models, rats
Keywords:Antilipolysis, Niacin, Insulin resistance, Dyslipidemia, Feedback modeling
URN:NBN:urn:nbn:se:slu:epsilon-e-3412
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-3412
ID Code:13324
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
Deposited By: Tobias Kroon
Deposited On:02 May 2016 09:48
Metadata Last Modified:02 May 2016 09:48

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