Raise Plasma Free Fatty Acids Research Articles

Role of preoperative carbohydrate loading for prevention of perioperative ketoacidosis in elective cesarean delivery.

Starvation of long duration during third trimester of pregnancy is undesirable as it is associated with accelerated fasting leading to hypoglycemia, raised plasma free fatty acid (FFA) levels, and increased plasma/urinary ketones. Carbohydrate (CHO)-rich drinks given preoperatively may ameliorate these deleterious effects. The enhanced recovery after surgery (ERAS) guidelines for perioperative care recommend that oral CHO fluid supplementation 2 h before cesarean delivery may be offered to nondiabetic pregnant women. The aim of the study was to evaluate the role of preoperative oral CHO loading for the prevention of perioperative ketoacidosis in elective cesarean deliveries. One hundred and twenty American Society of Anesthesiologists (ASA) II/III parturients undergoing elective cesarean section under subarachnoid block (SAB) were divided into two groups of 60 each after they gave written informed consent. Group A parturients received 400 ml of filtered water 2 h before surgery. Group B parturients received 400 ml of nonparticulate CHO drink 2 h before surgery. The primary outcome was the incidence of ketonuria studied by the dipstick method. Secondary outcomes included hunger and thirst scores, anxiety score, dominant hand grip strength, and the quality of recovery score. The urine ketone levels were positive (+1) in 8.3% parturients in group A and 1.7% parturients in the CHO group (P value- 0.094). The hunger and thirst scores as well as the modified Beck's anxiety scores were significantly lower in the CHO group (P value- 0.002). Dominant hand grip strength was preserved in both the groups (P value- 0.827). The quality of recovery score was significantly improved in the CHO group (P value- 0.002). No serious adverse effects were noted in either group. Oral CHO drink is safe when administered 2 h before uncomplicated elective cesarean deliveries. It may have a positive influence on a wide range of perioperative markers of clinical outcome.

Effects of Individual Circulating FFAs on Plasma and Hepatic FFA Epoxides, Diols, and Epoxide-Diol Ratios as Indices of Soluble Epoxide Hydrolase Activity.

Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively (p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels.

Caffeine intake increases plasma ketones: an acute metabolic study in humans.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: the roles of long chain fatty acids.

Insulin resistance is characterized by hyperglycaemia, dyslipidaemia and oxidative stress prior to the development of type 2 diabetes mellitus. To date, a number of mechanisms have been proposed to link these syndromes together, but it remains unclear what the unifying condition that triggered these events in the progression of this metabolic disease. There have been a steady accumulation of data in numerous experimental studies showing the strong correlations between mitochondrial dysfunction, oxidative stress and insulin resistance. In addition, a growing number of studies suggest that the raised plasma free fatty acid level induced insulin resistance with the significant alteration of oxidative metabolism in various target tissues such as skeletal muscle, liver and adipose tissue. In this review, we herein propose the idea of long chain fatty acid-induced mitochondrial dysfunctions as one of the key events in the pathophysiological development of insulin resistance and type 2 diabetes. The accumulation of reactive oxygen species, lipotoxicity, inflammation-induced endoplasmic reticulum stress and alterations of mitochondrial gene subset expressions are the most detrimental that lead to the developments of aberrant intracellular insulin signalling activity in a number of peripheral tissues, thereby leading to insulin resistance and type 2 diabetes.

The vascular endothelium in diabetes and its potential as a therapeutic target

The vascular endothelium in diabetes and its potential as a therapeutic target

Long- and Medium-Chain Fatty Acids Induce Insulin Resistance to a Similar Extent in Humans Despite Marked Differences in Muscle Fat Accumulation

Animal studies revealed that medium-chain fatty acids (MCFA), due to their metabolic characteristics, are not stored in skeletal muscle and may therefore not give rise to potentially hazardous lipid species impeding insulin signaling. We here hypothesized that infusion of medium-chain triacylglycerols (MCT) in healthy lean subjects does not lead to ectopic fat accumulation and hence does not result in lipid-induced insulin resistance. Nine healthy lean male subjects underwent a 6-h hyperinsulinemic-euglycemic clamp with simultaneous infusion of 1) a 100% long-chain triacylglycerols (LCT) emulsion, 2) a 50/50% MCT/LCT emulsion, or 3) glycerol in a randomized crossover design. Muscle biopsies were taken before and after each clamp. MCT/LCT infusion raised plasma free fatty acid levels to a similar level compared with LCT infusion alone. Despite elevated free fatty acid levels, intramyocellular triacylglycerol (IMTG) levels were not affected by the MCT/LCT emulsion, whereas LCT infusion resulted in an approximately 1.6-fold increase in IMTG. These differences in muscle fat accumulation did not result in significant differences in lipid-induced insulin resistance between LCT (-28%, P = 0.003) and MCT/LCT (-20%, P < 0.001). Total skeletal muscle ceramide content as well as lactosyl- and glucosylceramide levels were not affected by any of the interventions. In addition, the distribution pattern of all ceramide species remained unaltered. Although we confirm that MCFA do not lead to ceramide and IMTG accumulation in skeletal muscle tissue in humans, they do induce insulin resistance. These results indicate that, in humans, MCFA may not be beneficial in preventing peripheral insulin resistance.

Short-term oral α-lipoic acid does not prevent lipid-induced dysregulation of glucose homeostasis in obese and overweight nondiabetic men

Prolonged elevation of plasma free fatty acids (FFAs) induces insulin resistance and impairs pancreatic β-cell adaptation to insulin resistance. The mechanisms whereby lipid induces these impairments are not fully defined but may involve oxidative stress, inflammation, and endoplasmic reticulum stress. α-Lipoic acid (ALA), a commonly used health supplement with antioxidant, anti-inflammatory, and AMPK-activating properties, has been shown to have therapeutic value in type 2 diabetes and its complications. Here we examined the effects of ALA on insulin sensitivity and secretion in humans under the conditions of 24-h iv lipid infusion to elevate plasma FFAs. Eight overweight and obese male subjects underwent four randomized studies each, 4-6 wk apart: 1) SAL, 2-wk oral placebo followed by 24-h iv infusion of saline; 2) IH, 2-wk placebo followed by 24-h iv infusion of intralipid plus heparin to raise plasma FFAs approximately twofold; 3) IH + ALA, 2-wk ALA (1,800 mg/day) followed by 24-h infusion of intralipid plus heparin; and 4) ALA, 2-wk ALA followed by 24-h infusion of saline. Insulin secretion rates (ISR) and insulin sensitivity were assessed with a 2-h, 20-mmol/l hyperglycemic clamp and a hyperinsulinemic euglycemic clamp, respectively. ISR was not significantly different between treatments. Lipid infusion impaired insulin sensitivity with and without ALA pretreatment. These results indicate that ALA, administered orally at this dose for 2 wk, does not protect against lipid-induced insulin resistance in overweight and obese humans.

A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects

High-fat, low-carbohydrate diets are widely used for weight reduction, but they may also have detrimental effects via increased circulating free fatty acid concentrations. We tested whether raising plasma free fatty acids by using a high-fat, low-carbohydrate diet results in alterations in heart and brain in healthy subjects. Men (n = 16) aged 22 ± 1 y (mean ± SE) were randomly assigned to 5 d of a high-fat, low-carbohydrate diet containing 75 ± 1% of calorie intake through fat consumption or to an isocaloric standard diet providing 23 ± 1% of calorie intake as fat. In a crossover design, subjects undertook the alternate diet after a 2-wk washout period, with results compared after the diet periods. Cardiac (31)P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, and computerized cognitive tests were used to assess cardiac phosphocreatine (PCr)/ATP, cardiac function, and cognitive function, respectively. Compared with the standard diet, subjects who consumed the high-fat, low-carbohydrate diet had 44% higher plasma free fatty acids (P < 0.05), 9% lower cardiac PCr/ATP (P < 0.01), and no change in cardiac function. Cognitive tests showed impaired attention (P < 0.01), speed (P < 0.001), and mood (P < 0.01) after the high-fat, low-carbohydrate diet. Raising plasma free fatty acids decreased myocardial PCr/ATP and reduced cognition, which suggests that a high-fat diet is detrimental to heart and brain in healthy subjects.

Fitness Abrogates the Ability of Free Fatty Acids (FFA) to Inhibit Insulin's Microvascular Action

Insulin acutely (within 20 min) increases microvascular blood volume (MBV) within human forearm muscle as measured by contrast enhanced ultrasound (CEU). This serves to increase insulin delivery to muscle and facilitates insulin's metabolic action. This vascular effect of insulin is impaired by the insulin resistance that accompanies either chronic obesity or acute (within 2-4hr) increases in the circulating levels of FFA. Interestingly, and as yet unexplained, raising plasma FFA via infusion of Intralipid has less effect on insulin sensitivity in individuals who are highly trained. It is not known whether training affects the ability of FFA to inhibit insulin-induced microvascular recruitment. PURPOSE: The current study was undertaken to address whether the level of fitness (VO2 max) or adiposity (% body fat) predicted MBV and/or glucose infusion rate (GIR) during a euglycemic insulin clamp. METHODS: A group (n =11) of young (18-35), lean (BMI≤25), healthy subjects received Intralipid 20% + heparin for 5 hrs (3hr prior to and throughout a 2hr, 1mU/kg/min insulin clamp). MBV as measured by CEU was obtained continuously during the first 30 min of the clamp. Fitness level was assessed by conducting an exercise test (Bruce protocol) to obtain VO2 max in a subset (n=8) on a separate day. RESULTS: We found that VO2 max was a strong predictor of MBV (r = 0.74 p <0.05) the GIR likewise strongly correlated with MBV(r = 0.75, p= 0.01) supporting the hypothesis that insulin's vascular action is a significant contributor to its metabolic effects. We also observed the expected inverse relationship between VO2 max and % body fat (r = -0.79, p= 0.02). CONCLUSION: Fitness limits the ability of elevated FFA to block both insulin's vasodilatory and metabolic effects. The increased microvascular surface area in response to insulin seen in those with higher VO2 max can facilitate exchange of insulin and glucose with muscle interstitium thereby contributing to the higher GIR. In addition the lower body fat %, therefore greater % lean body mass, may also contribute to the higher GIR. Taken together these findings suggest that a more fit person is less likely to develop either vascular or metabolic insulin resistance in response to elevated circulation FFA. The mechanism for the protective effect of fitness is unclear. Supported by NIH Grant RO1 DK073759

Sutherlandia frutescens limits the development of insulin resistance by decreasing plasma free fatty acid levels

Intake of high caloric food induces raised plasma free fatty acids, culminating in insulin resistance (IR) and Diabetes mellitus type 2 (DMT2). The present study has shown for the first time that Sutherlandia frutescens reduces plasma free fatty acid levels in rats fed a high fat diet, thereby preventing the development of insulin resistance. A commercially available S. frutescens extract was administered to rats to examine its effects on the progression of high fat diet induced IR. In comparison to rats fed high fat diet only (positive control for IR), levels of plasma free fatty acids (FFA) were significantly reduced after one week (p < 0.025). Twelve weeks of treatment with S. frutescens reduced the level of plasma free fatty acids below that of rats fed a normal diet (negative control) (p < 0.025). QUICKI and HOMA-IR index confirmed that S. frutescens treated rats did not develop IR when fed a high fat diet for twelve weeks. In addition to preventing IR and reducing plasma FFA, chronic medication over twelve weeks decreased total cholesterol levels and the LDL/HDL ratio. We propose that S. frutescens is an effective medicinal remedy to prevent elevated plasma free fatty acids and IR, and therefore DMT2.

Evolution of beta-cell dysfunction in impaired glucose tolerance and diabetes.

Patients with overt Type 2 diabetes consistently have alterations in insulin secretion, including reduced insulin secretory responses to glucose, delayed and blunted meal-induced insulin secretion, increased pro-insulin and abnormal insulin secretory oscillations. More recently, it has become evident that abnormal insulin secretion antedates the onset of overt hyperglycaemia and is present in people with impaired glucose tolerance, i.e. normal fasting glucose and glycohaemoglobin concentrations. These defects are subtle and include shifts to the right in the dose-response curves that relate to glucose and insulin secretion, reduced ability of the beta-cell to detect and respond to oscillatory changes in the plasma glucose concentration and impaired beta-cell compensation for insulin resistance. In order to define the factors responsible for these defects in secretion, we have infused human patients with a lipid emulsion and heparin to raise plasma free fatty acid concentrations. This is associated with reduced ability of the beta-cell to detect and respond to small changes in the plasma glucose concentration. In summary, defects in insulin secretion are consistently present in patients with impaired glucose tolerance and play a critical role in the progression from impaired glucose tolerance to diabetes.

Is “fat-induced” muscle insulin resistance rapidly reversible?

Elevated plasma free fatty acids (FFA) cause insulin resistance and are thought to play a key role in mediating insulin resistance in patients with the metabolic syndrome (MTS) and type 2 diabetes mellitus (DM). Two experimental models used to study the mechanisms responsible for insulin resistance in patients are high-fat diet-fed rodents and administration of triglycerides and heparin to raise plasma FFA. As evidence that insulin resistance in high-fat diet-fed rats is due to high FFA, it has been reported that the insulin resistance is rapidly reversed by an overnight fast, a high-glucose meal, and an exercise bout. If true, these findings would invalidate the high-fat diet-fed rodent as a model for MTS or type 2 DM, because insulin resistance is not rapidly reversed by these treatments in patients. The purpose of this study was to determine whether diet-induced insulin resistance is, in fact, rapidly reversible. Incubation of muscles in vitro rapidly reversed insulin resistance induced by administration of triglycerides and heparin, but not by a high-fat diet. An overnight fast and a high-glucose meal were followed by a large increase in insulin-stimulated muscle glucose transport. However, these are adaptive responses, rather than reversals of insulin resistance, because they also occurred in muscles of insulin-sensitive, chow-fed control rats. Our results show that insulin resistance induced by high FFA, i.e., Randle glucose-fatty acid cycle, is transient. In contrast, the insulin resistance induced by a high-fat diet does not reverse rapidly.

Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for > or =3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by approximately 52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.

Endoplasmic Reticulum Stress: Another Link Between Obesity and Insulin Resistance/Inflammation?

Obesity, which has reached epidemic proportions in the U.S. and is increasing worldwide, is closely associated with insulin resistance (peripheral and hepatic) and with a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues (1). Insulin resistance and inflammation in turn are associated with type 2 diabetes, hypertension, atherogenic dyslipidemias, and disorders of blood coagulation and fibrinolysis, all of which are independent risk factors for the development of atherosclerotic vascular disease, including heart attacks, strokes, and peripheral arterial disease (1). The reason why obesity is so closely associated with insulin resistance and inflammation is not completely understood. On one hand, there is evidence to show that blood levels of free fatty acids (FFAs) play an important role in the development of obesity-related insulin resistance and inflammation (rev. in 2). Plasma FFA levels are increased in most obese people, and acutely raising plasma FFA levels increases insulin resistance as well as the expression of proinflammatory cytokines, whereas lowering plasma FFA levels reduces insulin resistance. Mechanisms involved in FFA-induced insulin resistance include accumulation (in muscle and liver) of lipids and lipid intermediates such as diacylglycerol, activation of several protein kinase C isoforms, reduction in tyrosine phosphorylation of the insulin receptor substrates 1 and 2 (2), and activation of the proinflammatory nuclear factor-κB pathway (3,4). On the other hand, not all obese insulin-resistant subjects have elevated plasma …

Abstract 2834: A Short-Term High Fat Diet Impairs Cardiac High Energy Phosphate Metabolism, Exercise Capacity and Cognitive Function

Background: Heart failure patients have low cardiac phosphocreatine/ATP (PCr/ATP) ratios, abnormal exercise tolerance and impaired cognitive function, which may be related to elevated circulating free fatty acids (FFAs). We tested whether briefly raising plasma FFAs, using diet, causes abnormalities in heart, brain and skeletal muscle in healthy subjects Methods and Results: Healthy males (n = 16, age 22 ± 1 years), recruited from the University of Oxford, were randomised to five days of a high fat diet containing 75 ± 1% of calorie intake through fat consumption, or an isocaloric control diet, providing 23 ± 1% of calorie intake as fat. In a cross-over design, subjects undertook the alternate diet after a two week wash out period. Cardiac 31 P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, exhaustive cycling for 1 h, and CDR computerised cognitive tests were used to assess cardiac PCr/ATP, cardiac function, exercise capacity and cognitive function, respectively, before and after the diets. Subjects on the HFD had a two-fold elevation in plasma FFAs, 12% lower cardiac PCr/ATP with no change in cardiac function, and a 12% lower maximal exercise performance (see Figure ). They also had impaired attention and speed (2.2 vs. 1.9 s, p &lt; 0.001, and 1.10 vs. 1.05 s, respectively, p &lt; 0.01) Discussion: We have shown a short term, high fat diet raised plasma FFA concentrations, impaired myocardial energetics, exercise capacity and cognition. Therefore high plasma FFAs may be detrimental for heart, skeletal muscle and brain in normal subjects and suggests a potential mechanism of impairment in heart failure patients.

Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle.

A number of studies have reported that a high-fat diet induces increases in mitochondrial fatty acid oxidation enzymes in muscle. In contrast, in two recent studies raising plasma free fatty acids (FFA) resulted in a decrease in mitochondria. In this work, we reevaluated the effects of raising FFA on muscle mitochondrial biogenesis and capacity for fat oxidation. Rats were fed a high-fat diet and given daily injections of heparin to raise FFA. This treatment induced an increase in mitochondrial biogenesis in muscle, as evidenced by increases in mitochondrial enzymes of the fatty acid oxidation pathway, citrate cycle, and respiratory chain, with an increase in the capacity to oxidize fat, as well as an increase in mitochondrial DNA copy number. Raising FFA also resulted in an increase in binding of peroxisome proliferator-activated receptor (PPAR) delta to the PPAR response element on the carnitine palmitoyltransferase 1 promoter. We interpret our results as evidence that raising FFA induces an increase in mitochondrial biogenesis in muscle by activating PPARdelta.

Cerebral processing of food-related stimuli: Effects of fasting and gender

To maintain nutritional homeostasis, external food-related stimuli have to be evaluated in relation to the internal states of hunger or satiety. To examine the neural circuitry responsible for integration of internal and external determinants of human eating behaviour, brain responses to visual and complex gustatory food-related stimuli were measured using functional magnetic resonance imaging in 18 healthy non-smokers (10 women, 8 men). Each individual was studied on two occasions, the order of which was counterbalanced; after eating as usual and after 24 h fasting. Raised plasma free fatty acids and lower insulin and leptin concentrations confirmed that participants fasted as requested. When fasted, participants reported more hunger, nervousness and worse mood and rated the visual (but not gustatory) food-related stimuli as more pleasant. The effect of fasting on hunger was stronger in women than in men. No circuitry was identified as differentially responsive in fasting compared to satiety to both visual and gustatory food-related stimuli. The left insula response to the gustatory stimuli was stronger during fasting. The inferior occipito-temporal response to visual food-related stimuli also tended to be stronger during fasting. The responses in the occipito-temporal cortex to visual and in the insula to gustatory stimuli were stronger in women than in men. There was no interaction between gender and fasting. In conclusion, food reactivity in modality-specific sensory cortical areas is modulated by internal motivational states. The stronger reactivity to external food-related stimuli in women may be explored as a marker of gender-related susceptibility to eating disorders.

Intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids in the fasting state: studies in insulin-resistant and insulin-sensitized Syrian golden hamsters.

It is not known whether intestinal lipoprotein production is stimulated by an acute elevation of plasma free fatty acids (FFA). We examined the effect of an intralipid and heparin infusion on the intestinal lipoprotein production rate (PR) in insulin-sensitive [chow-fed (CHOW)], insulin-resistant [60% fructose (FRUC) or 60% fat-fed (FAT)], and insulin-sensitized [FRUC or FAT plus rosiglitazone (RSG)-treated] Syrian Golden hamsters. After 5 wk of treatment, overnight-fasted hamsters underwent in vivo Triton WR-1339 studies for measurement of apolipoprotein B48 (apoB48) PR in large (Svedberg unit, >400) and small (Svedberg unit, 100-400) lipoprotein fractions, with an antecedent 90-min infusion of 20% intralipid and heparin (IH) to raise plasma FFA levels approximately 5- to 8-fold vs. those in the saline control study. IH markedly increased apoB48 PR in CHOW by 3- to 5-fold, which was confirmed ex vivo in pulse-chase experiments in primary cultured hamster enterocytes. Oleate, but not glycerol, infusion was associated with a similar elevation of apoB48 PR as IH. In FRUC and FAT, basal (saline control) apoB48 PR was approximately 4-fold greater than that in CHOW; there was no additional stimulation with IH in vivo and only minimal additional stimulation ex vivo. RSG partially normalized basal apoB48 PR in FAT and FRUC, and PR was markedly stimulated with IH. We conclude that intestinal lipoprotein production is markedly stimulated by an acute elevation of plasma FFAs in insulin-sensitive hamsters, in which basal production is low, but minimally in insulin-resistant hamsters, in which basal production is already elevated. With RSG treatment, basal PR is partially normalized, and they become more susceptible to the acute FFA stimulatory effect.

Effects of free fatty acids on glucose uptake and utilization in healthy women.

To study effects of sex on free fatty acid (FFA)-induced insulin resistance, we have examined the effects of acute elevations of plasma FFA levels on insulin-stimulated total body glucose uptake in nine healthy young women. Euglycemic-hyperinsulinemic (approximately 500 pmol/l) clamps were performed for 4 h with coinfusion of either lipid/heparin (L/H) to acutely raise plasma FFA levels (from approximately 600 to approximately 1,200 micro mol/l) or saline/glycerol to lower fatty acids (from approximately 600 to approximately 50 micro mol/l). L/H infusion inhibited insulin-stimulated glucose uptake (determined with [3-(3)H]glucose) and glycogen synthesis by 31 and 40%, respectively (P < 0.01), almost completely abolished insulin suppression of endogenous glucose production (EGP) (13.6 vs. 10.0 micro mol x kg(-1) x min(-1), NS), prevented the insulin induced increase in carbohydrate oxidation (8.1 vs. 7.4 micro mol x kg(-1) x min(-1), NS), and stimulated fat oxidation (from 3.6 to 5.1 micro mol x kg(-1) x min(-1), P < 0.01). These data showed that acute increases in plasma FFA levels inhibited the actions of insulin on glucose uptake, glycogen synthesis, and EGP in women to a degree similar to that previously reported in men. We conclude that at insulin and FFA levels in the postprandial range, women and men were susceptible to FFA-induced peripheral and hepatic insulin resistance.

Effects of short-term feeding of a highly palatable diet on vascular reactivity in rats.

Numerous studies have shown that long-term consumption of high-fat, high-energy diet results in obesity, which in turn, leads to cardiovascular disorders. However, there is little or no data on the acute effects of a highly palatable diet on vascular function. In this study we aimed to evaluate the changes in metabolic and vascular reactivity in Wistar rats fed a palatable diet for 2 days. Two-days feeding of rats with a palatable diet did not effect body weight, fat-pad mass or gastrocnemius muscles weights. Nor there were any changes in plasma glucose, insulin or leptin levels. However, compared with chow-fed rats, palatable diet-fed rats had significantly raised plasma free fatty acids and triglycerides levels (for both, P < 0.01). Compared with chow-fed animals, vasorelaxation responses to carbamylcholine and sodium nitroprusside were significantly attenuated in palatable diet-fed rats (for both, P < 0.01). However, there were no differences in histamine-induced vasorelaxation between chow-fed and palatable diet-fed rats. These data indicates that diet-induced endothelium-dependent and -independent vascular dysfunction occurs long before obesity develops.