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Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping.
Montastier, É, Ye, RZ, Noll, C, Bouffard, L, Fortin, M, Frisch, F, Phoenix, S, Guérin, B, Turcotte, ÉE, Lewis, GF, et al
American journal of physiology. Endocrinology and metabolism. 2021;(6):E1093-E1106
Abstract
The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis but could also be contributed to by reduced adipose tissue (AT) dietary fatty acid (DFA) trapping and increased "spillover" into the circulation. Thirty-one subjects with IGT (14 women, 17 men) and 29 with normal glucose tolerance (NGT, 15 women, 14 men) underwent a meal test with oral and intravenous palmitate tracers and the oral [18F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Rapalmitate) was higher in IGT versus NGT (P < 0.001), driven exclusively by Rapalmitate from obesity-associated increase in intracellular lipolysis (P = 0.01), as Rapalmitate from DFA spillover was not different between the groups (P = 0.19) and visceral AT DFA trapping was even higher in IGT versus NGT (P = 0.02). Plasma glycerol appearance was lower in IGT (P = 0.01), driven down by insulin resistance and increased insulin secretion. Thus, we found higher AT DFA trapping, limiting spillover to lean organs and in part offsetting the increase in Rapalmitate from intracellular lipolysis. Whether similar findings occur in frank diabetes, a condition also characterized by insulin resistance but relative insulin deficiency, requires further investigation (Clinicaltrials.gov: NCT04088344, NCT02808182).NEW & NOTEWORTHY We found higher adipose tissue dietary fatty acid trapping, limiting spillover to lean organs, that in part offsets the increase in appearance rate of palmitate from intracellular lipolysis in prediabetes. These results point to the adaptive nature of adipose tissue trapping and dietary fatty acid spillover as a protective mechanism against excess obesity-related palmitate appearance rate from intracellular adipose tissue lipolysis.
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2.
Enhanced fatty acid uptake in visceral adipose tissue is not reversed by weight loss in obese individuals with the metabolic syndrome.
Bucci, M, Karmi, AC, Iozzo, P, Fielding, BA, Viljanen, A, Badeau, RM, Borra, R, Saunavaara, V, Pham, T, Hannukainen, JC, et al
Diabetologia. 2015;(1):158-64
Abstract
AIMS/HYPOTHESIS Obesity causes an imbalance in fat mass distribution between visceral and subcutaneous adipose tissue (AT) depots. We tested the hypothesis that this relates to increased NEFA uptake between these depots in obese compared with healthy participants. Second, we hypothesised that a diet very low in energy (very low calorie diet [VLCD]) decreases fat mass in obese participants and that this is associated with the decline in NEFA uptake. METHODS NEFA uptake in AT depots was measured with [(18)F]-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA) and positron emission tomography (PET) in 18 obese participants with the metabolic syndrome before and after a 6 week VLCD. Whole body fat oxidation was measured using indirect calorimetry and [U-(13)C]palmitate. Sixteen non-obese participants were controls. RESULTS Obese participants had >100% higher (p < 0.0001) NEFA uptake in the visceral and subcutaneous abdominal AT depots than controls. VLCD decreased AT mass in all regions (12% to 21%), but NEFA uptake was decreased significantly (18%; p < 0.006) only in the femoral AT. Whole body carbohydrate oxidation decreased, while fat oxidation increased. CONCLUSIONS/INTERPRETATION The data demonstrate that weight loss caused by VLCD does not affect abdominal fasting NEFA uptake rates. We found that visceral fat takes up more NEFAs than subcutaneous AT depots, even after weight loss.
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3.
Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans.
Meier, JJ, Gethmann, A, Götze, O, Gallwitz, B, Holst, JJ, Schmidt, WE, Nauck, MA
Diabetologia. 2006;(3):452-8
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Abstract
AIMS/HYPOTHESIS Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed. METHODS 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1)) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a (13)C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. RESULTS GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, -0.023+/-0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31+/-5% after meal ingestion (p<0.01). CONCLUSIONS/INTERPRETATION GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.
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The effect of high-dose simvastatin on free fatty acid metabolism in patients with type 2 diabetes mellitus.
Isley, WL, Harris, WS, Miles, JM
Metabolism: clinical and experimental. 2006;(6):758-62
Abstract
Statins improve all major lipid fractions, reduce coronary heart disease risk, and may have a minor effect on glucose tolerance. A reduction in free fatty acid flux and concentrations could be partly responsible for these effects. We measured nocturnal and postprandial plasma palmitate concentrations and rate of appearance (R(a)) on 2 occasions in 12 obese dyslipidemic subjects with type 2 diabetes mellitus, using a single-blind, crossover format (placebo followed by simvastatin, 80 mg/d), and also on 1 occasion in 6 untreated control subjects. The diabetic subjects had increased average nocturnal (127+/-13 vs 80+/-10 micromol/L, P<.05) and 2-hour postprandial (49+/-6 vs 17+/-2 micromol/L, P<.001) palmitate concentrations, as well as increased nocturnal (31.6+/-3.7 vs 19.5+/-3.7 mmol/m(2) over 9 hours, P<.05) and postprandial (11.5+/-3.7 vs 5.5+/-3.7 mmol/m(2) every 4 hours, P<.005) integrated palmitate R(a) compared to normal controls. High-dose simvastatin reduced serum triglycerides by 35% but had no effect on plasma palmitate concentrations or R(a). These results suggest that the triglyceride-lowering effect of statins is not mediated through an effect on FFA metabolism.
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Elevated plasma free fatty acid concentrations do not modify cardiac repolarization in patients treated by electrolyte-glucose-insulin infusion.
Nappo, F, Loreto, M, Giugliano, G, Grella, E, Esposito, K, Lettieri, B, Giugliano, D
Journal of endocrinological investigation. 2002;(7):RC19-22
Abstract
Fat emulsion infusion is routinely used as a source of calories and essential fatty acids for critically ill patients who may be at risk for acquired ventricular repolarization alterations due either to drugs or electrolyte disturbances. The aim of this study was to evaluate whether acute elevations of plasma free fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion and sympathetic nervous system activity in patients requiring parenteral nutrition. Thirty hospitalized patients (mean +/- SD: 62 +/- 17 yr of age) requiring total parenteral nutrition received an infusion of 10% (500 ml) triacylglycerol emulsion as a source of calories (450 Kcal); on another occasion, and in random order, the same patients received an infusion of 20% (500 ml) triacylglycerol emulsion (900 Kcal). The infusion lasted 8 h and was preceded by a sc injection of heparin (5,000 U). Infusions of both 10% and 20% triacylglycerol emulsion increased plasma free fatty acid (p<0.00 1) and triacylglycerol (p<0.01) concentrations, and was associated with no significant change in mean BP, heart rate, and plasma catecholamines. At baseline, Q-Tc and Q-Tc dispersion were within the normal range (<440 milliseconds for QTc and <40 ms for QTc-d) and did not show any significant change at any time during infusion of triacylglycerol emulsion at both concentrations. In the setting of a balanced parenteral nutrition, acute elevation of plasma free fatty acid concentrations in critically ill patients do not modify ventricular repolarization.
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Effects of lowering circulating free fatty acid levels on protein metabolism in adult growth hormone deficient patients.
Nielsen, S, Jørgensen, JO, Hartmund, T, Nørrelund, H, Nair, KS, Christiansen, JS, Møller, N
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2002;(6):425-33
Abstract
Our study was conducted to define the roles of lowering circulating free fatty acids (FFA) and of growth hormone (GH) replacement on protein metabolism in GH deficient patients. To isolate the specific effects of FFA and GH we studied seven adult subjects with GH deficiency four times: (A) with administration of GH and Acipimox (an inhibitor of lipolysis), (B) with GH, without Acipimox, (C) without GH, with Acipimox and (D) without either. Each study included a 3 h basal period and a 3 h euglycemic clamp. Amino acid metabolism was assessed by stable isotope dilution technique at the whole body level and across the forearm. Overall, we saw no intervention effect on protein metabolism, but when the two situations in which Acipimox was given were combined, Acipimox decreased basal plasma FFA concentrations by 75% and increased serum urea concentrations by 20%, whole body appearance rates (reflecting protein degradation) of phenylalanine (by 7%) and tyrosine (by 11%) and protein synthesis rates for phenylalanine (by 7%), whereas phenylalanine-to-tyrosine conversion was unaffected. Acipimox more than doubled net forearm phenylalanine release during the clamp and increased basal forearm phenylalanine disappearance (reflecting muscle protein synthesis). During the clamp whole body amino acid fluxes and phenylalanine-to-tyrosine conversion decreased together with a decrease in forearm protein breakdown. GH replacement did not affect any of these metabolic parameters. Although we failed to show any role for GH, the results show that lowering of FFA concentrations with Acipimox has pronounced effects on protein metabolism, including increased whole body and forearm protein breakdown, together with increased protein synthesis systemically and locally in the forearm. The increase in serum urea and a doubling of net forearm phenylalanine release after lowering of FFA strongly indicate that the overall effect is catabolic and supports a pivotal protein conserving role of lipids.
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Men at increased risk of coronary heart disease are not different from age- and weight-matched healthy controls in their postprandial triglyceride, nonesterified fatty acid, or incretin responses to sucrose.
Brynes, AE, Edwards, CM, Ghatei, MA, Bloom, SR, Frost, GS
Metabolism: clinical and experimental. 2002;(2):195-200
Abstract
Short-term studies suggest that extreme sucrose consumption has a detrimental effect on triglycerides (TG) in hypertriglyceridemic people. There is currently no consensus on the short-term inclusion of a moderate intake of sucrose in middle-aged men at increased risk of coronary heart disease (CHD). It is also unknown whether gut hormones that are released in response to carbohydrate ingestion modulate any of the effects of sucrose. The aim of this study was to further elucidate whether men at increased risk of CHD have an exaggerated response to sucrose compared with age- and weight-matched controls over an acute postprandial period. Twenty middle-aged men were recruited and separated into control (total cholesterol < 5.5 mmol/L) and increased risk of CHD (> 5.5 mmol/L) groups. We measured postprandial TG, nonesterified fatty acids (NEFA), insulin, glucose, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations in response to a meal containing 75 g glucose or 75 g sucrose with a moderate fat load. The increased risk group had significantly higher Framingham risk assessment (12% v 4%), TG (2.4 +/- 1.5 v 1.1 +/- 0.4 mmol/L), low-density lipoprotein-cholesterol (LDL-C) (4.4 +/- 0.5 v 2.7 +/- 0.4 mmol/L), and lower high-density lipoprotein-cholesterol (HDL-C) (1.2 +/- 0.2 v 1.5 +/- 0.2 mmol/L) (P <.05 for all). There was no significant difference in the incremental area under the curve (IAUC, 0 to 360 minutes) for TG, NEFA, glucose, GLP-1, or GIP in response to glucose or sucrose within or between the groups. Absolute total area under the curve (not IAUC) for TG was significantly higher in the increased risk group for both glucose and sucrose, respectively (P =.01). A total of 75 g of sucrose given as part of a single meal appears to make little difference in the postprandial TG and NEFA response in men with or without risk of CHD compared with glucose. Although long-term data is needed, this begs the question whether a moderate intake of sucrose has been overemphasized as a detrimental dietary message in middle-aged men.