Role of plasma non-esterified fatty acids during and after exercise.

1. The importance of circulating non-esterified fatty acids as a substrate during and after low-grade exercise has been examined by using a nicotinic acid analogue to inhibit lipolysis. Seven healthy men received acipimox or placebo on separate occasions. After 90 min, bicycle exercise was performed for 45 min (40% of pre-determined maximum oxygen uptake), followed by a 60 min recovery period. 2. The plasma concentration of non-esterified fatty acids increased during exercise after placebo (320 +/- 80 to 630 +/- 110 mumol/l) and remained elevated in the post-exercise period. Basal concentrations were lower after acipimox (100 +/- 10 mumol/l; P less than 0.05); they declined to 60 +/- 10 mumol/l during exercise and remained at this level for the rest of the study. 3. Lipid oxidation increased from 0.8 +/- 0.1 to 4.2 +/- 0.5 mg min-1 kg-1 during exercise after placebo (P less than 0.001) and remained elevated in the post-exercise period (1.2 +/- 0.1 mg min-1 kg-1). It was lower after acipimox, but still increased from 0.3 +/- 0.1 to 2.3 +/- 0.2 mg min-1 kg-1 with exercise. Carbohydrate oxidation was increased after acipimox compared with after placebo, but only reached significance during the post-exercise period (P less than 0.05). 4. Although acipimox abolished the rise in the plasma concentration of non-esterified fatty acids during exercise, there was only a 50% decrease in the rate of lipid oxidation. This suggests that an alternative source of non-esterified fatty acids makes an important contribution to the supply of lipid for oxidation during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

In situ studies of catecholamine-induced lipolysis in human adipose tissue using microdialysis

The effects of catecholamines on lipolysis in situ were investigated in humans. Subcutaneous adipose tissue was microdialyzed with solvents containing adrenergic agents. Norepinephrine caused a rapid increase in the glycerol level in adipose tissue (lipolysis index) that was further increased by the alpha adrenoreceptor blocker phentolamine. At 10(-11) mol/l of norepinephrine caused a 100% stimulation of lipolysis (P less than .025). In the presence of phentolamine the lipolytic effects of catecholamines at 10(-12) mol/l was isoproterenol greater than epinephrine greater than norepinephrine. All these three lipolytic catecholamines caused a transient increase in the adipose tissue dialysate glycerol level, which peaked after 20 to 30 min of catecholamine exposure and then declined. The apparent tachyphylaxia could not be overcome by a gradual increase of the catecholamine concentration from 10(-12) to 10(-8) mol/l. However, the selective alpha-2 adrenoreceptor agonist clonidine caused a continuous and dose-dependent decrease in the dialysate glycerol level; the minimum effective concentration was 10(-9) mol/l. In conclusion, catecholamines have a lipolytic effect in situ at much lower concentrations than those in the circulation. This effect is transient and is related to beta adrenoreceptors. In additio, catecholamines have alpha adrenoreceptor-mediated effects on lipolysis in situ.     

Microdialysis assessment of local adipose tissue lipolysis during beta-adrenergic stimulation in upper-body-obese subjects with type II diabetes.

The present study was designed to investigate indicators of abdominal adipose tissue lipolysis (microdialysis), and subcutaneous adipose tissue blood flow and whole-body lipolysis, in obesity-associated type II diabetes during overnight-fasted conditions (baseline) and during intravenous infusion of the non-selective beta-agonist isoprenaline. Basal subcutaneous adipose tissue blood flow and isoprenaline-induced increases in adipose tissue blood flow were not significantly different between subjects with type II diabetes and non-obese, non-diabetic controls. Adipose tissue interstitial glycerol concentrations were significantly higher in subjects with type II diabetes compared with controls (P<0. 01), and during isoprenaline infusion there was a decrease in interstitial glycerol in both groups (P<0.001). Arterial glycerol concentrations were higher in subjects with type II diabetes compared with controls (P<0.05), whereas the increases in arterial glycerol concentration in response to isoprenaline infusion were of a similar magnitude in the two groups. Estimated subcutaneous adipose tissue glycerol release was not significantly different between the groups (controls and subjects with type II diabetes: baseline, -129+/-32 and -97+/-72 micromol.min(-1).100 g(-1) adipose tissue respectively; isoprenaline, -231+/-76 and -286+/-98 micromol. min(-1).100 g(-1) respectively). Values for fat oxidation were not significantly different between groups, whereas the isoprenaline-induced increase in fat oxidation tended to be less pronounced in subjects with type II diabetes compared with controls (0.022+/-0.008 and 0.038+/-0.003 g/min respectively; P=0.058). Thus estimated basal subcutaneous adipose tissue glycerol release, expressed per unit of fat mass, is not different in controls and in subjects with type II diabetes. Additionally, the isoprenaline-induced increases in indicators of local abdominal subcutaneous adipose tissue, systemic lipolysis and abdominal adipose tissue blood flow responses were comparable in obese subjects with type II diabetes and in controls. The last two findings contrast with previous data from obese subjects, indicating that the regulation of lipolysis may differ in obesity and obesity-associated type II diabetes.     

Acute metabolic and hormonal responses to the inhibition of lipolysis in non-obese patients with non-insulin-dependent (type 2) diabetes mellitus: effects of acipimox.

1. Increased rates of fatty acid oxidation are frequently observed in patients with non-insulin-dependent diabetes mellitus and may contribute to hyperglycaemia by both decreasing peripheral glucose disposal and, more importantly, by increasing the rate of gluconeogenesis and therefore hepatic glucose output. Despite this relationship between lipid and carbohydrate metabolism, fasting glucose concentrations do not fall acutely in patients with non-insulin-dependent diabetes mellitus when plasma non-esterified fatty acid concentrations and lipid oxidation rates are decreased, questioning the importance of this interaction to glycaemic control. We have therefore measured the acute changes that occur 120-150 min after administration of 500 mg of the antilipolytic agent acipimox in eight non-obese male patients with non-insulin-dependent diabetes mellitus. 2. After administration of acipimox, lipolysis was inhibited as reflected by lower plasma non-esterified fatty acid (0.05 +/- 0.02 versus 0.55 +/- 0.05 mmol/l, P less than 0.001) and blood glycerol (8 +/- 1 versus 56 +/- 8 mumol/l, P less than 0.001) concentrations. The lipid oxidation rate was decreased (0.63 +/- 0.05 versus 1.02 +/- 0.08 mg min-1 kg-1, P less than 0.001), whereas there was a significant increase in the carbohydrate oxidation rate (1.93 +/- 0.17 versus 1.22 +/- 0.18 mg min-1 kg-1, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glycerol production in subcutaneous adipose tissue in lean and obese humans.

To estimate the regional subcutaneous glycerol production rate in normal and obese humans, the venous arterialized plasma glycerol, interstitial glycerol in the subcutaneous adipose tissue together with adipose tissue blood flow (ATBF, ml/100 g.min) were measured in the postabsorptive state and for 2 h after ingestion of 100 g of oral glucose. Eight lean and eight obese men with normal oral glucose tolerance tests were investigated with the subcutaneous microdialysis technique and 133Xe clearance. In the postabsorptive state, the interstitial glycerol concentrations in lean and obese subjects were 170 +/- 21 vs. 282 +/- 28 microM (P less than 0.01) and 156 +/- 23 vs. 225 +/- 12 microM (P less than 0.05) in the abdominal and femoral subcutaneous adipose tissue, respectively. The corresponding arterial glycerol levels were 54 +/- 4 vs. 75 +/- 14 microM (NS). Abdominal ATBF was greater in lean subjects (3.2 +/- 0.6 vs. 1.6 +/- 0.3; P less than 0.05), whereas femoral ATBF was similar in both groups (2.7 +/- 0.4 vs. 2.4 +/- 0.7). Estimated mean local glycerol release (mumol/100 g.min) was similar in the lean and obese group (0.16 +/- 0.03 vs. 0.20 +/- 0.05 and 0.18 +/- 0.02 vs. 0.17 +/- 0.04) in the abdominal and femoral site, respectively. We conclude that glycerol production from the subcutaneous tissue is increased in obesity, irrespective of adipose tissue distribution. This enhancement is due to the increased adipose tissue mass.     

Synthesis of fatty acids and cholesterol by liver, adipose tissue and intestinal mucosa from obese and control patients

Biopsies of adipose tissue, liver and small bowel mucosa obtained from grossly obese and control subjects were used to study absolute rates of fatty acid, cholesterol, and other nonsaponifiable lipid synthesis using glucose as substrate and 3H2O as the isotopic marker. Fatty acid synthesis in subcutaneous adipose tissue expressed on a cell basis was greater in obese than control subjects and was stimulated by a high concentration of insulin (1000 micro U/ml), but not by a lower amount (100 micro U/ml). Fatty acid synthesis in omental adipose tissue exceeded by 3-fold that of subcutaneous fat. Fatty acid synthesis in obese liver was twice that of control liver and 20 times greater than obese adipose tissue. In terms of total organ activity fatty acid synthesis in fat tissue equalled or exceeded that of liver in both obese and control subjects. The cholesterol content of obese adipose tissue 1.86 +/- 0.11 mg/g exceeded that of controls 1.47 +/- 0.07 mg/g. All tissues examined synthesized cholesterol and nonsaponifiable lipids, liver greater than adipose tissue greater than small bowel mucosa. Nonsaponifiable lipid synthesis per gram of adipose tissue or liver was similar in obese and control tissue. The synthesis of total nonsaponifiable lipids including sterols, hydrocarbons and squalene was appreciable in adipose tissue and was approximately 15% of that of liver. However, cholesterol synthesis in the liver exporessed in terms of total organ activity was 50 times that in adipose tissue. The study demonstrates by direct comparison that liver is the dominant cholesterogenic organ in man and also shows that adipose tissue is a significant site of formation of fatty acids and nonsaponifiable lipids.     

Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus.

Increased nonesterified fatty acid (NEFA) levels may be important in causing insulin resistance in skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM). The acute effect of the antilipolytic nicotinic acid analogue Acipimox (2 X 250 mg) on basal and insulin-stimulated (3 h, 40 mU/m2 per min) glucose metabolism was therefore studied in 12 patients with NIDDM. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated steady-state periods. Acipimox reduced NEFA in the basal state and during insulin stimulation. Lipid oxidation was inhibited by Acipimox in all patients in the basal state (20 +/- 2 vs. 33 +/- 3 mg/m2 per min, P less than 0.01) and during insulin infusion (8 +/- 2 vs. 17 +/- 2 mg/m2 per min, P less than 0.01). Acipimox increased the insulin-stimulated glucose disposal rate (369 +/- 49 vs. 262 +/- 31 mg/m2 per min, P less than 0.01), whereas the glucose disposal rate was unaffected by Acipimox in the basal state. Acipimox increased glucose oxidation in the basal state (76 +/- 4 vs. 50 +/- 4 mg/m2 per min, P less than 0.01). During insulin infusion Acipimox increased both glucose oxidation (121 +/- 7 vs. 95 +/- 4 mg/m2 per min, P less than 0.01) and nonoxidative glucose disposal (248 +/- 47 vs. 167 +/- 29 mg/m2 per min, P less than 0.01). Acipimox enhanced basal and insulin-stimulated muscle fractional glycogen synthase activities (32 +/- 2 vs. 25 +/- 3%, P less than 0.05, and 50 +/- 5 vs. 41 +/- 4%, P less than 0.05). Activities of muscle pyruvate dehydrogenase and phosphofructokinase were unaffected by Acipimox. In conclusion, Acipimox acutely improved insulin action in patients with NIDDM by increasing both glucose oxidation and nonoxidative glucose disposal. This supports the hypothesis that elevated NEFA concentrations may be important for the insulin resistance in NIDDM. The mechanism responsible for the increased insulin-stimulated nonoxidative glucose disposal may be a stimulatory effect of Acipimox on glycogen synthase activity in skeletal muscles.     

Effects of nicotinic acid treatment on glyceride formation and lipolysis in adipose tissue of hyperlipidemic patients

Summary Thirty-one weight-stable patients with different types of hyperlipoproteinemia were treated daily with 4g nicotinic acid for 6 weeks. Effects of this therapy on adipose tissue metabolism were evaluated. By using biopsy specimens of subcutaneous adipose tissue, fatty acid and glucose incorporation into adipose tissue glycerides were measured in vitro as well as glycerol and fatty acid release, which allowed us to estimate adipose tissue lipolysis. The amount of fatty acids produced by lipolysis and thereafter utilized within adipose tissue without being released (fatty acid retention) was estimated. Fatty acid and glucose incorporation into adipose tissue, glycerol release and fatty acid retention values increased, but serum triglyceride levels decreased (allP<0.001) after nicotinic acid treatment. The change in fatty acid incorporation was positively correlated with changes in glucose incorporation into adipose tissue (r=0.53,P<0.01) and fatty acid retention (r=0.76,P<0.001). Although adipose tissue lipolysis, measured as glycerol release, increased, the lipolyzed fatty acids were retained in adipose tissue, suggesting an enhanced synthesis of glycerides both from exogenous and endogenous sources. The increase in fatty acid incorporation into adipose tissue indicates that the decrease in serum triglyceride levels produced by nicotinic acid treatment may partly be due to the fact that this drug promotes incorporation of fatty acids, derived from lipoprotein-carried triglycerides in the blood, into adipose tissue glycerides.     

Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet.

A new experimental approach was used to determine whether a eucaloric, low fat, high carbohydrate diet increases fatty acid synthesis. Normally volunteers consumed low fat liquid formula diets (10% of calories as fat and 75% as glucose polymers, n = 7) or high fat diets (40% of calories as fat and 45% as glucose polymers, n = 3) for 25 d. The fatty acid composition of each diet was matched to the composition of each subject's adipose tissue and compared with the composition of VLDL triglyceride. By day 10, VLDL triglyceride was markedly enriched in palmitate and deficient in linoleate in all subjects on the low fat diet. Newly synthesized fatty acids accounted for 44 +/- 10% of the VLDL triglyceride. Mass isotopomer distribution analysis of palmitate labeled with intravenously infused 13C-acetate confirmed that increased palmitate synthesis was the likely cause for the accumulation of triglyceride palmitate and "dilution" of linoleate. In contrast, there was minimal fatty acid synthesis on the high diet. Thus, the dietary substitution of carbohydrate for fat stimulated fatty acid synthesis and the plasma accumulation of palmitate-enriched, linoleate-deficient triglyceride. Such changes could have adverse effects on the cardiovascular system.     

Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man.

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h-1 kg-1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 +/- 0.20 versus 0.67 +/- 0.10 mmol/l), plasma nonesterified fatty acid (395 +/- 13 versus 51 +/- 1 mumol/l), blood glycerol (152 +/- 2 versus 11 +/- 1 mumol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64-104) versus 4 (3-5) mumol/l] were all significantly higher (all P less than 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 +/- 0.07 versus 0.27 +/- 0.08 mg min-1 kg-1, P less than 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 +/- 0.77 to 6.17 +/- 0.71 mg min-1 kg-1, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue.

The role of alpha-2 adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in nonobese healthy subjects. The alpha-2 agonist clonidine caused dose-dependent biphasic response with increased glycerol levels at low clonidine concentrations and decreased glycerol levels at concentrations > 10(-7) mol/liter. Similar results were observed with epinephrine plus propranolol. Clonidine action was unaffected in the presence of labetalol (beta-/alpha-1 antagonist) but completely blunted by the presence of yohimbine (alpha-2 antagonist). The pseudolipolytic effect of clonidine was significantly more pronounced in gluteal as compared with abdominal adipose tissue. When clonidine was added together with the vasodilating agents nitroprusside or hydralazine, the pseudolipolytic effect was abolished and a dose-dependent decrease in dialysate glycerol was observed at all clonidine concentrations (10(-10)-10(-4) mol/liter). When ethanol was added to the perfusate to monitor blood flow, the escape of alcohol from the dialysate was accelerated by 30% with hydralazine or nitroprusside (P < 0.01) and 30% retarded (P < 0.05) by clonidine (10(-10) mol/liter). Thus, the results demonstrate an important role of blood flow for regulating lipid mobilization from adipose tissue in vivo. Alpha-2 adrenoceptor activation causes marked retention of lipids in adipose tissue due to vasoconstriction in combination with antilipoiysis.     

In vivo interactions between beta-1 and beta-2 adrenoceptors regulate catecholamine tachyphylaxia in human adipose tissue.

Catecholamine tachyphylaxia was investigated in human s.c. adipose tissue in situ by using microdialysis. The tissue was dialyzed with adrenergic agents (10(-8) mol/l) and the glycerol concentration (lipolysis index) was determined. Perfusion with adrenaline caused a 3-fold rise in the glycerol concentration, which peaked at 30 min and then (within 1 hr) declined to a level 75% higher than base line; the latter elevation was constant for at least 2 hr. Noradrenaline or isoprenaline in the absence and presence of a selective beta-2 receptor antagonist, or the selective beta-1 adrenergic agonist dobutamine, caused a 2- to 2.5-fold transient lipolytic response which also peaked at 30 min but then (within 3 hr) declined to the base-line level. On the other hand, isoprenaline plus a selective beta-1 receptor antagonist or the beta-2 selective adrenergic agonist terbutaline caused a constant lipolytic effect for at least 3 hr. Noradrenaline or adrenaline plus a nonselective beta adrenergic antagonist as well as the alpha-2 selective adrenergic antagonist clonidine caused a sustained antilipolytic action for at least 3 hr. In conclusion, the adrenoceptor subtypes involved in lipolysis regulation in humans have different in vivo sensitivities to homologous desensitization. Beta-2 and alpha-2 adrenoceptors are resistant in this respect whereas activation of beta-1 adrenoceptors leads to rapid desensitization. However, simultaneous beta-1 and beta-2 receptor activation is accompanied by different degrees of tachyphylaxia, indicating regulatory in vivo interactions within this receptor family in human adipose tissue.     

The effect of circulating non-esterified fatty acids on the entero-insular axis

BACKGROUND: Circulating non-esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero-insular axis, either in obesity or health, is unknown. MATERIALS AND METHODS: Glucose, insulin, glucagon-like peptide-1 (7-36 amide) (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non-esterified fatty acids (NEFAs). A total of 10,000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean +/- SEM: age 40 +/- 3.7 years; body mass index (BMI) 38.9 +/- 2.1 kg m-2] and seven lean (age 39.6 +/- 3.6 years; BMI 22.4 +/- 0.4 kg m-2) women. RESULTS: Higher fasting levels and post-heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP-1 responses to oral carbohydrate post-heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only. CONCLUSION: The inverse relationship in GIP and GLP-1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B-cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin-induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus.     

Plasma adiponectin is modestly decreased during 24-hour insulin infusion but not after inhibition of lipolysis by Acipimox

OBJECTIVE: Plasma adiponectin is associated with insulin resistance and atherosclerosis. Adiponectin expression in adipose tissue is up-regulated by peroxisome proliferator-activated receptor (PPAR)-gamma agonist treatment and its plasma level may be affected by insulin. We tested the hypothesis that prolonged exogenous insulin infusion decreases plasma adiponectin, and examined whether a possible effect of insulin on plasma adiponectin is attributable to inhibition of lipolysis. MATERIAL AND METHODS: The effect of insulin infusion on plasma adiponectin (Linco enzyme-linked immunosorbent assay) was evaluated during a 24-h moderately hyperinsulinemic clamp (8.3 microU kg(-1) s(-1)) in 8 male type 2 diabetic patients and in 8 healthy men. On a separate day, acipimox (250 mg/4 h for 24 h) was administered to inhibit lipolysis. Insulin and acipimox were administered in random order with 1 week between study days. RESULTS: In type 2 diabetic patients, insulin infusion decreased plasma adiponectin from 7.74+/-2.53 mg/l to 6.76+/-2.41 mg/l after 24 h (p<0.05). In healthy subjects, the change in plasma adiponectin after 24 h of insulin was not significant (8.10+/-2.76 and 7.55+/-2.41 mg/l at baseline and after 24 h of insulin, respectively). The change in plasma adiponectin after 24 h insulin in healthy subjects was not different from the change in diabetic patients. Plasma adiponectin did not decrease after 24 h acipimox administration in either group (type 2 diabetic patients: 6.84+/-2.19 and 6.54+/-2.93 mg/l at baseline and after 24 h, respectively (NS); healthy subjects; 7.35+/-2.52 and 8.31+/-3.37 mg/l, at baseline and after 24 h, respectively (NS)). When the results from diabetic and healthy subjects were combined, the decrease in plasma adiponectin after 24 h of insulin infusion (-0.76+/-1.08 mg/l, equivalent to a -9% change from baseline, p<0.05) was different (p = 0.05) from the change after 24 h acipimox (+0.33+/-1.74 mg/l, equivalent to a +4% change from baseline). Plasma free fatty acids decreased during insulin infusion (p<0.01 for both groups after 24 h) as well as in response to acipimox (p<0.05 for healthy subjects; p<0.01 type 2 diabetic patients after 24 h). After administration of acipimox, plasma insulin did not change in either group. CONCLUSIONS: Plasma adiponectin is modestly decreased during 24 h of insulin infusion. It is unlikely that this response to exogenous insulin is attributable to inhibition of lipolysis, since plasma adiponectin did not decrease after acipimox.     

Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle.

To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.     

Effects of insulin on human adipose tissue metabolism in vivo

1. The metabolic effects of insulin on human adipose tissue were studied by combining the euglycaemic clamp technique with measurement of arteriovenous differences across the subcutaneous adipose tissue of the anterior abdominal wall. 2. Eight normal subjects were studied after an overnight fast, and for 120 min during infusion of insulin (mean arterialized plasma insulin 50-55 m-units/l). 3. During the insulin infusion, the arterialized and abdominal venous levels of both non-esterified fatty acids and glycerol fell, and the arteriovenous differences for the release of these substances narrowed. The fractional rate of re-esterification of fatty acids was around 20% in the fasting state and increased to almost 100% during hyperinsulinaemia. 4. In the fasting state the uptake of glucose and 3-hydroxybutyrate by adipose tissue could account for only 20% of the oxygen uptake. During insulin infusion, adipose tissue glucose uptake increased and could account for more than 100% of oxygen uptake, implying storage of glucose. 5. Net balances of different substrates across adipose tissue were examined by calculating fluxes in terms of microgram-atoms of carbon. In the fasting state adipose tissue was in marked negative carbon balance (because of the export of non-esterified fatty acids); during insulin infusion it just reached 'carbon balance'. These results were in contrast to those from a previous study of glucose ingestion, in which the adipose tissue showed marked positive carbon balance (net substrate deposition).     

Effect of a high-carbohydrate, low-saturated-fat diet on apolipoprotein B and triglyceride metabolism in Pima Indians.

The mechanisms by which high-carbohydrate, low-saturated-fat diets lower LDL cholesterol (LDLC) concentrations are unknown. In this study, kinetics of VLDL, intermediate density lipoprotein (IDL), and LDL apoprotein B and VLDL triglyceride were determined in seven nondiabetic (ND) and seven non-insulin-dependent diabetic (NIDDM) Pima Indian subjects on high-fat and high-carbohydrate (HICHO) diets. Metabolic changes were similar in ND and NIDDM. On the HICHO diet, LDLC decreased (131 +/- 8 vs. 110 +/- 7 mg/dl, P less than 0.0001) in all subjects. Mean fasting and 24-h triglyceride (TG) concentrations were unchanged, as were mean production rates and fractional clearance rates (FCR) of VLDL apoB and VLDL TG. The mean VLDL apoB pool size (303 +/- 20 vs. 371 +/- 38 mg, P = 0.01) increased owing to a decrease in the mean transport rate (10.7 +/- 1.1 vs. 8.4 +/- 0.9 mg/kg fat-free mass (ffm) per day, P less than 0.0001) and the mean rate constant (2.3 +/- 0.2 vs. 1.5 +/- 0.2, P less than 0.001) for the VLDL apoB to IDL apoB conversion pathway. The mean transport rate of VLDL apoB to LDL apoB via IDL (10.2 +/- 0.9 vs. 8.0 +/- 0.8 mg/kg ffm per day, P less than 0.001) decreased. Mean LDL apoB concentrations decreased (70 +/- 5 vs. 61 +/- 5 mg/dl, P less than 0.001) on the HICHO diet. Means for total LDL apoB transport rate, LDL apoB FCR, and LDLC/apoB ratios were unchanged. In summary, the HICHO diet decreased the activity of mechanisms that convert VLDL to LDL, which contributed to the decrease in LDLC in all subjects. There was also evidence in some subjects for increased activity of LDL apoB clearance mechanisms, and a decrease in the LDLC to apoB ratio.     

Regulation of forearm lipolysis in different types of obesity. In vivo evidence for adipocyte heterogeneity.

Forearm and systemic adipose tissue free fatty acid (FFA) release was measured in eight nonobese, six lower-body obese, and eight upper-body obese women under basal, hyperinsulinemic, and hypoinsulinemic conditions to determine whether forearm fat is regulated in a similar manner as whole body fat. Results: Adipose tissue palmitate release was greater from forearm than whole body (5.97 +/- 0.75 vs. 3.84 +/- 0.34 mumol.kg fat-1.min-1, respectively, P less than 0.005, n = 22 subjects). Systemic palmitate release, relative to fat mass, was significantly (P less than 0.01) greater in nonobese than upper-body obese, and upper-body obese than lower-body obese women, and forearm adipose tissue palmitate release followed the same pattern. Hyperinsulinemia suppressed systemic and forearm lipolysis to similar degrees, however, hypoinsulinemia consistently increased systemic palmitate flux without increasing forearm palmitate release. These results confirm the heterogeneity of adipose tissue in an in vivo model and emphasize the need to consider which adipose tissue depots are responsible for the differences in systemic FFA flux in obese and nonobese humans.     

Effect of vasoactive intestinal polypeptide (VIP) on glucose and lipid metabolism of isolated rat adipocytes

The biologic actions of vasoactive intestinal polypeptide (VIP) on insulin binding, glucose uptake and utilization, and on lipolysis were studied. At concentrations between 10(-10) and 10(-7) mol/l VIP influenced neither glucose uptake nor glucose incorporation into lipids under basal and insulin-stimulated conditions. This effect was independent of the presence of adenosine deaminase in the incubation medium. At 10(-8) mol/l VIP increased insulin binding affinity slightly but not significantly, shifting the ID-50 from 12.4 ng/ml to 10.3 ng/ml, without any change in receptor number. However, VIP showed a marked dose-dependent lipolytic activity with the lowest effective concentration at 10(-9) mol/l. At 10(-6) mol/l glycerol release increased 7.3-fold as compared to basal lipolysis. In conclusion, VIP did not affect adipose tissue metabolism at physiologic concentrations. In the rare Verner-Morrison syndrome, however, the potent lipolytic activity of VIP may contribute to the metabolic disturbances observed.     

Effects of nicotinic acid treatment on fatty acid composition of plasma lipids and adipose tissue in hyperlipidaemia.

Effects of 6-week treatment with 4 g daily of nicotinic acid on fatty acid composition in different serum lipids and in adipose tissue glycerides were studied in 31 hyperlipidemic patients. The percentages of eight fatty acids in triglycerides, phospholipids and cholesteryl esters of whole plasma as well as in subcutaneous adipose tissue glycerides were measured. Nicotinic acid treatment produced decreases in triglyceride and total cholesterol concentrations of VLDL and LDL, whereas HDL total cholesterol levels in serum increased after drug therapy, all p less than 0.01. There were reductions in the relative contents of myristic acid in plasma phospholipids (from 0.4% to 0.3%; p less than 0.05) and cholesteryl esters (from 0.9% to 0.7%; p less than 0.001). There were decreases in the percentages of stearic acid in plasma phospholipids (from 17.0% to 15.0%) and cholesteryl esters (from 1.2% to 1.0%; both p less than 0.001). The relative contents of polyunsaturated fatty acids, mainly linoleic acid, in plasma phospholipids were increased (from 32% to 33.5%; p less than 0.05). There were reductions in the linolenic acid contents of adipose tissue (from 1.5% to 1.1%) and plasma triglycerides (from 1.1% to 0.8%), both p less than 0.05, possibly indicating increased conversion of linolenic acid to prostaglandins. There was no relationship between changes in the percentages of individual fatty acids and changes in triglyceride or total cholesterol levels of whole serum and its VLDL, LDL and HDL fractions.(ABSTRACT TRUNCATED AT 250 WORDS)