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Biomedical subjects

P Arner

Publications and source records attributed to P Arner.

At least 217 records · Page 12Linked to original sources
PubMed1988

Effects of insulin on adrenoceptor binding and the rate of catecholamine-induced lipolysis in isolated human fat cells.

The mechanisms by which insulin inhibits catecholamine-induced lipolysis in fat cells are unknown. In this study the possible role of an interaction between insulin and the adrenoceptors on human fat cells was investigated. Insulin inhibited, in a dose-dependent fashion, the specific binding of hydrophobic as well as hydrophilic nonselective beta-receptor radioligands but had no effect on the binding of alpha 2-selective radioligands. The results of saturation experiments and competition-inhibition experiments under both equilibrium conditions and nonequilibrium conditions revealed that insulin reduced the total number of beta-adrenergic binding sites (maximum effect 25%) without changing the beta-adrenoceptor affinity. This insulin effect was rapid and reversible; one-third of the effect occurred within 1 min of incubation and it was completely reversed within 30 min after withdrawal of insulin. It could be mimicked by a polyclonal rabbit insulin receptor antibody but not by insulin mimickers acting distal to the initial interaction between the hormone and its specific insulin-receptor binding site. The beta-adrenoceptor binding to a plasma membrane-enriched fraction decreased at the same time as it increased to a microsomal enriched fraction after insulin treatment, indicating a redistribution of beta-adrenoceptors in the cell. In lipolysis experiments performed under conditions like those in the binding experiments, insulin inhibited the rate of lipolysis with a lag period of 3 min. Furthermore, the hormone caused a dose-dependent maximum 10-fold shift to the right of the dose-response curve for isoprenaline-induced lipolysis without changing the amplitude of the curve. This effect of insulin was specific for the beta-adrenergic receptors system, since insulin markedly decreased the amplitude of the dose-response curve for parathyroid hormone-induced lipolysis. In addition, the effect of insulin on isoprenaline-induced lipolysis could be mimicked by long-lasting fractional inactivation of the beta-adrenoceptors. The dose-response relationships for the inhibitory effects of insulin on beta-adrenoceptor binding and the lipolytic sensitivity to isoprenaline were almost identical. Half-maximum and maximum effects occurred at about 5 and 100 microunits/ml of insulin, respectively. In conclusion, the exposure of human fat cells to physiological insulin doses is followed by a rapid and dose-dependent translocation of beta-adrenoceptors from the exterior to the interior of the cell and a subsequent dose-dependent decrease in the lipolytic sensitivity to beta-adrenergic agonists, without a change in maximum lipolysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1988

Adrenoceptor occupancy in isolated human fat cells and its relationship with lipolysis rate.

The relationship between lipolysis and adrenoceptor occupancy was determined in isolated human fat cells, which possess both lipolytic beta-adrenoceptors and antilipolytic alpha 2-adrenoceptors. The beta-adrenoceptor agonist, isoprenaline, and the alpha 2-adrenoceptor agonist, clonidine, had lower affinities to compete with antagonist radioligands (Ki) than to affect the rate of lipolysis (Ka). At 1 min of incubation human fat cells bound isoprenaline and clonidine with high affinity to beta- and alpha 2-adrenoceptors, respectively, but this high-affinity binding rapidly converted to a low-affinity state. The relationship between lipolysis and adrenoceptor occupancy was also assessed after long-lasting receptor inactivation. The inactivation of a small receptor fraction shifted the dose-response curves for isoprenaline and clonidine to the right but did not alter the maximum effect of the agonists (responsiveness). These results suggest that alpha 2- and beta-adrenoceptors are coupled to lipolysis according to similar models. There is a non-linear relationship between receptor and effector for both receptors, which can be explained by the co-existence of spare receptors and a transient high-affinity state of the receptors for agonists.

Adipose Tissue↗
PubMed1988

Characterisation of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects.

The insulin-like growth factor I receptor and the activity of its associated tyrosine kinase activity were characterised in wheat germ agglutinin extracts from skeletal muscle biopsies from nine control and ten obese Type 2 (non-insulin-dependent) diabetic subjects, who had marked peripheral in vivo insulin resistance for glucose disposal and hyperinsulinaemia. In parallel studies, the concentration of the insulin receptor and its tyrosine kinase activity were examined in the biopsy extracts and compared to the findings for the insulin-like growth factor I receptor system. Specific binding sites for insulin-like growth factor I were detected. The receptor binding of insulin-like growth factor I was not changed in the obese diabetic subjects as compared to binding activity in the biopsies from the control subjects. The molecular weight of the insulin-like growth factor I receptor alpha subunit was similar in both groups (135 kDa). The insulin-like growth factor I stimulated tyrosine kinase activity was also similar for the two groups. In contrast, insulin binding activity was 30% less in the receptor extracts from the in vivo insulin resistant group when compared to the control group. Moreover, insulin-stimulated tyrosine kinase activity was reduced in the former group by 40% when the value was corrected for insulin binding. Thus, specific insulin-like growth factor I receptors are present in human skeletal muscle. These receptors are normal in insulin resistant obese Type 2 diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1988

Role of antilipolytic mechanisms in adipose tissue distribution and function in man.

Regional differences have been found in the hormone regulation of adipose tissue lipolysis. Lipolytic activity is greater in omental than in subcutaneous adipocytes owing, in part, to a less marked insulin action and lower alpha 2-adrenoceptor antilipolytic activity in the omental region. In the subcutaneous region catecholamines are less lipolytic in gluteal/femoral than in subcutaneous abdominal adipocytes, which is partly due to enhanced alpha 2-adrenoceptor responsiveness in the gluteal/femoral cells. Insulin action also differs in the two subcutaneous adipose regions in a complex way that is influenced by the degree of obesity and nutritional factors. The regional differences in the antilipolytic effects of hormones seem to be caused by site variations in the receptors as well as in the signals from the receptors. The site variations may be involved in the development of regional forms of obesity, such as android or gynoid obesity and may raise the free fatty acid levels in the portal system and therefore impair metabolism of glucose and insulin by the liver.

Adipose Tissue↗
PubMed1988

Antilipolytic effect of insulin in non-insulin-dependent diabetes mellitus after conventional treatment with diet and sulfonylurea.

Insulin-induced antilipolysis was investigated in fat cells obtained after an overnight fast and 60 min after glucose ingestion in seven non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was performed before and after long-term therapy with diet and glibenclamide. After treatment, the antilipolytic potency of insulin in fat cells was threefold enhanced (p less than 0.05) in the fasting state and remained unaltered after glucose ingestion. In untreated NIDDM oral glucose induced a significant (p less than 0.01) increase in insulin sensitivity. In consequence, in the glucose-fed state insulin sensitivity was similar before and after therapy. Adipocyte insulin receptor binding was comparable before and after therapy, both in the fasting state and following glucose intake. In untreated NIDDM, despite relative hypoinsulinemia, plasma glycerol was markedly reduced after oral glucose. After therapy, plasma glycerol was significantly reduced both in the fasting state and following glucose ingestion. At the same time, fasting and glucose-stimulated circulating insulin were significantly (p less than 0.01) increased. It is concluded that conventional antidiabetes therapy in NIDDM mediates a suppression of adipose tissue lipolysis. This seems to be due to an improvement in insulin secretion in combination with a potentiation of the antilipolytic effectiveness of insulin in fat cells in the fasting state, the latter being secondary to post-binding alterations in insulin action.

Adipose Tissue↗
PubMed1988

Microdialysis of adipose tissue and blood for in vivo lipolysis studies.

Glycerol levels (lipolysis index) were continuously monitored in intact rats using simultaneous microdialysis of venous blood and subcutaneous adipose tissue. Dialysis probes (0.5 X 4 mm) were implanted and perfused using a microinjection pump. The basal glycerol levels in perfusates of blood and adipose tissue were stable. Intravenous isoproterenol (isoprenaline) increased the glycerol levels in a similar fashion in blood perfusate as compared with plasma and the dialysate of two different adipose tissue probes implanted in the same animal. Isoproterenol included in the adipose tissue dialysis solvent increased the glycerol level in adipose tissue perfusate but not in the blood perfusate; this indicates a local lipolytic effect of catecholamines. Increases in intravenous doses of isoproterenol caused a transient and marked dose-dependent elevation of glycerol in the adipose tissue perfusate and a gradual but less marked rise of glycerol in blood perfusate. This indicates that glycerol kinetics in blood and adipose tissue differ after catecholamine stimulation. In conclusion, microdialysis of blood and subcutaneous adipose tissue offers new and unique possibilities for in vivo lipolysis studies in intact animals.

Adipose Tissue↗
PubMed1988

Regulation of lipolysis during the neonatal period. Importance of thyrotropin.

We investigated the lipolytic effect of several hormones on isolated human adipocytes obtained at different donor ages. In neonates, noradrenaline and adrenaline had an insignificant lipolytic effect (70% over basal). In this age group only thyrotropin (TSH) had a significant effect in physiological concentrations, and the maximal lipolytic effect (700% over basal) was the same as that of isoprenaline. The lipolytic effect of TSH was the same in premature 4-10-wk-old infants with a gestational age of 27-33 wk as in neonates, but fat cells from infants 4-10 wk old, born at term, showed a significantly lower effect. In children and adults, the lipolytic effect of TSH gradually decreased further and was present only in unphysiological concentrations. The catecholamine-induced lipolysis was pronounced and was similar in children and adults (350% over basal). TSH is the dominating lipolytic hormone in vitro during the neonatal period. Thus, the peak elevation of circulating TSH, which is seen immediately after birth, may be essential to lipolysis during this part of life.

Adenosine Deaminase↗
PubMed1988

Lipolysis in human adipocytes, effects of cell size, age and of regional differences.

In man only catecholamines and insulin have pronounced and acute effects on lipolysis in fat cells. In obesity the effects of these hormones seem to be normal or even increased. When the rate of lipolysis is expressed per cell there is a strong association between hormonal effect and cell size. Indicating that catecholamines and insulin may be involved in the regulation of adipocyte volume. There are, however, site variations in the effects of the regulatory hormones, which may be of importance for the development of various regional forms of obesity. The lipolytic effect of catecholamines is more pronounced in the abdominal than in the femoral/gluteal subcutaneous fat depots, partly owing to an increased alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines in the latter region. This alteration in lipolysis favour accumulation of fat in the femoral/gluteal region and may be of importance for the development of the female type of obesity. Furthermore, in omental fat cells the lipolytic activity is higher than in subcutaneous fat cells owing in part to less marked insulin action and lower alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines. These alterations may cause elevation of the free fatty acid levels in the portal blood so that the handling of glucose and insulin is impaired in the liver which may be one mechanism behind the increased risk to develop cardiovascular complications in the male type of obesity. Age also influences hormone-induced lipolysis. Catecholamine resistance is observed at birth and at the latest stages of life. Insulin resistance is observed in old as compared to middle-aged subjects.

Adipose Tissue↗
PubMed1987

Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus.

The tyrosine kinase activity of the insulin receptor was investigated in skeletal muscle biopsies from insulin-resistant males with obesity or with Type 2 (non-insulin-dependent) diabetic males who were lean or overweight. The kinase activity of the receptor from all three groups of insulin-resistant subjects was 40% less when compared to the activity of lean control subjects. This alteration was present in the absence of changes in the level of the insulin receptor on its insulin binding characteristics. We conclude that the tyrosine kinase activity of the skeletal muscle insulin receptor is defective in obesity and Type 2 diabetes, and that this alteration contributes to the insulin-resistant characteristics of both disorders.

Aged↗
PubMed1987

Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus.

Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus.

Adenylyl Cyclases↗
PubMed1987

Role of alpha-adrenoceptors for adipocyte size in man.

Catecholamines have dual effects on lipid mobilization in man. Lipolysis is stimulated via beta-adrenoceptors and inhibited via alpha 2-adrenoceptors. The relationship between fat-cell size and catecholamine-induced lipolysis (expressed per cell surface area) was investigated in vitro in subcutaneous adipocytes of thirty-five non-obese subjects between 1 month and 45 years of age. Fat-cell volume showed a positive correlation with noradrenaline-induced lipolysis (r = 0.7). Furthermore, fat-cell size showed a negative correlation with the alpha 2-effect of noradrenaline (r = 0.8) but no correlation with the beta-effect of the hormone (r less than 0.1). Although age showed a positive correlation with noradrenaline-induced rate of lipolysis (r = 0.6) it did not contribute to the relationship between cell size and the catecholamine effect. There was no relationship between adipocyte size and the basal (unstimulated) rate of lipolysis (r less than 0.1). In conclusion, ageing in non-obese subjects is associated with enlargement of fat-cell size and enhancement of the lipolytic effect of catecholamines. The latter is due to diminished alpha 2-anti-lipolytic effect of the hormones. This modulation of the alpha 2-adrenoceptor activity may be of importance for the regulation of adipocyte size in man.

Adipose Tissue↗
PubMed1987

Fasting-mediated alteration studies in insulin action on lipolysis and lipogenesis in obese women.

The effects of fasting on insulin-induced antilipolysis and lipogenesis were investigated in vitro in isolated human fat cells of 11 obese females. Glycerol release and lipogenesis were determined simultaneously in the same test tube and related to methylglucose transport and specific insulin binding. Insulin binding and sensitivity and the responsiveness (maximum effect) of insulin-induced antilipolysis were enhanced by fasting. The latter was strongly correlated with an enhancement in the lipolysis rate. The effects of fasting on antilipolysis were not dependent on the glucose concentration, unlike insulin-stimulated lipogenesis. At 1 mumol/l of glucose, where hexose transport is rate limiting, sensitivity and responsiveness of insulin-induced lipogenesis were inhibited by fasting. Similar results were obtained with methylglucose transport. At 1-10 mmol/l of glucose, where hexose metabolism is rate limiting, insulin stimulated lipogenesis before fasting but was totally ineffective after fasting. In conclusion, fasting induces multiple alterations in insulin action on lipolysis and lipogenesis in adipocytes. Antilipolysis is enhanced because of stimulation at the receptor and postreceptor levels, which may be associated with an enhanced rate of lipolysis. Fasting inhibits the lipogenic effect of insulin due to postreceptor changes involving both transport and metabolism of glucose, making lipogenesis unresponsive to insulin at physiological glucose concentrations.

Adipose Tissue↗
PubMed1987

Acute adaptation in adrenergic control of lipolysis during physical exercise in humans.

During prolonged exercise, the free fatty acids derived from adipocyte lipolysis are the principal fuel utilized by muscles. In humans, the lipid mobilization from adipose tissue is mainly regulated by insulin and catecholamines: the latter hormones have both beta-adrenergic stimulatory and alpha 2-adrenergic inhibitory effects on lipolysis. The aim of this study was to determine whether rapid alterations in the peripheral action of the regulatory hormones occur during physical work and whether they are of importance for the enhanced lipid mobilization. The acute effects of exercise on the regulation of lipolysis were investigated in isolated adipocytes removed from the gluteal region of 14 healthy volunteers before and immediately after the exercise period. Exercise induced a 20-35% significant increase in the lipolytic response to noradrenaline alone and in combination with the selective alpha 2-antagonist yohimbine and to the pure beta-agonist isoproterenol in isolated adipocytes. The antilipolytic effects of both the alpha 2-agonist clonidine and insulin were unaffected by exercise. Exercise did not influence the specific adipocyte receptor binding of 125I-cyanopindolol (beta-adrenergic receptor), [3H]yohimbine (alpha-adrenergic receptor), and mono-125I-[Tyr A14]insulin (insulin receptor). In conclusion, a single period of submaximal exercise increases adipocyte lipolytic responsiveness to catecholamines through an increased beta-adrenoceptor-mediated effect at steps distal to the receptor binding. Thus the increased peripheral action of catecholamines may be of importance for the observed enhanced lipid mobilization during physical work.

Adaptation, Biological↗
PubMed1987

Changes in catecholamine-induced lipolysis in isolated human fat cells during the first year of life.

Catecholamine-induced lipolysis in isolated human adipocytes during the first year of life was investigated. During this period fat cell size increased markedly. Basal and catecholamine-induced glycerol release were positively correlated with age when lipolysis was expressed per cell. However, when lipolysis was expressed per unit of cell surface area (micrometer squared), this correlation was observed only for noradrenaline. Basal lipolysis and the effect of the pure beta-agonist, isoprenaline, were identical in infants and adults. From 0 to 2 mo of age noradrenaline had very little lipolytic effect. The addition of the alpha-2-adrenoceptor antagonist, yohimbine, to noradrenaline equalized lipolysis per micrometer squared in infants and adults and the alpha-2-adrenoceptor sensitivity was significantly enhanced in infants. In both groups the lipolytic adrenoceptor was of the beta-1 type. In conclusion, adipocytes from infants have a poor lipolytic response to noradrenaline partly because of the small fat cells but mainly because of an enhanced alpha-2-adrenoceptor activity.

Adenosine Deaminase↗
PubMed1987

Studies of acute effects of insulin-like growth factors I and II in human fat cells.

The acute metabolic effects and receptor binding of insulin-like growth factors (IGFs) I and II were studied in human adipose tissue. The IGFs inhibited fat cell glycerol release and stimulated adipocyte 3-O-methylglucose transport and adipose tissue glucose oxidation as effectively as did insulin, but the biological potencies of the IGFs, on a molar basis, were 600-1000 times less than that of insulin. The insulin dose-response curve for antilipolysis gradually shifted to the left in the presence of submaximally and maximally effective IGF-I concentrations, whereas no additive response was found when fat cells were incubated with maximally effective concentrations of insulin and the IGFs. Adipocyte [125I]IGF-I and -II binding was low and was not inhibited by excess unlabeled IGF. In contrast, IGF-I inhibited [125I]insulin binding with a molar potency 1600 times lower than that of native insulin. In adipose tissue segments obtained from patients with untreated noninsulin-dependent diabetes mellitus, IGF-I and insulin inhibited glycerol release in a normal way. Conversely, neither insulin nor IGF-I increased the rate of glucose oxidation significantly above the nonhormone-stimulated level. We conclude that human fat cells lack specific cell surface IGF-binding sites. However, the IGFs definitely produce acute insulin-like effects in the human adipocyte, which seems to be mediated via the insulin receptor.

Adipose Tissue↗
PubMed1987

Insulin receptor binding and metabolic effects of insulin in human subcutaneous adipose tissue in untreated non-insulin dependent diabetes mellitus.

Insulin action at the target tissue level in non-insulin dependent diabetes mellitus was investigated using human adipose tissue. Specific adipocyte receptor binding of insulin and the effects of the hormone on glucose oxidation and lipolysis were determined in subcutaneous adipose tissue. The study included 25 patients with untreated non-insulin dependent diabetes mellitus and 38 healthy control subjects matched for age, sex and body weight. Insulin stimulated adipose tissue glucose oxidation in a dose-dependent way in the control subjects. On the other hand, a marked inhibition of this insulin effect was observed in the diabetics. A weak stimulation was observed only at high unphysiological hormone concentrations [greater than or equal to 0.7 nmol/l] and the maximal insulin response was 6 times lower than that in the control subjects. However, neither specific insulin receptor binding nor the antilipolytic effect of insulin were inhibited in diabetes. Similar results with insulin binding and the metabolic effects of insulin were obtained in non-obese normoinsulinemic diabetics as compared to moderately obese hyperinsulinemic diabetics. It is concluded that adipose tissue insulin resistance in non-insulin dependent diabetes mellitus only involves glucose metabolism and not antilipolysis. Furthermore, it may solely be due to postreceptor defects in insulin action and seems not to be influenced by obesity or oversecretion of insulin.

Adipose Tissue↗
PubMed1986

Insulin action in human adipose tissue in acromegaly.

The mechanisms underlying insulin resistance in acromegaly were investigated. Adipose tissue was obtained from nine patients with acromegaly who had in vivo insulin resistance and from 14 matched healthy control subjects. Receptor binding and the antilipolytic effect of insulin were determined in isolated fat cells. Insulin-induced glucose oxidation at a physiological hexose concentration was investigated in fat segments. In fat cells obtained from acromegaly patients after an overnight fast, insulin binding at low hormone concentrations was significantly reduced by 20-30%, insulin-induced antilipolysis was unchanged, but glucose oxidation was unresponsive to insulin. Since it has recently been observed that glucose feeding may rapidly modify insulin action in human adipocytes, fat cells were also obtained 60 min after an 100-g oral glucose load. In this situation, insulin binding at low hormone concentrations was further reduced to one-half of that in the control group, and the sensitivity of insulin-induced antilipolysis was markedly decreased in acromegaly. It is concluded that, in the fasting state, the action of insulin on glucose utilization but not on lipolysis is impaired in adipose tissue of acromegalic patients because of a postreceptor defect. After glucose ingestion, the resistance to insulin in acromegaly is further enhanced and antilipolysis is also impaired. Altered coupling between receptor and effector alone or in combination with an additional decrease in receptor binding may explain the enhancement of insulin resistance. These mechanisms may be essential factors in the pathogenesis of insulin resistance in acromegaly.

Acromegaly↗