Biomedical subjects

P Arner

Publications and source records attributed to P Arner.

At least 253 records · Page 14Linked to original sources

PubMed1983

Effect of nicotinic acid on acylglycerol metabolism in human adipose tissue.

1. The effect of nicotinic acid on the metabolism of acylglycerols was investigated in human adipose tissue incubated with [U-14C]-glucose. 2. Nicotinic acid caused a 25% inhibition of the conversion of [U-14C]glucose into total lipids of adipose tissue, which was solely attributed to a decrease in the formation of the glyceride-glycerol moiety of triacylglycerols. There was no effect on the conversion of [U-14C]glucose to carbon dioxide by nicotinic acid. The drug inhibited the rate of glycerol release by 50% and significantly reduced the tissue level of diacylglycerols but did not alter the tissue concentration of monoacylglycerols. 3. It is concluded that in human adipose tissue nicotinic acid inhibits both the synthesis and hydrolysis of triacylglycerols and influences the metabolism of diacylglycerols.

Adipose Tissue↗

PubMed1983

Determination of adrenoceptors of the alpha 2-subtype on isolated human fat cells.

Binding state for the selective alpha 2-adrenergic antagonist (3H)-yohimbine on isolated intact human subcutaneous abdominal fat cells is described in the present study. Specific binding was rapid, reversible, saturable and stereospecific. Adrenergic antagonists competed with (3H)-yohimbine binding in the order indicative of alpha-receptors. Competition studies with adrenergic antagonists revealed that (3H)-yohimbine binding sites displayed properties consistent with those of alpha 2-subtype. Saturation experiments demonstrated that (3H)-yohimbine specific binding was of high affinity with a dissociation constant (Kd) of 3.7 +/- 0.4 nmol/l and a maximum occupancy (BO) of 10.5 +/- 2.1 pmol/10(7) cells. The latter corresponded to approximately 600,000 alpha 2-receptors/fat cell. A significant (P less than 0.002) linear relationship was found between the fat cell volume and BO. A complete saturation experiment for the determination of Kd and BO could be performed using 0.5 g adipose tissue (0.5 ml isolated fat cells), which is 30 times less required when adipocyte membranes are used for these studies. It is concluded that the method can be used for the study of alpha 2-receptor properties and regulation in subcutaneous adipose tissue in a given individual.

Adipose Tissue↗

PubMed1983

Marked increase in insulin sensitivity of human fat cells 1 hour after glucose ingestion.

The effect of glucose ingestion on insulin action was investigated in isolated human fat cells. Subcutaneous adipose tissue was obtained from eight normal adult volunteers before and 1 h after oral intake of 100 g of glucose. Lipolysis (glycerol release) and specific insulin receptor binding were determined. Insulin binding increased significantly by 20-30% after glucose ingestion. This was due to an increase in insulin binding affinity, without any change in the receptor number. The concentration of insulin producing half-maximum inhibition (ED(50)) of basal lipolysis was 50 muU/ml before and 0.25 muU/ml after glucose ingestion (P < 0.01), which represented a 200-fold difference. As regards isoprenaline-induced lipolysis, the ED(50) for insulin inhibition was 30 muU/ml before and 2.5 muU/ml after oral glucose (P < 0.01), which was a 12-fold difference. The maximum insulin-induced inhibition of basal and isoprenaline-induced lipolysis were not altered after oral glucose. It is concluded that glucose ingestion is accompanied by a marked increase in insulin sensitivity of human fat cells and this may be an important modulating factor in the overall scheme of insulin action.

Adipose Tissue↗

PubMed1983

Studies of liver insulin receptors in non-obese and obese human subjects.

The insulin-binding isotherms and the structural composition of human liver insulin receptors were examined by using plasma membranes that were prepared from liver biopsies of nine non-obese and 10 obese subjects undergoing elective surgery. The insulin-binding characteristics of liver membranes from non-obese subjects were quite similar to those previously described in rat liver membranes. However, when the membranes from obese subjects were compared with the non-obese group, insulin-binding activity was reduced by 50% (P less than 0.01). The reduction in obesity resulted primarily from a decrease in total receptor number, although a small decrease in receptor affinity was also observed. Insulin binding was not correlated with sex or with the fasting plasma insulin level. The insulin-binding sites of liver membranes were affinity-labeled with 125I-insulin and the cross-linking reagent, disuccinimidyl suberate. The liver membranes from both the non-obese and the obese group had heterogenous (nonreduced) insulin-binding species of 300,000, 260,000, and 150,000 mol wt, which were again comparable to the findings reported in rat liver. Sulfhydryl reduction demonstrated a major sub-unit of 125,000 and a minor component of 40,000-45,000 in both groups. These results indicate a close similarity between the hepatic insulin receptor of man and the more intensely studied rat hepatic receptor. Obesity in human subjects is associated with a loss of hepatic insulin receptors. This alteration may contribute to the insulin resistance reported in this organ as well as to obesity-mediated glucose tolerance.

Adult↗

PubMed1983

Studies on the regulation of phosphodiesterase in human adipose tissue in vitro.

The influence of several agents known to affect the rate of lipolysis or the phosphodiesterase (PDE) activity in rat adipose tissue was studied in human adipose tissue in vitro. Only insulin, catecholamines, prostaglandin E1, and cAMP increased PDE activity in man (by 20-40% over the control values). In dose-response studies, it was found that the ED50 values for insulin and isopropyl noradrenaline were of the same magnitude as the previously observed ED50 values for lipolysis in human adipose tissue. The time course for insulin and isopropyl noradrenaline showed maximum stimulation after 10 min, followed by a decline, with the curve approaching zero at 60 min. In subcellular fractions of adipose tissue, the highest specific PDE activity was found in the particulate fraction, in which the effects of both insulin and isopropyl noradrenaline were most marked. It is concluded that the stimulatory effect of catecholamines on PDE may be one reason for the failure of these agents to produce a sustained increase in the cAMP level and that the effect of insulin on PDE may be one mechanism by which insulin reduces the rate of lipolysis.

Adipose Tissue↗

PubMed1983

Site differences in insulin receptor binding and insulin action in subcutaneous fat of obese females.

Regional differences in insulin-induced sc adipose tissue metabolism in 7 weight-stable obese women were investigated. Insulin receptor binding to isolated fat cells and the effects of insulin on glucose oxidation and lipolysis in adipose tissue segments obtained from abdominal and femoral regions were determined. The mean dose-response relationships for the antilipolytic effect of insulin were almost identical in both regions; the half-maximum effect (ED50) was obtained with 100 microU/ml, and the maximum effect (responsiveness) was a decrease of about 7 mumol glycerol/10(7) cells X 2 h. The mean insulin dose-response curves for glucose oxidation differed; the ED50 was 100 microU/ml in femoral and 300 microU/ml in abdominal adipose tissue (P less than 0.01), and responsiveness was enhanced 2-fold in femoral fat (P less than 0.01). Insulin receptor number was higher in femoral than in abdominal adipocytes (600,000 and 250,000 sites/cell, respectively; P less than 0.01). However, the apparent insulin receptor affinity was increased 2- to 3-fold in abdominal fat cells. The ED50 for insulin stimulation of glucose utilization occurred at a higher level of receptor occupancy in abdominal than in femoral fat. Thus, significant regional differences in insulin binding and insulin action were found in sc fat depots in obese women. Differences at the postreceptor rather than at the receptor level are probably responsible for the enhanced insulin-induced glucose utilization in femoral fat.

Abdomen↗

PubMed1983

Influence of aging on insulin receptor binding and metabolic effects of insulin on human adipose tissue.

The influence of aging on the peripheral action of insulin was studied using subcutaneous adipose tissue from eight young (range 22-30 yr) and seven middle-aged (40-59 yr), healthy, normal-weight subjects. Insulin binding per cell was 50% lower in the older than in the younger group (P less than 0.01), essentially owing to a decrease in the insulin receptor number. Concomitantly, insulin sensitivity, as reflected in the degree of antilipolysis and stimulation of glucose oxidation, was 10-20 times smaller in the older subjects (P less than 0.01). Basal lipolysis and the maximum antilipolytic effect of insulin were similar in the two groups. The basal rate of glucose oxidation in the older subjects was less than one-half that for the younger group (P less than 0.025), and the maximum level of insulin-induced glucose oxidation was lower by about 75% (P less than 0.012). Age was significantly and negatively correlated with insulin receptor number (r = -0.81), basal production of 14CO2 (r = -0.73) and maximum level of insulin-induced glucose oxidation (r =- -0.68). The decreases in the receptor number and insulin sensitivity were larger in early adulthood than in the elderly, while the decrease in insulin responsiveness was more uniform. It is concluded that aging is accompanied by impairment of the action of insulin on target cells, owing to alterations at both the receptor and the postreceptor levels. These mechanisms, and especially the postreceptor defect, may be essential factors in the development of relative glucose intolerance in the aged.

Adipose Tissue↗

PubMed1983

Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis.

The possible existence of regional differences in the antilipolytic action of insulin in human adipose tissue was investigated in vitro. Insulin-induced inhibition of glycerol release and insulin binding, measured in terms of receptor number, receptor affinity, and dissociation rates, were determined in omental and subcutaneous adipose tissue segments and isolated fat cells of 16 nonobese subjects who were undergoing elective abdominal surgery but were otherwise healthy. The sensitivity of the antilipolytic effect of insulin was higher in subcutaneous than in omental adipose tissue; the half-maximal effect was obtained with 1 and 3 microU/ml of insulin, respectively (P less than 0.01). Responsiveness of the antilipolytic effect of insulin was threefold higher in the subcutaneous than in the omental region (P less than 0.005). Insulin receptor affinity was significantly higher in subcutaneous than in omental fat cells, but there was no difference in receptor number (about 300,000 sites/cell). 125I-insulin dissociated more rapidly from omental than from subcutaneous adipocytes in both the absence and the presence of excess native insulin. The data suggest that significant regional differences exist in the antilipolytic action of insulin in man; omental fat being less responsive than subcutaneous fat. The difference involves the insulin receptor affinity, which is caused at least partly by variations in the insulin dissociation rate but is also due to differences in insulin action at the postreceptor level.

Adipose Tissue↗

PubMed1983

The relationship between the basal lipolytic and lipoprotein lipase activities in human adipose tissue.

The basal rate of lipolysis and basal lipoprotein lipase activity were determined in vitro in subcutaneous adipose tissue obtained from eight healthy non-obese subjects, ten obese subjects before and during one week's starvation, nine untreated non-insulin dependent diabetics and seven treated non-insulin dependent diabetics whose disease had been under metabolic control for at least three months. There was a negative correlation between the rate of lipolysis and activity of lipoprotein lipase in untreated diabetes mellitus and during starvation (r from -0.87 to -0.81). Under these two conditions the rate of lipolysis is increased and the lipoprotein lipase activity is decreased. There was no correlation between lipolysis and lipoprotein lipase in non-obese subjects, non-starving obese subjects and treated diabetic patients (r from 0.11 to 0.36). Thus, during starvation and in untreated diabetes, there is a strong reciprocal relationship between basal lipolytic activity and basal lipoprotein lipase activity in human adipose tissue which is not found under normal conditions or in obesity and well-controlled diabetes. It is concluded that a negative connection between lipolysis and lipoprotein lipase in human adipose tissue may be of physiological importance for the regulation of the energy balance in conditions such as untreated non-insulin dependent diabetes and starvation where adipose tissue lipids are the major source of energy.

Adipose Tissue↗

PubMed1982

Changes in phosphodiesterase activity of human subcutaneous adipose tissue during starvation.

The phosphodiesterase (PDE) activity, the basal rate of lipolysis and the basal cyclic AMP level in adipose tissue were determined in hypogastric and gluteal specimens obtained from 14 obese healthy subjects before and after one week of starvation. During starvation there was a significant increase in both the tissue level of cyclic AMP and the rate of lipolysis, whereas the apparent values of Vmax of the low and high Km forms of PDE decreased significantly-i.e. by about 50 and 30 percent. respectively. The substrate concentration of cyclic AMP at Vmax of the low Km PDE corresponded to the tissue level of the nucleotide. During, but not before, starvation there was a positive correlation between Vmax of the low Km PDE and the cyclic AMP level (r = 0.7-0.8). The metabolism in the tissues from the two fat depots exhibited similar variations during starvation. The findings suggest that the low Km form of PDE is inhibited during starvation. This may be one factor responsible for the starvation-mediated increase in the cyclic AMP levels and the rate of lipolysis in adipose tissue.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1982

Effect of metoprolol and alprenolol on the metabolic, hormonal, and haemodynamic response to insulin-induced hypoglycaemia in hypertensive, insulin-dependent diabetics.

Insulin hypoglycaemia was induced three times in 6 insulin-dependent, hypertensive diabetics: before instituting antihypertensive long-term treatment and after obtaining a satisfactory blood pressure with either alprenolol or metoprolol given in a randomized order. The blood glucose concentration (1.6-1.9 mmol/l) at which the hypoglycaemia necessitated intravenous administration of glucose was almost identical on all three occasions. During hypoglycaemia the systolic and diastolic blood pressures increased significantly by a mean maximal rise of 27/14 mmHg on alprenolol treatment, but remained unchanged on metoprolol. The responses of adrenaline, noradrenaline, cortisol, and growth hormone did not differ significantly on the three occasions. None of the beta-adrenergic drugs counteracted the early hormone defence mechanisms in hypoglycaemia and the signs of hypoglycaemia were not masked. The haemodynamic response was altered only by the non-selective (alprenolol) and not by the selective beta-adrenergic blocking agent (metoprolol).

Adult↗

PubMed1982

Phosphodiesterase activity in human subcutaneous adipose tissue in hyper- and hypothyroidism.

Phosphodiesterase (PDE) activity was determined in sc adipose tissue from 12 patients with untreated hyperthyroidism, 8 patients with untreated hypothyroidism, and 10 healthy nonobese subjects. Eight of the hyperthyroid group were reexamined after treatment when they were euthyroid. The apparent Vmax of the low Km form of PDE was 25% lower in untreated hyperthyroidism (P less than 0.05) and 100% higher in untreated hypothyroidism (P less than 0.01) than in the controls; treatment of the hyperthyroidism resulted in normalization of the value. There was a positive correlation between the mean fat cell volume and the Vmax of the low Km PDE in all conditions (r = 0.64-0.85). As regards the high Km form of PDE, the Vmax values for both hyper- and hypothyroid patients did not differ from those for the control group. The results of this study suggest that in man, the apparent Vmax for the PDE with low Km is determined by the thyroid hormones.

Adipose Tissue↗

PubMed1982

Phosphodiesterase activity in human subcutaneous adipose tissue in insulin- and noninsulin-dependent diabetes mellitus.

The influence of diabetes mellitus on phosphodiesterase (PDE) activity in human sc adipose tissue was investigated in 8 patients with insulin-dependent (IDDM) and 9 with noninsulin-dependent (NIDDM) diabetes mellitus. The results were compared with data from 10 healthy normal weight subjects. The apparent maximal PDE activity (Vmax) of the low Km form of PDE was 60% lower (P less than 0.01) in untreated IDDM and NIDDM than in the control state. After treatment of IDDM and NIDDM, the Vmax of the low Km PDE was normalized. In untreated IDDM and NIDDM, the Vmax of the low Km PDE was correlated to the cAMP level (r = 0.8). This correlation was not observed after antidiabetic treatment or in the control state. The apparent Vmax values of the high Km form of PDE were similar in the diabetic states and in control subjects. The results suggest that the low Km PDE is inhibited in untreated IDDM and NIDDM. In these conditions, PDE may be one factor responsible for regulation of the cAMP level.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1982

Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus.

The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-125I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.

Adipose Tissue↗

PubMed1982

An assay for beta-adrenergic receptors in isolated human fat cells.

The beta-adrenergic receptors have been characterized in isolated human adipocytes using a potent beta-adrenergic antagonist (-)-[3H]dihydroalprenolol. Binding of (-)-[3H]dihydroalprenolol to isolated fat cells was stereospecific and saturable, the maximum number of binding sites calculated being 7.8 +/- 2.2 pmol of bound ligand/10(7) cells, corresponding to 450,000 binding sites/cell. The dissociation constant was estimated to be 2.7 +/- 1.1 nM. The results with competition-inhibition experiments using beta-adrenergic agonists and antagonists indicated that the binding sites in isolated adipocytes were predominantly of the beta1-subtype; about 80% of the receptors were of this type. With the present method, specific beta-adrenergic receptor number and affinity in isolated human adipocytes could be determined in about 1 g of human adipose tissue.

Adipose Tissue↗

PubMed1982

Changes in the metabolism of fatty acids in adipose tissue in obese patients with primary hypertriacylglycerolemia.

Changes in the release and esterification of free fatty acids (FFA) in adipose tissue were looked for as a cause of moderate primary hypertriacylglycerolemia (HTG) in five obese subjects. Comparison was made with six obese normolipidemic subjects. The two groups were matched for body weight, tolerance of intravenous glucose, fat cell size, fasting levels of serum immunoreactive insulin, and serum insulin response to an intravenous glucose load. Subcutaneous adipose tissue was incubated in vitro with [1-14C]palmitic acid for 30, 60, and 120 min. There was a significant, twofold increase in the rate of FFA mobilization, but no change of glycerol release in HTG patients. The adipose tissue levels of mono- and diacylglycerols were similar in the two groups of subjects and did not change during incubation. Re-esterification of FFA, calculated from the net changes in medium and in tissue FFA and glycerol release, was lower in HTG patients than in the controls (3 and 12 mumol/10(7) cells/hr, respectively; P less than 0.025). In adipose tissue of HTG patients, the amount of radioactive fatty acids incorporated into triacylglycerols (TG) was 50% lower (P less than 0.025), whereas that incorporated into tissue FFA was three times higher (P less than 0.01) when compared with control patients. It is concluded that, in adipose tissue of obese patients with primary hypertriacylglycerolemia, the esterification of free fatty acids to triacylglycerol is decreased. As a consequence, free fatty acids are mobilized at an increased rate.

Adipose Tissue↗

PubMed1981

The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation.

The antilipolytic effect of insulin in vitro was investigated in conditions known to be associated with resistance to the effect of insulin on glucose metabolism. Human subcutaneous adipose tissue was obtained from 14 obese subjects before and during starvation for 7 days, 12 untreated non-insulin dependent diabetics (NIDDM), 6 untreated insulin dependent diabetics (IDDM), and 10 nonobese control subjects. The tissue was incubated with and without insulin in concentration ranging from 1-10,000 microunits/ml. Responsiveness (maximum effect) and sensitivity to insulin were determined under basal induction conditions, since insulin had a bimodal effect on noradrenaline stimulated lipolysis. Under normal conditions both insulin sensitivity and insulin responsiveness were positively correlated with the basal rate of lipolysis. In obesity, IDDM and NIDDM there were no change in insulin sensitivity or in insulin responsiveness. When the obese subjects were divided into one hyperinsulinemic group (6 individuals) and one group with normal fasting serum insulin levels (7 individuals) a similar antilipolytic effect of insulin was observed in the two groups. During starvation there was a 20-fold increase in insulin sensitivity (p less than 0.01) but no change in insulin responsiveness in femoral fat and only a decrease in responsiveness (p less than 0.01) in abdominal fat. The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.

Adipose Tissue↗

PubMed1981

Post receptor activation of lipolysis in starvation, diabetes mellitus and hyperthyroidism.

Activation of lipolysis by cyclic AMP in conditions with accelerated lipid mobilization was examined in subcutaneous adipose tissue incubated in vitro. In (a) 16 obese patients before and during therapeutic starvation, (b) 18 diabetics before and after antidiabetic treatment and (c) 11 hyperthyroid patients before and after anti-thyroid treatment, a positive correlation was found between stimulation of basal cyclic AMP accumulation and stimulation of basal glycerol release using either isopropyl noradrenaline or noradrenaline (r = 0.6-0.9). During antidiabetic treatment stimulation of lipolysis increased in relation to that of cyclic AMP accumulation (F = 10.1, p less than 0.01), whereas during antithyroid therapy there was a decrease (F = 95.2, p less than 0.01). Starvation did not alter the relationship between lipolysis and cyclic AMP in hypogastric adipose tissue whereas in femoral tissue stimulation of lipolysis decreased in relation to that of cyclic AMP accumulation (F = 9.6, p less than 0.01). It is concluded that the amount of cyclic AMP needed to promote lipolysis is increased during starvation and in diabetes mellitus but is decreased in hyperthyroidism. From the studies during starvation it appears that regional differences in the post-receptor activation of lipolysis exist in human adipose tissue.

Adult↗