Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

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#adipose-tissue #animals #disease-models-animal #dose-response-relationship-drug #fatty-acids-nonesterified

Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments

Andersson et al., 2017 | J Pharmacokinet Pharmacodyn | Meta Analysis

Citation

Andersson Robert, Kroon Tobias, ... Gabrielsson Johan. Modeling of free fatty acid dynamics: insulin and nicotinic acid resistance under acute and chronic treatments. J Pharmacokinet Pharmacodyn. 2017-Jun;44(3):203-222. doi:10.1007/s10928-017-9512-6

Abstract

Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc-FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework. We also developed a new turnover model that describes the adaptation seen in plasma FFA concentrations in lean Sprague-Dawley and obese Zucker rats following acute and chronic NiAc exposure. The adaptive mechanisms within the system were described using integral control systems and dynamic efficacies in the traditional [Formula: see text] model. Insulin was incorporated in parallel with NiAc as the main endogenous co-variate of FFA dynamics. The model captured profound insulin resistance and complete drug resistance in obese rats. The efficacy of NiAc as an inhibitor of FFA release went from 1 to approximately 0 during sustained exposure in obese rats. The potency of NiAc as an inhibitor of insulin and of FFA release was estimated to be 0.338 and 0.436 [Formula: see text], respectively, in obese rats. A range of dosing regimens was analyzed and predictions made for optimizing NiAc delivery to minimize FFA exposure. Given the exposure levels of the experiments, the importance of washout periods in-between NiAc infusions was illustrated. The washout periods should be [Formula: see text]2 h longer than the infusions in order to optimize 24 h lowering of FFA in rats. However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.

Key Findings

However, the predicted concentration-response relationships suggests that higher AUC reductions might be attained at lower NiAc exposures.

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size See abstract
Age Range See abstract
Condition See abstract

MeSH Terms

  • Adipose Tissue
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fatty Acids, Nonesterified
  • Insulin
  • Insulin Resistance
  • Male
  • Models, Biological
  • Niacin
  • Obesity
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Zucker

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis
  • Vertical: niacin

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09