Regulation of free fatty acid metabolism by insulin in humans: Role of lipolysis and reesterification
ABSTRACT The regulation of lipolysis, free fatty acid appearance into plasma (FFA R(a)), an FFA reesterification and oxidation were examined in seven healthy humans infused intravenously with insulin at rates of 4, 8, 25, and 400 mU.m-2.min-1. Glycerol and FFA R(a) were determined by isotope dilution methods, and FFA oxidation was calculated by indirect calorimetry or by measurement of expired 14CO2 from infused [1-14C]palmitate. These measurements were used to calculate total FFA reesterification, primary FFA reesterification occurring within the adipocyte, and secondary reesterification of circulating FFA molecules. Lipolysis, FFA R(a), and secondary FFA reesterification were exquisitely insulin sensitive [the insulin concentrations that produced half-maximal suppression (EC50), 106 +/- 26, 91 +/- 20 vs. 80 +/- 16 pM, P = not significant] in contrast to insulin suppression of FFA oxidation (EC50, 324 +/- 60, all P < 0.01). The absolute rate of primary FFA reesterification was not affected by the increase in insulin concentration, but the proportion of FFA molecules undergoing primary reesterification doubled over the physiological portion of the insulin dose-response curve (from 0.23 +/- 0.06 to 0.44 +/- 0.07, P < 0.05). This served to magnify insulin suppression of FFA R(a) twofold. In conclusion, insulin regulates FFA R(a) by inhibition of lipolysis while maintaining a constant rate of primary FFA reesterification.
- SourceAvailable from: Francisco Artacho-Cordón
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- "Onset of type 2 diabetes is commonly preceded by early metabolic changes (prediabetes), including a progressive development of insulin resistance, which is first compensated by the overproduction of insulin by beta cells until the insulin production becomes inadequate (Hsueh et al., 2010). The effects of insulin include a reduction in blood glucose and free fatty acids, the latter being derived from a suppression of lipolysis (Campbell et al., 1992). Hence, assuming equal insulin levels, higher blood glucose levels are related to lower insulin sensitivity. "
ABSTRACT: The aim of the present study was to assess the relationship between serum concentrations of several persistent organic pollutants and insulin resistance markers in a cohort of women with a history of gestational diabetes mellitus. ∑POPs was computed as the sum of individual serum POP concentrations. No statistically significant associations were found between levels of any POP and fasting glucose. However, polychlorinated biphenyl (PCB) congeners 138 and 180 were positively associated with 2-h glucose levels and PCB 180 also with fasting immunoreactive insulin (IRI). We also found a positive association of p,p'- dichlorodiphenyldichloroethylene (p,p'- DDE), PCBs (138, 153, and 180), hexachlorobenzene, and ∑POPs with 2-h IRI. Serum concentrations of PCBs (138, 153, and 180), hexachlorobenzene, and ∑POPs were also positively associated with homeostasis model assessment (HOMA2-IR) levels. Moreover, p,p'- DDE, PCBs (138, 153 and 180), hexachlorobenzene, and ∑POPs were negatively associated with Insulin Sensitivity Index (ISI-gly) levels. No significant association was found between glycated hemoglobin and the concentrations of any POP. The removal of women under blood glucose lowering treatment from the models strengthened most of the associations previously found for the whole population. Our findings suggest that exposure to certain POPs is a modifiable risk factor contributing to insulin resistance. Copyright © 2014 Elsevier Inc. All rights reserved.Environmental Research 11/2014; 136C:435-440. DOI:10.1016/j.envres.2014.11.007 · 3.95 Impact Factor
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- "The synthesis, degradation, and transformation of FA in hepatic cells are catalyzed by over 300 enzymatic reactions (Kanehisa et al., 2008) involved in distinct pathways (e.g., FA oxidation and elongation). These reactions are regulated at the metabolic and genetic levels by various hormones (e.g., insulin (Campbell et al., 1992), leptin (Unger et al., 1999)) and nutrients (e.g., poly unsaturated FA (Sessler and Ntambi, 1998)). However, the simple aggregation of abundant literature data cannot account for all underlying interactions responsible for both FA metabolism and lipid phenotype. "
ABSTRACT: The purpose of this study is to identify the hierarchy of importance amongst pathways involved in fatty acid (FA) metabolism and their regulators in the control of hepatic FA composition. A modeling approach was applied to experimental data obtained during fasting in PPARalpha knockout (KO) mice and wild-type mice. A step-by-step procedure was used in which a very simple model was completed by additional pathways until the model fitted correctly the measured quantities of FA in the liver. The resulting model included FA uptake by the liver, FA oxidation, elongation and desaturation of FA, which were found active in both genotypes during fasting. From the model analysis we concluded that PPARalpha had a strong effect on FA oxidation. There were no indications that this effect changes during the fasting period, and it was thus considered to be constant. In PPARalpha KO mice, FA uptake was identified as the main pathway responsible for FA variation in the liver. The models showed that FA were oxidized at a constant and small rate, whereas desaturation of FA also occurred during fasting. The latter observation was rather unexpected, but was confirmed experimentally by the measurement of delta-6-desaturase mRNA using real-time quantitative PCR (QPCR). These results confirm that mathematical models can be a useful tool in identifying new biological hypotheses and nutritional routes in metabolism.Journal of Theoretical Biology 08/2009; 261(2):266-78. DOI:10.1016/j.jtbi.2009.07.025 · 2.30 Impact Factor
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- "Just as important to the regulation of fat metabolism is the involvement of insulin hormone in the regulation of FA mobilization and oxidation. Plasma NEFA reesterification is particularly sensitive to insulin action (Campbell et al., 1992), such that even low concentrations of plasma insulin can be sufficient to suppress adipose tissue lipolysis at rest (Bonadonna et al., 1990). Thus, whereas catecholamine-activated α-adrenoceptors modulate lipolysis at rest, insulin action modulates lipolysis postprandially. "
ABSTRACT: In discussion of the physiological mechanisms that regulate fat metabolism, and with consideration of the metabolic stimuli that modulate substrate metabolism, the issue of how an acute state of negative lipid balance can be maximized is addressed. The regulation of lipolysis by catecholamines and insulin is reviewed, and the mechanisms of fatty acid mobilization and uptake by muscle are also briefly discussed. The implications of substrate availability and the hormonal response during physiological states such as fasting, exercise, and after food intake are also addressed, with particular regard to the influences on fatty acid mobilization and/or oxidation from eliciting these stimuli conjointly. Finally, a brief discussion is given of both the nature of exercise and the exercising individual, and how these factors influence fat metabolism during exercise. It is also a primary thrust of this paper to underline gaps in the existing literature with regard to exercise timing concerning food ingestion for maximizing acute lipid utilization.Canadian journal of applied physiology = Revue canadienne de physiologie appliquée 09/2005; 30(4):475-99. DOI:10.1139/h05-134 · 1.30 Impact Factor