Decrease In Free Fatty Acids Research Articles

Change in glyceride composition of olive pomace oil during enzymatic esterification.

Enzymatic esterification of free fatty acids of olive pomace oil with glycerol was investigated. The esterification reaction was carried out in the absence and presence of glycerol (glycerol to free fatty acids (FFA) molar ratio of 1/3 and 1/6). In the absence of glycerol, the FFA concentration decreased from 32 to 21% while the triglyceride concentration increased from 33 to 40% after of 8 h of reaction time. The most significant decrease in FFAs and increase in triglycerides was observed at the limiting concentration of glycerol (glycerol to FFA molar ratio of 1/3). The FFA concentration decreased to 2.5% and the triglyceride concentration increased up to 78%. The change in both FFA and triglyceride concentrations was found to be statistically significant (P < 0.05).

Lepidium peruvianum chacon restores homeostasis impaired by restraint stress.

Lepidium peruvianum root has been traditionally utilized by native Peruvians, since before the time of the Incas, for both nutritional and putative medicinal purposes as an adaptogen and also to enhance fertility in humans and animals. The present research was conducted to evaluate the anti-stress activity of the methanolic extract of Lepidium peruvianum. The drug is capable of attenuating or even eliminating variations in homeostasis produced by stress since it reduces or abolishes stress-induced ulcers, elevated corticosterone levels, the reduction of glucose and the increase in the weight of adrenal glands produced by stress. It also eliminates the decrease in free fatty-acids (FFA) in plasma produced by stress and we obtain a positive result in the forced-swimming test. Thus, it did not appear to affect restraint stress-induced immunosuppression.

How free fatty acids inhibit glucose utilization in human skeletal muscle.

Rat muscle studies suggest competition between free fatty acids (FFA) and glucose for oxidation, resulting in glucose-6-phosphate accumulation. However, FFA decrease glucose-6-phosphate in human skeletal muscle, indicating direct inhibition of glucose transport/phosphorylation. This mechanism could redirect glucose from muscle to brain during fasting and explain the insulin resistance associated with high-lipid diets and obesity.

Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration

Background Hyperinsulinemia/insulin resistance and elevated plasma free fatty acids (FFA) levels are involved in the hypertension and cardiac sympathetic overactivity. Metformin improves insulin action and lower plasma FFA concentrations. We investigate the possible effect of metformin on arterial blood pressure (BP) and cardiac sympathetic nervous system. Methods One hundred twenty overweight type 2 diabetic patients were treated by placebo ( n = 60) + diet or metformin (850 mg twice daily) ( n = 60) + diet for 4 months, to evaluate the effect of metformin treatment on the cardiac autonomic nervous system. Insulin resistance was measured by the Homeostasis Model Assessment (HOMA) index. Heart rate variability (HRV) assessed cardiac sympathovagal balance. Results Metformin treatment, but not placebo treatment, was associated with a decrease in fasting plasma glucose ( P < .05), insulin ( P < .05), triglyceride ( P < .05), and FFA ( P < .03) concentrations and HOMA index ( P < .03). Metformin treatment was also associated with a significant improvement in cardiac sympathovagal balance but not in mean arterial BP. Furthermore, in a multivariate analysis, delta change in sympathovagal balance index (LF/HF ratio) were associated with delta change in plasma FFA concentrations and HOMA index independently of gender and delta change in plasma triglyceride and HbA1c concentrations. Conclusions Our study demonstrated that metformin treatment might be useful for improving cardiac sympathovagal balance in obese type 2 diabetic patients.

NO-1886 inhibits size of adipocytes, suppresses plasma levels of tumor necrosis factor-α and free fatty acids, improves glucose metabolism in high-fat/high-sucrose-fed miniature pigs

The synthetic compound NO-1886 is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides and elevating high-density lipoprotein cholesterol. Recently, we found that NO-1886 also had a plasma glucose-reducing action in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 on the morphology of adipocytes, plasma levels of tumor necrosis factor-α (TNF-α) and free fatty acids (FFA) in miniature pigs fed a high-fat/high-sucrose diet. Our results showed that feeding a high-fat/high-sucrose diet to miniature pigs increased the size of adipocytes, and the plasma levels of TNF-α, FFA, and glucose. This diet also induced insulin resistance and impaired the acute insulin response to glucose loading. Supplementing 1% NO-1886 to the high-fat/high-sucrose diet inhibited adipocyte enlargement, and suppressed plasma levels of TNF-α, FFA, and glucose. The decrease in plasma TNF-α and FFA was simultaneous with the decrease in plasma glucose. We also found an increased whole body glucose clearance and an increased acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 improves the glucose metabolism in high-fat/high-sucrose diet-induced diabetic minipigs by decreasing fat deposit, and suppressing plasma TNF-α and FFA levels. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistant syndrome.

Free fatty acids and fatty acids of triacylglycerols profiles in muscle and plasma of fed and underfed Boer goats

The aim of this study was the determination of muscle and plasma profiles of free fatty acids and of triacylglycerols incorporated fatty acids in fed and underfed Boer goat bucks. This trial with 15 Boer goat bucks weighting 28 Kg had a duration of 30 days during which the 2 distinctive groups of animals were organised (control group—C—fed ad libitum and a restricted group—R—fed 80% of energetic maintenance needs). The content of blood and muscle free fatty acids in the fraction of triacylglycerols was studied. % C16:0 as free fatty acid in the plasma suffered a significant effect of undernutrition (increase) and C18:1 showed a relative decrease in muscle fatty acid incorporated in triacylglycerols in underfed goats. C18:2 revealed a relative increase in muscle fatty acid incorporated in triacylglycerols and a relative decrease in free fatty acid in the plasma in the restricted group.

PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect.

Nicotinic acid (niacin), a vitamin of the B complex, has been used for almost 50 years as a lipid-lowering drug. The pharmacological effect of nicotinic acid requires doses that are much higher than those provided by a normal diet. Its primary action is to decrease lipolysis in adipose tissue by inhibiting hormone-sensitive triglyceride lipase. This anti-lipolytic effect of nicotinic acid involves the inhibition of cyclic adenosine monophosphate (cAMP) accumulation in adipose tissue through a G(i)-protein-mediated inhibition of adenylyl cyclase. A G-protein-coupled receptor for nicotinic acid has been proposed in adipocytes. Here, we show that the orphan G-protein-coupled receptor, 'protein upregulated in macrophages by interferon-gamma' (mouse PUMA-G, human HM74), is highly expressed in adipose tissue and is a nicotinic acid receptor. Binding of nicotinic acid to PUMA-G or HM74 results in a G(i)-mediated decrease in cAMP levels. In mice lacking PUMA-G, the nicotinic acid-induced decrease in free fatty acid (FFA) and triglyceride plasma levels was abrogated, indicating that PUMA-G mediates the anti-lipolytic and lipid-lowering effects of nicotinic acid in vivo. The identification of the nicotinic acid receptor may be useful in the development of new drugs to treat dyslipidemia.

Reduction of mutagenicity of the fumes from cooking oil by degumming treatment

The fume of cooking oil has been reported to increase the risk of respiratory tract cancer. The influence of a degumming treatment of peanut oil on the contents of mutagenic compounds in fumes from heated peanut oil was investigated. The results indicate that the peanut oil prepared from roasted peanut kernels which underwent degumming treatment had a lower free fatty acid (FFA) content and a higher smoke point, was more clear in color, and produced less fumes when heated at smoke point. Moreover, when compared to untreated peanut oil, the mutagenicity of oil fumes of degummed peanut oil toward Salmonella typhimurium TA98 and TA100 was reduced to 81% and 73% ( p<0.05), respectively. The degummed peanut oil which was obtained by adding 3% water and heating at 60°C for 20 min produced the least amount of mutagenic fume. The contents of four mutagenic compounds, trans-trans-2,4-decadienal ( t-t-2,4-DDE), trans-trans-2,4-nonadienal ( t-t-2,4-NDE), trans-2-decenal ( t-2-DCA), and trans-2-undecenal ( t-2-UDA) in oil fumes of degummed peanut oils were drastically decreased ( p<0.05), especially the t-t-2,4-DDE. The results also indicate that the FFA content had a high linear correlation with mutagenicity ( r 2=0.9978) and content of t-t-2,4-DDE ( r 2=0.7685). Moreover, there was a correlation ( r 2=0.7816) between the content and the mutagenicity of t-t-2,4-DDE. The decrease of FFA by degumming might explain the reduction of mutagenic alkenal compounds and mutagenicity of fumes from heated peanut oil.

Relationship between visceral fat accumulation and anti-lipolytic action of insulin in patients with type 2 diabetes mellitus.

Insulin resistance is closely related to developing type 2 diabetes mellitus. Visceral fat accumulation is associated with insulin resistance, which affects the free fatty acid (FFA) metabolism. We investigated the interactions among visceral fat accumulation, FFA metabolism and insulin resistance in 20 patients with type 2 diabetes mellitus, including 11 obese and 9 non-obese subjects. Body fat distribution was estimated by measuring the areas of both subcutaneous and visceral fat mass on abdominal computed tomography at the umbilical level. Glucose infusion rate (GIR) and plasma FFA responses to insulin were determined as an index of insulin resistance and anti-lipolytic action, respectively, in a euglycemic hyperinsulinemic clamp study. There was an inverse correlation between GIR and insulin-induced decrease in plasma FFA in all diabetic patients (r = -0.652, P < 0.01). Visceral fat mass area was well correlated with GIR (r = -0.583, P < 0.01) and insulin-induced decrease in plasma FFA (r = 0.724, P < 0.001), whereas subcutaneous fat mass area was not correlated either with GIR or plasma FFA decrease. These findings suggest that visceral fat accumulation results in increasing the resistance against the anti-lipolytic action of insulin, and that FFA metabolism is closely related with glucose utilization in patients with type 2 diabetes mellitus.

The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance.

Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARgamma and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARgamma by PPARgamma agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARgamma activity by heterozygous PPARgamma deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARgamma deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARgamma deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor alpha, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARgamma deficiency and PPARgamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.

Differential role of adrenoceptors in control of plasma glucose and fatty acids in carp, Cyprinus carpio (L.).

Carp were cannulated in the dorsal aorta, and after 2 days of recovery they were infused with 1) norepinephrine, 2) yohimbine (alpha(2)-antagonist) plus norepinephrine, 3) clonidine (alpha(2)-agonist), and 4) isoproterenol (nonselective beta-agonist). Norepinephrine lowered the plasma free fatty acid (FFA) level and raised the plasma glucose level for several hours. Norepinephrine in combination with the alpha(2)-antagonist yohimbine resulted in retardation of the FFA decrease, indicating the involvement of alpha(2)-adrenoceptors. Infusion with the partial alpha(2)-agonist clonidine had a smaller effect. Infusion with isoproterenol caused a marked increase of glucose levels, and unexpectedly a decline of plasma FFA levels, indicating a direct involvement of beta-adrenoceptors. Combination of isoproterenol with either atenolol (beta(1)-antagonist) or ICI-118,551 (beta(2)-antagonist) showed that both beta(1)- and beta(2)-adrenoceptors were involved in the glucose release by isoproterenol. Remarkably, the decline of FFA levels was augmented in the presence of ICI-118,551, whereas with atenolol present plasma FFA levels were increased by isoproterenol. Thus it is concluded that in carp both beta(1)- and beta(2)-adrenoceptors mediate glucose release, whereas lipolysis is controlled by inhibitory beta(1)-adrenoceptors and stimulatory beta(2)-adrenoceptors, as well as by inhibitory alpha(2)-adrenoceptors.

In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia

Overproduction of very low density lipoprotein (VLDL) is the major characteristic of subjects with familial combined hyperlipidemia (FCHL). As enhanced free fatty acid (FFA) flux to the liver may be one of the determinants of VLDL overproduction, we studied FFA changes and products of hepatic FFA metabolism in response to a 24-h oral fat loading test (50 g/m2) in 7 FCHL subjects and 7 matched control subjects. The response to the meal was subdivided into a postprandial (up to 8 h after ingestion of the meal) and postabsorptive period (from 8 to 24 h). Although postheparin plasma lipolytic activities were not different between both groups, the postprandial FFA area under the curve (FFA-AUC) and FFA incremental area under the curve (FFA-dAUC) were higher in FCHL subjects than in control subjects (6.05 ± 0.45 vs. 3.43 ± 0.46 and 2.60 ± 0.49 vs. 0.96 ± 0.31 mmol·h/L, respectively; P < 0.01 for each). The postprandial increase in ketone bodies was almost four times higher in FCHL patients. As ketogenesis occurs predominantly in hepatocytes, these findings suggest that during the postprandial period in FCHL an increased flux of FFA to the liver occurs, possibly because of inadequate incorporation of FFA into triglycerides (TGs) in adipocytes. In the postabsorptive period, FFA and ketone bodies significantly decreased in FCHL subjects, in contrast to control subjects, in whom both increased. These results may represent a diminished release of FFA from adipocytes by hormone-sensitive lipase (HSL) in FCHL patients. The decrease in postabsorptive FFA and ketone bodies in FCHL patients could not be explained by insulin-mediated inhibition of HSL, as both FCHL subjects and control subjects had similar postabsorptive insulin concentrations, which were below fasting concentrations.This study provides in vivo evidence of impaired metabolism of postprandial FFA in FCHL, which may explain in part the hepatic VLDL overproduction characteristic of FCHL subjects.

Changing pattern of prevalence of insulin resistance in Psammomys obesus, a model of nutritionally induced type 2 diabetes

Psammomys obesus (a desert gerbil, nicknamed the "sand rat") with innate insulin resistance was transferred to a high-energy (HE) diet at a young (8 to 20 weeks) and older (38 to 45 weeks) age. The young Psammomys progressed to in vivo insulin resistance, followed by pronounced hyperglycemia and hyperinsulinemia, as described previously. Analysis of the time dependency of these changes in response to the HE diet showed that the increase in serum glucose preceded the increase in insulin and plateaued earlier, reverting to normal together with insulin in the older Psammomys. Implants releasing insulin 2 IU/24 h did not induce appreciable hypoglycemia, a decrease in free fatty acids (FFAs), or a suppression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity in young animals after 5 hours, despite a markedly increased circulating insulin. However, in the older Psammomys, the exogenous hyperinsulinemia produced a significant decline in serum glucose and FFA and a suppression of hepatic PEPCK activity. A euglycemic-hyperinsulinemic clamp confirmed that hepatic glucose production (HGP) was lower in older Psammomys versus the young and was almost completely abolished by insulin (from 5.6 +/- 0.6 to 0.2 +/- 0.1 mg x min(-1) x kg(-1) v 10.9 +/- 0.8 to 3.9 +/- 0.5 mg x min(-1) x kg(-1)). This indicates that HGP, rather than glucose underutilization, was the main contributor to the hyperglycemia and that the hepatic insulin resistance in Psammomys is attenuated with age. In relation to the human condition, these findings point out that while the type 2 diabetes prevalence in Western populations generally increases with age, the excessive nutritional intake in high-risk populations produces a pattern of diabetes prevalence that tapers off with age. As such, the nutritionally induced diabetes in Psammomys represents a similar model for a differing pattern of the age-related prevalence of diabetes.

The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects.

We have quantitatively determined gluconeogenesis (GNG) from all precursors, using a novel method employing 2H20 to address the question of whether changes in plasma free fatty acids (FFA) affect GNG in healthy, nonobese subjects. In the first study (n = 6), plasma FFA were lowered at 16 to 20 hours with nicotinic acid (NA) and were then allowed to rise at 20 to 24 hours (FFA rebound after administration of NA). FFA decreased from 387 microM at 16 hours to 43 microM at 20 hours, and then rebounded to 1,823 microM at 24 hours. GNG decreased from 58.1% at 16 hours to 38.6% of endogenous glucose production at 20 hours (P < 0.005) and then rebounded to 78. 9% at 24 hours (P < 0.05). Conversely, glycogenolysis (GL) increased from 41.9% at 16 hours to 61.4% at 20 hours (P < 0.05), and then decreased to 21.1% at 24 hours (P < 0.05). In the second study (controls; n = 6), volunteers were analyzed between 16 and 24 hours after the last meal. FFA rose from 423 to 681 microM (P < 0.05), and GNG from 50.3% to 61.7% (P < 0.02), whereas GL decreased from 49.7% to 38.3% (P < 0.05). Endogenous glucose production decreased at the same rate in both studies, from 10.7 to 8.6 micromol/kg/min (P < 0. 05). In study 3 (n = 6), in which the NA-mediated decrease of plasma FFA was prevented by infusion of lipid and heparin, neither FFA nor GNG changed significantly. In summary, our data suggest that (a) acute changes in plasma FFA produce acute changes in GNG and reciprocal changes in GL; (b) the decrease in EGP between 16 and 24 hours of fasting is due to a fall in GL; and (c) NA has no direct effect on GNG.

Pantethine stimulates lipolysis in adipose tissue and inhibits cholesterol and fatty acid synthesis in liver and intestinal mucosa in the normolipidemic rat

In vitro effects of pantethine on adipose tissue lipolysis and on both hepatic and intestinal cholesterol and fatty acid synthesis in normolipidemic rats are determined and related to their respective in vivo hypolipidemic effects after acute oral administration. At 3, 5, 7 and 24 h after a single high dose of pantethine to rats, free fatty acids (FFA), cholesterol and triglycerides levels decreased whereas plasma glycerol increased, the effect becoming significant at 7 h. The release of glycerol and FFA by epididymal fat pad pieces from rats was measured in Krebs Ringer bicarbonate-albumin buffer supplemented or not with epinephrine and several concentrations of pantethine (0, 10 −5, 10 −4, or 10 −3 M), and it turned out to be enhanced as pantethine concentration increased. Besides, when glucose was present in the medium, this drug lowered fatty acid re-esterification in a dose-dependent manner, the effect being specially evident in the presence of epinephrine. In vitro synthesis of both cholesterol and fatty acids by slices of liver or intestinal epithelial cells was depressed as the concentration of pantethine increased in the medium. Thus, an inhibition of both cholesterolgenesis and lipogenesis seems to contribute to the hypocholesterolemic and hypotriglyceridemic effects of pantethine. On the other hand, the stimulation of lipolysis and the inhibition of fatty acid re-esterification on adipose tissue caused by pantethine must be counteracted by a high fatty acid oxidation in the liver which would explain the decrease in FFA and the increase in glycerol levels detected in the plasma of the pantethine-treated animals.

7 Interaction between body composition, leptin and growth hormone status

Administration of growth hormone (GH) induces changes in body composition, namely, increases in both bone and lean mass and a decrease in fatty tissue. However, the contrary issue, i.e. the way in which body composition affects the secretion of GH, is highly controversial. Disease states such as obesity and chronic hypercortisolism are associated with increased adiposity and/or the central distribution of fat. Ageing, characterized by excess adiposity, is also associated with impaired secretion of GH. In these states, both spontaneous and stimulated secretion of GH is severely impeded. At the other extreme, malnutrition and fasting are both associated with increased secretion of GH when confronted with most, if not all, stimuli. As the common factor in all of these situations is the increased or decreased adiposity, or the changes in energy homeostasis, it has been postulated that adipose tissue exerts a relevant role in the control of GH secretion in man. The link between adipose tissue and GH seems to be exerted through at least two signals produced by adipocytes: free fatty acids (FFA) and the recently cloned protein, leptin. An increase in FFA blocks secretion of GH, while a decrease in FFA enhances secretion. Leptin, a hormone whose main role is to regulate the intake of food and energy expenditure, seems to regulate GH secretion by acting at the hypothalamic level. In summary, body composition affects GH secretion by way of the degree of adiposity, and free fatty acids and leptin would appear to be the messages through which adipocytes participate in the regulation of GH secretion. This framework clarifies the metabolic control of GH, a hormone with profound metabolic activities.

Hypoglycemic and hypotensive effects of 6-cyclohexyl-2′- O-methyl-adenosine, an adenosine A 1 receptor agonist, in spontaneously hypertensive rat complicated with hyperglycemia

Metabolic and cardiovascular effects of 6-cyclohexyl-2′- O-methyl-adenosine (SDZ WAG 994), a selective and orally-active adenosine A 1 receptor agonist, were examined in spontaneously hypertensive rats (SHR) with hyperglycemia (SHR-DM). This model was made by the administration of streptozotocin (STZ; 60 mg/kg s.c.) to SHR 2 days after their birth. The serum glucose concentration and systolic/mean blood pressures (MBP) in 18–22-week-old rats were 14.7±0.8 mmol/l and 153±3/124±3 mmHg in SHR-DM, 13.7±0.3 mmol/l and 123±3/96±4 mmHg in normotensive with STZ (WKY-DM), 10.3±0.3 mmol/l and 165±1/136±3 mmHg in non-treated (without STZ) SHR, and 10.0±0.3 mmol/l and 115±3/90±4 mmHg in non-treated WKY. SDZ WAG 994 at 0.1 mg/kg p.o. lowered the serum glucose concentration, blood pressure and heart rate in SHR-DM. The effects were associated with the decrease in free fatty acid (FFA), triglyceride (TG), phospholipid (PL) and total cholesterol (TC) in serum of both SHR-DM and WKY-DM. On the contrary, the hypoglycemic effect was not found in WKY-DM, although the hypotensive effect was still observed. These data suggest that the risk factors for metabolic and cardiovascular complications in diabetes are reduced by SDZ WAG 994 through activation of adenosine A 1 receptors in adipocyte.

Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) in obese Zucker rats in vivo.

Beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) consists of a nonmetabolizable long-chain fatty acid designed to probe the effect exerted by fatty acids on insulin sensitivity. The effect of MEDICA 16 was evaluated in insulin-resistant Zucker (fa/fa) rats in terms of liver, muscle, and adipose tissue response to clamped euglycemic hyperinsulinemia in vivo. Nontreated Zucker rats were insulin resistant, maintaining basal rates of total-body glucose disposal, glucose production in liver, free fatty acid (FFA) flux into plasma, and FFA reesterification in adipose tissue, irrespective of the insulin levels induced. MEDICA 16 treatment resulted in an insulin-induced decrease in hepatic glucose production, together with an insulin-induced increase in total-body glucose disposal. Intracellular reesterification of lipolysed FFA in adipose tissue was specifically activated by MEDICA 16, resulting in a pronounced decrease in FFA release, with a concomitant decrease in plasma FFA. In conclusion, MEDICA 16 treatment results in the sensitization of liver, muscle, and adipose tissue to insulin in an animal model for obesity-induced insulin resistance.

Hyperglycemia results in an increase in myocardial interstitial glucose and glucose uptake during ischemia

The purpose of this investigation was to assess the effects of hyperglycemia, in the absence of changes in plasma insulin and arterial free fatty acid (FFA) levels, on interstitial glucose levels and glucose uptake across the left ventricular wall during ischemia in domestic swine. Insulin secretion was suppressed with a continuous infusion of somatostatin. Arterial FFA levels remained stable due to the suppression of insulin. Microdialysis probes were used to estimate changes in interstitial glucose and lactate, and were placed in the subepicardium and the subendocardium of the left anterior descending ([LAD] ischemic) coronary artery perfusion bed and in the midmyocardium of the circumflex ([CFX] nonischemic) perfusion bed. The LAD coronary artery was cannulated and perfused with blood from the femoral artery through an extracorporal perfusion circuit. Ischemia was induced in the LAD perfusion bed by reducing the flow of the LAD perfusion pump by 60% for 50 minutes, and was followed by 30 minutes of reperfusion. Twenty minutes into the ischemic period, seven animals were given a bolus injection of 50% glucose (200 mg/kg) followed by a glucose infusion (10 mg/kg/min), resulting in an increase in arterial glucose levels from 5 to 13 mmol/L in the hyperglycemic group. Hyperglycemia resulted in a marked increase in dialysate glucose during ischemia and a greater than twofold increase in glucose extraction and uptake. Dialysate glucose correlated with plasma glucose in all three perfusion beds. In conclusion, hyperglycemia, in the absence of an increase in insulin and a decrease in arterial FFA, resulted in a doubling of glucose extraction, delivery, and uptake, which corresponded to the twofold elevation in interstitial glucose during ischemia.

Involvement of alpha 2-adrenoceptors in metabolic and hormonal responses to a mixed meal in beagle dogs.

The effects of alpha 2-adrenoceptor blockade or activation on glucose, insulin, free fatty acids (FFA), and glycerol responses to a mixed meal were studied in the beagle dog. The alpha 2-adrenoceptor antagonist deriglidole (1 mg/kg po), administered 45 min before feeding, significantly reduced glycemia and increased insulin, FFA, and glycerol levels. Although the alpha 2-adrenoceptor agonist UK-14.304 (3 micrograms/kg sc), administered 15 min before feeding, had no effect per se, it completely blocked meal-induced insulin release, thus promoting a mild increase in glycemia, and prolonged the meal-induced FFA decrease. Deriglidole antagonized the reduction of insulin secretion and the hyperglycemia induced by UK-14.304. The meal-induced fall in FFA levels was still observed after deriglidole treatment and was markedly amplified when UK-14.304 was administered with deriglidole. These results suggest that, in the dog, insulin release and lipolysis are very sensitive to alpha 2-adrenoceptor stimulation. It is also suggested that the meal-evoked decrease in lipid mobilization results from an increase in alpha 2-adrenoceptor stimulation rather than from an increase in insulin secretion.