Non-esterified Fatty Acid Availability Research Articles

Respective role of plasma nonesterified fatty acid oxidation and total lipid oxidation in lipid-induced insulin resistance

To investigate the respective role of nonesterified fatty acids (NEFA) oxidation and total lipid oxidation in lipid-induced insulin resistance, we measured the response of glucose metabolism to insulin in normal subjects without (control study) or with either heparin (heparin study) or triglycerides (TG) emulsion (Ivelip study) infusion. Three-step euglycemic—mild-hyperinsulinemic clamp studies were performed. Lipid and glucose metabolism were studied using indirect calorimetry and [6,6- 2H 2]glucose and [1- 13C]palmitate infusions. NEFA concentration and turnover and oxidation rates were decreased by insulin in the control study, but were maintained during the heparin and Ivelip infusion studies. Total lipid oxidation was decreased similarly in the control and heparin studies, but was increased during the Ivelip infusion. Stimulation of glucose oxidation and utilization by insulin was reduced in the Ivelip study, but not in the heparin study. Thus, peripheral insulin resistance was observed in the presence of a combined increase in total lipid and NEFA oxidation, but not during an isolated increase in NEFA oxidation. On the other hand, insulin-induced inhibition of glucose production was impaired in both the heparin and Ivelip studies. We conclude that total lipid oxidation is a major determinant of peripheral insulin resistance, whereas hepatic insulin resistance could be induced even by a moderate increase in NEFA availability.

Lipid metabolism and insulin resistance in cirrhosis

Fasting patients with cirrhosis have high plasma non-esterified fatty acids, and a high turnover and oxidation of non-esterified fatty acids, despite high plasma insulin levels. To assess whether increased non-esterified fatty acid availability impairs utilisation of circulating glucose, and contributes to the insulin insensitivity in cirrhosis, we measured glucose, non-esterified fatty acid and glycerol flux rates, in patients with cirrhosis and controls, in the basal state and during a 0.05 U.kg-1.h-1 hyperinsulinaemic euglycaemic clamp. After an overnight fast, basal blood glucose and glucose turnover were similar in both groups. Basal plasma glycerol and non-esterified fatty acid levels were higher in patients with cirrhosis as were 1-14C-nonesterified fatty acid turnover (4.48 +/- 0.53 vs 2.54 +/- 0.45 mumol.kg-1.min-1, p < 0.05) and 2H5-glycerol turnover (3.27 +/- 0.34 vs 2.24 +/- 0.15 mumol.kg-1.min-1, p < 0.05), indicating increased lipolysis in patients with cirrhosis; metabolic clearance rate of non-esterified fatty acids and glycerol were similar in both groups, suggesting no impairment of tissue uptake in patients. The euglycaemic clamp showed patients with cirrhosis to be markedly insensitive to insulin. The glucose metabolic clearance rate increased during the clamp in controls (p < 0.005) but not in patients with cirrhosis, indicating that infused insulin had little or no effect on glucose disposal in the patients. Clamp glucose turnover in controls was higher than in the basal state (p < 0.001); in patients with cirrhosis it was lower. The profound insulin insensitivity and the clamping of blood glucose below fasting levels explains the fall in glucose turnover in patients with cirrhosis during the clamp. In both groups serum non-esterified fatty acid and glycerol levels, and their appearance rates, were suppressed during the clamp, but levels remained significantly higher in patients with cirrhosis (non-esterified fatty acids, 0.20 +/- 0.4 vs 0.10 +/- 0.01 mmol/l, p < 0.05; glycerol 74 +/- 9 vs 46 +/- 4 mumol/l, p < 0.05). This, with the high basal non-esterified fatty acid and glycerol levels seen in patients with cirrhosis, despite high insulin levels, suggests resistance of adipose tissue lipolysis to insulin. There was no correlation between glucose infusion requirements and non-esterified fatty acid turnover. The normal turnover of blood glucose in fasting patients with cirrhosis, despite increased non-esterified fatty acid turnover, suggests utilisation mainly by tissues with an obligatory requirement for glucose, which may be similar in patients with cirrhosis and controls.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of changes in plasma nonesterified fatty acid levels on oxidative metabolism during moderate exercise in patients with non-insulin-dependent diabetes mellitus

Blood levels of intermediary metabolites were measured and indirect calorimetry was performed in 10 otherwise healthy, non-insulin-dependent diabetic (NIDDM) patients before, during, and after 30 minutes of moderate exercise on three occasions in random order at weekly intervals with (1) heparin treatment to increase preexercise plasma nonesterified fatty acid (NEFA) levels (HEPARIN); (2) acipimox, a nicotinic acid analogue, to reduce preexercise plasma NEFA levels (ACIPIMOX); and (3) no manipulation of preexercise plasma NEFA levels (NIL). With ACIPIMOX, preexercise blood levels were significantly reduced for NEFAs and glycerol ( P < .01) and marginally reduced for acetoacetate and 3-hydroxybutyrate (NS) compared with preexercise levels for the other two treatments; these low levels seen with acipimox treatment increased only slightly during exercise and the postexercise period. Plasma NEFA levels increased by approximately 150% ( P < .001) with HEPARIN at the same times. The levels of ketone bodies during either NIL or HEPARIN increased rapidly postexercise by approximately 90% to 110% for both acetoacetate and 3-hydroxybutyrate (both P < .01). Plasma insulin levels tended to be lowest (despite similar plasma glucose levels during the three treatments) with ACIPIMOX, while growth hormone (hGH) and, perhaps, noradrenaline levels were highest both during and after exercise. The respiratory quotient (RQ) was highest with ACIPIMOX ( P < .05 for exercise and postexercise periods compared with the other two treatments), which, compared with NIL, reduced fat oxidation by 27% and 60% and increased carbohydrate oxidation by 29% and 74% during and after exercise, respectively (all P < .05). These changes in substrate oxidation due to ACIPIMOX were almost opposite to those observed with HEPARIN. The increased fat oxidation with exercise during NIL (800%; P < .001 compared with preexercise value) was likely due to increased NEFA supply from the 700% exercise-induced increase in the leg blood flow. In contrast, the 340% increase in NEFA supply with ACIPIMOX could not have accounted for the 900% increase in fat oxidation during exercise ( P < .001 compared with preexercise). It is thus likely that alternative (eg, intramuscular) lipid pools are mobilized for oxidative metabolism during exercise with reduced plasma NEFA levels due to ACIPIMOX, and may constitute an adaptive response. These results support the glucose/fatty acid cycle, albeit in the converse, ie, reduced NEFA availability improves glucose oxidation, and are of likely benefit to the diabetic patient.

Effect of Increased Plasma Non-Esterified Fatty Acid Concentrations on Endurance Performance During Beta-Adrenoceptor Blockade

Inhibition of adipose tissue lipolysis, leading to a reduced availability of non-esterified fatty acids for energy production in the active skeletal muscles, may be involved in the impairment of endurance exercise capacity after administration of a beta-adrenoceptor blocking agent. The effect of increasing the availability of plasma NEFA during exercise after beta-blocker administration was studied. In a double-blind, randomized cross-over study 12 healthy volunteers were treated for 14 days with placebo, atenolol, and propranolol. On the 7th and 14th day of each treatment period an endurance exercise test at 70% of maximal aerobic power until exhaustion was performed while a continuous infusion of saline or triglycerides (Intralipid)+heparin was administered. Endurance time was reduced by 11% (n.s.) during atenolol and 40% (p < 0.01) during propranolol. Intralipid administration had no statistically significant effect on endurance in any treatment. Plasma NEFA and glycerol concentrations were elevated above control levels during Intralipid infusion, plasma glucose and lactate concentrations were unaffected. These results suggest that reduced availability of NEFA is not a major factor in the reduction of endurance performance during beta-adrenoceptor blockade, although an effect of beta-blockade on NEFA membrane transport cannot be excluded.

Docosahexaenoic acid shows no triglyceride-lowering effects but increases the peroxisomal fatty acid oxidation in liver of rats.

The effect of docosahexaenoic acid (DHA) on mitochondrial and peroxisomal fatty acid oxidation and on key enzymes in triglyceride metabolism was investigated in the liver of rats fed a standard diet, a cholesterol diet, and a pelleted chow diet. Unexpectedly, in all three rat models repeated administration of highly purified DHA (92% pure) at different doses and times, at a dose of 1000 mg/day per kg body weight, resulted in no significant decrease of hepatic and plasma concentration of triglycerides. The serum concentrations of cholesterol and phospholipids showed an increase in a time-dependent manner in rats fed the pelleted chow diet. The hepatic concentration of cholesterol was increased in rats fed the cholesterol diet and pelleted chow diet after administration of DHA compared to palmitic acid. In all rat models, treatment with DHA tended to increase the peroxisomal beta-oxidation. This was accompanied with a significant increase (1.5-fold) of fatty acyl-CoA oxidase activity. The mitochondrial fatty acid oxidation system and carnitine palmitoyl-transferase activity, however, were almost unchanged. Moreover, palmitoyl-CoA synthetase activity was increased, whereas the palmitoyl-CoA hydrolase activity was decreased. Neither microsomal phosphatidate phosphohydrolase activity nor cytosolic phosphatidate phosphohydrolase activity was affected by DHA feeding in the three rat models. Acyl-CoA:1,2-diacylglycerol acyltransferase activity was also unaffected. In contrast to docosahexanoic acid feeding, eicosapentaenoic acid (EPA) administration possessed a hypotriglyceridemic effect and resulted in an increase of mitochondrial and peroxisomal oxidation of fatty acids. Carnitine palmitoyltransferase activity was also stimulated. Phosphatidate phosphohydrolase activity was unaffected whereas diacylglycerol acyltransferase activity was increased by EPA treatment compared with palmitic acid feeding. The results indicate that docosahexaenoic acid, in contrast to eicosapentaenoic acid, does not inhibit the synthesis and secretion of triglycerides in the liver. In addition, the results emphasize the importance that stimulation of peroxisomal beta-oxidation by these n-3 fatty acids is not sufficient to decrease the serum levels of triglycerides. In addition, increased mitochondrial beta-oxidation of fatty acids and thereby decreased availability of nonesterified fatty acids may be a mechanism by which EPA inhibits triglyceride, and subsequently very low density lipoprotein-triglyceride, production. Whether DHA and EPA possess different metabolic properties should be considered.

Serum lipids, hepatic glycerolipid metabolism and peroxisomal fatty acid oxidation in rats fed omega-3 and omega-6 fatty acids.

Rats were fed, for 3 weeks, high-fat (20% w/w) diets containing sunflower-seed oil, linseed oil or fish oil. Chow-fed rats were used as a low-fat reference. The high-fat diets markedly reduced non-fasting-rat serum triacylglycerol as compared with the low-fat reference, and the highest reduction (85%) was observed with the fish-oil group, which was significantly lower than that of the other high-fat diets. The serum concentration of phospholipids was significantly reduced (30%) only in the fish-oil-fed animals, whereas serum non-esterified fatty acids were reduced 40-50% by both the fish-oil- and linseed-oil-fed groups. The liver content of triacylglycerol showed a 1.7-fold increase with the fish-oil diet and 2-2.5-fold with the other dietary groups when compared with rats fed a low-fat diet, whereas the hepatic content of phospholipids was unchanged. Peroxisomal fatty acid oxidation (acyl-CoA oxidase) was 2-fold increased for the rats fed fish oil; however this was not significantly higher when comparison was made with rats fed the linseed-oil diet. There was no difference in phosphatidate hydrolysis (microsomal and cytosolic fractions) among animals fed the various diets. Acyl-CoA:diacylglycerol acyltransferase activity was increased by all high-fat diets, but the fish-oil-diet-fed group showed a significantly lower enzyme activity than did rats fed the other high-fat diets. A linear correlation between acyl-CoA:diacylglycerol acyltransferase activity and liver triacylglycerol was observed, and the microsomal enzyme activity was decreased 40-50% by incubation in the presence of eicosapentaenoyl-CoA. CoA derivatives of arachidonic, linolenic and linoleic acid had no inhibitory effect when compared with the control. These results indicate that dietary fish oil may have greater triacylglycerol-lowering effect than other polyunsaturated diets, owing to decreased triacylglycerol synthesis caused by inhibition of acyl-CoA:diacylglycerol acyltransferase. In addition, increased peroxisomal fatty acid oxidation and decreased availability of non-esterified fatty acids could also contribute by decreasing the amounts of fatty acids as substrates for triacylglycerol synthesis and secretion.

Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans

To determine the effect of insulin and glucagon on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB), we measured simultaneously in normal subjects NEFA and KB kinetics at different NEFA levels in the presence of basal (control test) or increasing insulin concentrations with glucagopenia (somatostatin + insulin infusion, insulin test) and without glucagopenia (somatostatin + insulin + glucagon infusion, glucagon test). NEFA levels were controlled during these tests by an intravenous (IV) infusion of a triglyceride emulsion. During the control test, a moderate increase of NEFA (464 ± 30 to 715 ± 56 μmol/L) increased the percentage of NEFA converted into KB (13.3% ± 1.4% to 26.4% ± 2.1%, P < .05), and there was a linear relationship between this percentage and NEFA levels ( r = .788, P < .01). During the insulin and glucagon tests, the progressive increase in NEFA induced by the triglyceride emulsion infusion was associated, despite the increase of insulinemia, with an increase in KB production rate ( P < .05) and in the proportion of NEFA used for ketogenesis in the presence (8.1% ± 1.2% to 14.2% ± 6.3%, P < .05) and absence (15.7% ± 2.8% to 25.2% ± 3.99%, P < 0.05) of glucagopenia. In both tests, this percentage was always linearly related with NEFA levels ( P < .05) and the slopes of these relationships were comparable to that observed in the control test. However, the fraction of NEFA used for ketogenesis was always higher ( P < .05) during glucagon substitution than in its absence. Last, the study of type 1 diabetic patients with various degrees of metabolic control showed that this percentage of NEFA used for ketogenesis was rather related to increasing NEFA level ( P < .05) than to decreasing insulin concentration ( P>10). In conclusion, within the range of NEFA and insulin attained in this study, we did not obtain evidence for a direct hepatic antiketogenic action of insulin, whereas glucagon appears to stimulate ketogenesis at physiological concentrations.

Lipolytic and Ketogenic Fluxes in Human Hyperthyroidism*

The effect of hyperthyroidism on lipolytic and ketogenic fluxes was determined by measuring simultaneously (stable isotope methodology) glycerol, nonesterified fatty acids (NEFA), and ketone body (KB) kinetics in euthyroid and hyperthyroid subjects. In the postabsorptive state hyperthyroid patients had normal concentrations of insulin and glucagon, but increased concentrations (P less than 0.01) and turnover rates (P less than 0.01) of glycerol, NEFA, and KB. The ratio of NEFA appearance rate to glycerol appearance rate was decreased in hyperthyroid subjects (2.34 +/- 0.23 vs. 3.15 +/- 0.22; P less than 0.05), indicating that intracellular cycling between triglycerides and fatty acids was increased. The percentage of NEFA flux used for KB production, calculated from NEFA disappearance rates and KB appearance rates, was increased in hyperthyroid patients (21.20 +/- 2.75% vs. 13.37 +/- 0.63%; P less than 0.05), suggesting a diversion during hyperthyroidism of hepatic fatty acid metabolism toward ketogenesis. However, when the plasma NEFA levels of control subjects were raised by the infusion of a triglyceride emulsion to levels comparable to those observed in hyperthyroid patients their percentage of NEFA flux used for ketogenesis rose to values slightly higher (26.30%) than those of hyperthyroid subjects. In conclusion, 1) hyperthyroidism results not only in increased lipolysis, but also in enhanced triglyceride-fatty acid cycling, which could contribute to the excessive energy expenditure; and 2) the increased KB production of hyperthyroid patients results more from an increase in NEFA availability than from a direct stimulation of hepatic ketogenesis.

Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus

To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol.m2-1.min-1) clamp studies combined with indirect calorimetry and infusion of [3-3H]-glucose and [1-14C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151 +/- 36 mumol/l, (2) 949 +/- 178 mumol/l, and (3) 65 +/- 9 mumol/l; in healthy control subjects 93 +/- 13 mumol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p less than 0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255 +/- 42 vs 51 +/- 29 mumol/min, p less than 0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231 +/- 49 mumol/min), whereas Acipimox significantly enhanced the suppression (21 +/- 53 mumol/min, p less than 0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat

The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (approximately 1.5 mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-3H-glucose turnover were 20-25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41 +/- 4 vs 8 +/- 6 mumol.min-1.kg-1, p less than 0.001) but did not further decrease 3-3H-glucose turnover. Elevated non-esterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

Fatty acids in cardiac muscle compete with glucose for oxidation, thereby inhibiting glucose utilisation. It is not clear whether a similar mechanism is important in resting skeletal muscle. We used the hyperinsulinaemic euglycaemic clamp technique in conscious rats fasted for 20 h to examine the effects of increased plasma non-esterified fatty acid levels (approximately 1 mmol/l) on glucose metabolism. Insulin was infused at 75 mU/h (plasma insulin, 2.27 +/- 0.21 micrograms/l) or 300 mU/h (16.41 +/- 0.47 micrograms/l). An increase in non-esterified fatty acid levels decreased clamp glucose requirement and 3-3H-glucose turnover by 35% (p less than 0.001) when the higher insulin dose was used but there was no change at the lower dose. At both insulin infusion rates, clamp blood lactate and pyruvate responses suggested inhibition of muscle glycolysis by elevated plasma non-esterified fatty acid concentrations. Quadriceps muscle glycogen deposition during the clamps was enhanced by increased non-esterified fatty acid availability at the lower insulin dose (p less than 0.001) but not at the higher insulin concentration. Activation of pyruvate dehydrogenase during the clamps was partially inhibited by increased plasma non-esterified fatty acid in the heart, adipose tissue and quadriceps muscle. This was evident at both insulin levels in heart but only at the higher insulin concentration in muscle (p less than 0.002). The findings are consistent with an inhibition of glycolysis in skeletal muscle of mixed fibre type as a result of increased fatty acid availability. At low rates of glucose flux glycogen synthesis may compensate for decreased glycolysis so that glucose turnover is not decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Nonesterified Fatty Acid Availability on Insulin Stimulated Glucose Metabolism in Rats in Vivo

Effects of Nonesterified Fatty Acid Availability on Insulin Stimulated Glucose Metabolism in Rats in Vivo

Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo.

The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P less than 0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P less than 0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P less than 0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P less than 0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P less than 0.001) that was directed toward glycogen (+175%, P less than 0.05) and lipid deposition (+125%, P less than 0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P less than 0.005) and brown adipose tissue (e.g., FFA2, +200%, P less than 0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.

Beta-adrenoceptor blockade and exercise. An update.

Blockade of beta-adrenoceptors interferes with haemodynamic and metabolic adaptations and ion balance during dynamic exercise. After administration of a beta-blocker exercise heart rate is reduced. Exercise cardiac output and blood pressure are reduced also, but to a lesser extent than heart rate. At submaximal exercise intensities blood flow to the active skeletal muscle is also reduced. The availability of non-esterified fatty acids for energy production is decreased, due to inhibition of beta-adrenoceptor-mediated adipose tissue lipolysis, and possibly also of intramuscular triglyceride breakdown. During submaximal exercise muscle glycogenolysis is unaffected, but there are indications that the maximal glycogenolytic rate at high exercise intensities is decreased. In normally fed subjects plasma glucose concentration is maintained at a normal level during submaximal endurance exercise after beta-blocker administration, although lower glucose concentrations are found in fasting subjects and during high intensity exercise after beta-blocker administration. Plasma lactate concentrations tend to be somewhat lower after beta-blocker administration while plasma potassium concentration during exercise is increased. beta-Blocker administration may also interfere with thermoregulation during prolonged exercise. Maximal aerobic exercise capacity is reduced in normotensive and probably also in hypertensive subjects after beta-blocker administration. Submaximal endurance performance is impaired to a much more important extent in both groups of subjects. In patients with coronary artery disease, on the other hand, symptom-limited exercise capacity is improved during beta-blocker treatment. Studies on trainability during beta-blocker treatment show inconsistent results in healthy subjects, although the majority of studies suggest a similar training-induced increase in VO2max during placebo and beta-blocker treatment. In patients with coronary artery disease the training effects are also similar in patients treated with beta-blockers and those without. The negative effects of beta-blockers on maximal and especially submaximal exercise capacity should be considered when prescribing beta-blockers to physically active hypertensive patients. The negative influence is shared by all types of beta-blockers, although the impairment of submaximal exercise capacity is more pronounced with non-selective than with beta 1-selective beta-blockers. beta-Blockers with intrinsic sympathomimetic activity have similar effects during exercise to those without intrinsic sympathomimetic activity.

The effect of diazoxide-induced hormonal secretion on plasma triglyceride concentration in the rat.

The relationship between non-esterified fatty acid (NEFA) mobilization and hepatic conversion to plasma triglycerides (TG), as modulated by diazoxide-induced effects upon endogenous catecholamine, glucagon, and insulin secretion, was examined in vivo in the rat. Thyrotropin (TSH)-induced NEFA mobilization provided the control study.--In all control experiments, TSH (1.5 IU/100 g) induced a 110% increase in NEFA availability, which was associated with a subsequent 52% increase in plasma TG concentration and a 73% increase in plasma ketone bodies. Following diazoxide administration (30 mg/kg), endogenous secretion of both catecholamines and glucagon was observed, resulting in a comparable 100% increase in NEFA availability, with the appropriate ketonaemic response. However, in contrast to the control TSH study, plasma triglyceride concentration did not increase. This suppression was secondary, at least in part, to a direct 40% inhibition of hepatic secretion of triglycerides.--Although plasma NEFA concentration is an important determinant of plasma triglyceride levels, the concurrent concentration of endogenous catecholamines, glucagon, and insulin modulate the hepatic conversion of NEFA to triglycerides in vivo.