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Biomedical subjects

P Arner

Publications and source records attributed to P Arner.

At least 235 records · Page 13Linked to original sources
PubMed1986

Studies of the human liver insulin receptor in noninsulin-dependent diabetes mellitus.

The insulin binding characteristics and the structural components of the insulin receptor were studied in the purified liver plasma membranes from seven patients with noninsulin-dependent diabetes (NIDDM) and seven control subjects. In comparison to the controls, diabetic subjects had a 65% reduction in plasma insulin levels in response to an oral glucose load. Specific insulin binding by liver membranes from diabetic patients was, however, twofold greater than the binding activity by membranes from control subjects. This alteration resulted largely from an increase in the number of insulin receptors and a modest increase in receptor binding affinity. Holo (nonreduced) receptor species of similar molecular weights were detected by an affinity labeling technique in the two membrane preparations and sulfhydryl reduction demonstrated an insulin binding subunit of 125,000 mol wt. Overall, these results show that the hepatic insulin resistance of NIDDM cannot be explained by a deficiency in insulin binding.

Diabetes Mellitus, Type 2↗
PubMed1986

Adrenergic regulation of lipolysis in human adipocytes: findings in hyper- and hypothyroidism.

In isolated sc adipocytes removed from hyperthyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol was greater than that in adipocytes from normal subjects. Based on Scatchard analysis of the [125I] iodocyanopindolol data, this difference was due to a significant (P less than 0.01) increase in adrenoceptor number, which was 1.72 +/- 0.18 (+/- SEM) pmol/10(7) cells in the hyperthyroid patients and 0.94 +/- 0.16 pmol/10(7) cells in the normal subjects. When the patients were restudied when they were euthyroid, a significant decrease in the specific binding of the two radioligands was found. In hyperthyroidism, the lipolytic responsiveness (maximum effect) to norepinephrine was increased 5-fold, and that to isopropylnorepinephrine was increased 2-fold. No changes in either the binding of [3H]yohimbine or the antilipolytic effect of clonidine were found. In isolated adipocytes from hypothyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol did not differ from that in the normal subjects. The basal rate of lipolysis (P less than 0.025) and the lipolytic responsiveness to isopropylnorepinephrine (P less than 0.025) were significantly lower than normal, and the response to norepinephrine was almost completely abolished in the hypothyroid state. The sensitivity and responsiveness to clonidine were comparable in the adipocytes of the hypothyroid patients and normal subjects. There was no difference between hypothyroid patients and normal subjects in the binding of [3H]yohimbine. We conclude that the sc adipocytes in hyperthyroidism have beta-adrenergic, but not alpha 2-adrenergic abnormalities. Although there was a moderate increase in the beta-adrenoceptor density in hyperthyroidism, the most important abnormality, namely the increased responsiveness to the catecholamines, seems to be located beyond the receptor level. On the other hand, in hypothyroidism, there was no evidence of changes in either the alpha 2- or the beta-adrenoceptors. The chief abnormality in hypothyroidism, decreased responsiveness to beta-adrenergic agonists, also would appear to be localized beyond the adrenoceptor level.

Adipose Tissue↗
PubMed1986

Effects of obesity, hyperinsulinemia, and glucose intolerance on insulin action in adipose tissue of sixty-year-old men.

The relative effects of obesity alone, and in combination with fasting hyperinsulinemia and glucose intolerance, on the peripheral action of insulin in adipose tissue were investigated in twenty-four 60-yr-old men, who had been followed for 10 yr. They were divided into four groups of six subjects each on the basis of the following criteria: (1) normal body weight, normal fasting insulin level, and normal glucose tolerance; (2) moderate obesity, normal fasting insulin level, and normal glucose tolerance; (3) moderate obesity, fasting hyperinsulinemia, and normal glucose tolerance; and (4) moderate obesity, fasting hyperinsulinemia, and newly developed, moderate, untreated fasting hyperglycemia and/or glucose intolerance (i.e., mild type II diabetes mellitus). Specific adipocyte insulin binding and the effects of the hormone on adipose tissue lipolysis and glucose oxidation were determined. Insulin receptor binding per cell and per cell surface area were similar in all four groups. Regarding antilipolysis, the insulin sensitivity was the same in all groups and the maximum effect was significantly increased in the three obese groups, as compared with the normal-weight control group. In groups 1-3, insulin stimulated adipose tissue glucose oxidation in a dose-dependent way, and the sensitivity and responsiveness to insulin were comparable. In contrast, in the obese glucose-intolerant subjects (4) there was no significant effect of insulin on glucose oxidation when the hormone was added in increasing concentrations of less than or equal to 35 nmol/L. The basal glucose oxidation was similar in all four study groups. The in vivo insulin tolerance was gradually reduced in groups 2-4, as compared with the normal-weight control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Long-term beta 1-selective adrenergic blockade and adrenergic receptors in human subcutaneous adipocytes.

The influence of beta-adrenergic blockade with metoprolol, a beta 1-selective agent, on the adrenergic regulation of lipid mobilization was explored in subcutaneous adipocytes removed from 13 patients with essential hypertension. Treatment with metoprolol, which was associated with adequate beta-adrenergic blockade and an antihypertensive effect, resulted in a significant increase (p less than 0.05) in the binding of the beta-adrenergic antagonist (-)-(3H)-dihydroalprenolol and a 50% increase (p less than 0.01) in the maximum lipolytic response to the beta-adrenergic agonist isopropylnoradrenaline. In 7 patients with normotriglyceridaemia the total plasma triglyceride level increased significantly (p less than 0.025) during metoprolol treatment, a change that was due to an increase in the very low density lipoprotein triglycerides. The findings suggest that chronic treatment with the beta 1-selective adrenergic blocker metoprolol leads to a significant increase in beta-adrenoceptor density and an increase in the lipolytic response to beta-adrenergic agonists. This latter finding may, in some measure, account for the increased plasma triglyceride level observed.

Adipose Tissue↗
PubMed1985

Glucagon receptor of human liver. Studies of its molecular weight and binding properties, and its ability to activate hepatic adenylyl cyclase of non-obese and obese subjects.

The glucagon receptor and the adenylyl cyclase system of human liver membranes were studied in six non-obese and six obese subjects who had elevated insulin and plasma glucagon levels. Analysis of specific glucagon binding by the method of Scatchard demonstrated a linear (monocomponent) plot with a dissociation constant of 2-3 nM, and the binding at low hormone concentrations was sensitive to guanosine triphosphate (GTP). The molecular weight of the glucagon receptor was 63,000 D as determined by an affinity labeling procedure and sodium dodecyl sulfate gel electrophoresis. Affinity labeling of this structure was specific for glucagon and inhibited by GTP. Glucagon stimulated the production of cyclic adenosine monophosphate (cAMP) by human membranes with half-maximal activation elicited by 6 nM hormone. The human cyclase system required GTP to facilitate an optimal glucagon response. NaF (10 mM) also activated the cyclase system and produced the same magnitude of response as maximum glucagon activation. A comparison of the liver adenylyl cyclase system of non-obese and obese subjects was made using glucagon (5 nM and 1 microM) and NaF (10 mM). No significant differences in cAMP production were noted between the two groups, regardless of the agent used to activate the enzyme. These findings agree with the glucagon binding studies that showed similar amounts of binding activity in the membranes from the two groups. Also, there was no influence of either age or sex of the subjects on the adenylyl cyclase response. In conclusion, human liver membranes contain a glucagon receptor and an adenylyl cyclase system that correspond closely to the well-studied system in animal liver. This system in human obesity is not altered by the approximately twofold elevation in plasma glucagon that occurs in this metabolic disorder.

Adenylyl Cyclases↗
PubMed1985

Effect of fasting on insulin receptor binding and insulin action in different human subcutaneous fat depots.

The possible existence of regional variations in fasting-mediated changes on insulin action an human adipose tissue was investigated in vitro. Subcutaneous adipose tissue was obtained from the femoral, abdominal, and gluteal areas of obese but otherwise normal subjects (16 women and 7 men) before and after 7 days of total fasting. Specific insulin receptor binding to isolated fat cells was similar in femoral and abdominal adipose tissues before and after fasting. However, the latter condition was associated with a significant increase in insulin receptor binding at low hormone concentrations (less than 2 nmol/liter) in gluteal adipocytes. Insulin stimulated glucose oxidation in a dose-dependent way in all 3 adipose regions before fasting. In the femoral and gluteal sites after fasting, the maximum insulin effect was significantly decreased, but a dose-dependent insulin effect was still present, and there was no change in insulin sensitivity. However, abdominal adipose tissue after fasting was completely unresponsive to insulin stimulation when the hormone was added in increasing concentrations up to 80 nmol/liter. The results in fasting women were similar to those in the whole study group. In conclusion, there appear to be marked regional variations in fasting-mediated changes in insulin action on glucose metabolism in human adipose tissue. Alterations at the postreceptor level which lead to insulin resistance appear to be of greater importance than the counteracting receptor changes.

Adipose Tissue↗
PubMed1985

Reversal of insulin resistance in adipose tissue of non-insulin-dependent diabetics by treatment with diet and sulphonylurea.

The effect of conventional treatment on insulin action in subcutaneous adipose tissue was studied in 6 patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of the hormone on glucose oxidation were determined before and after 6-14 months of treatment with diet plus sulphonylurea. Glycaemic control and in vivo insulin sensitivity were significantly improved by the treatment. Before treatment, the adipocyte insulin receptor binding and the sensitivity to insulin stimulation of adipose tissue glucose oxidation were normal and did not change after treatment. In contrast, the maximum insulin-induced glucose oxidation was markedly decreased before treatment, whereas it was totally normalized after treatment. The conclusion is that insulin resistance in adipose tissue of NIDDM subjects is solely due to post-receptor defects in insulin action. This resistance is completely off-set by conventional treatment with diet plus sulphonylurea.

Adipose Tissue↗
PubMed1985

Influence of fasting and refeeding on the antilipolytic effect of insulin in human fat cells obtained from obese subjects.

The antilipolytic effect of insulin was investigated in obese subjects before and after 7 days of total fasting, and 1 h after oral refeeding with 100 g glucose. Isolated fat cells were prepared from subcutaneous gluteal adipose tissue and incubated in vitro. Specific insulin receptor binding and insulin inhibition of basal and isoprenaline-stimulated lipolysis were determined. During the fasting period, a 15% increase (P less than 0.05) in high-affinity insulin binding and a concomitant 3-4-fold increase in insulin sensitivity were noted, and there was a marked enhancement of the maximum insulin-induced inhibition of basal lipolysis, from 4 to 10 mumol of glycerol/10(7) cells/2 h. The maximum insulin-induced inhibition of isoprenaline-induced lipolysis was similar before and after fasting, about 10 mumol/10(7) cells/2 h. Glucose refeeding induced a 30% decrease (P less than 0.02) in high-affinity insulin binding and a 20-60-fold decrease (P less than 0.01) in the sensitivity of the antilipolytic effect of insulin under basal conditions and in the presence of isoprenaline. The maximum antilipolytic effect of insulin, however, was not altered by glucose refeeding. Thus, in the basal state, maximum antilipolytic effect was larger after refeeding as compared with that before fasting. The high-affinity insulin binding and insulin sensitivity were significantly lower after refeeding than before fasting. Before the fasting period, neither the insulin binding nor the antilipolytic effect of the hormone was altered by oral glucose. It is concluded that fasting and glucose refeeding are associated with marked alterations in the antilipolytic effect of insulin on human fat cells of obese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Effects of intravenous and oral glucose administration on insulin action in human fat cells.

The effects of various forms of glucose administration on insulin action were investigated in isolated human fat cells. Subcutaneous (s.c.) adipose tissue was obtained before and (1) 30 min (eight subjects) and 60 min (seven subjects) after an intravenous (i.v.) glucose load, and (2) after a 60-min continuous i.v. glucose infusion (five subjects). In addition, five subjects were reinvestigated before and 60 min after oral glucose ingestion. Lipolysis (glycerol release) and insulin receptor binding were determined. After all forms of i.v. glucose administration, adipocyte insulin binding was significantly reduced by 20% owing to a decrease in the high-affinity binding, whereas the concentrations of insulin producing the half-maximum inhibitions of basal and isoprenaline-induced rates of glycerol release were unaltered. Sixty minutes after oral glucose ingestion, insulin sensitivity increased 7-30-fold (P less than 0.05-0.01) and high-affinity insulin binding increased by 25% (P less than 0.05). The maximum insulin-induced inhibitions of basal and isoprenaline-stimulated lipolysis were not altered after oral or i.v. glucose. The plasma level of glycerol was markedly and rapidly reduced after oral glucose, but the fall was slow and less pronounced after i.v. glucose. It is concluded that oral, but not i.v., glucose administration mediates a rapid increase in the antilipolytic potency of insulin in human fat cells in vitro. This may explain why antilipolysis in vivo is more pronounced after oral than after i.v. glucose challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Nature of the inhibitory effect of collagenase on phosphodiesterase activity.

The level of phosphodiesterase (PDE) activity is lower in collagenase-isolated human fat cells than in adipose tissue fragments. The inhibition is not species-specific since collagenase also inhibits PDE in rat adipose tissue and bovine heart. In subcellular fractions from isolated fat cells, the PDE activities were lowest in the plasma membrane-enriched fractions and highest in the cytosolic fractions. This is opposite to PDE in subcellular fractions obtained from adipose tissue fragments. In dose-response experiments, collagenase inhibited particulate PDE to a much larger extent than it inhibited soluble PDE. The extracellular activities of PDE were completely eliminated by collagenase. Repeated washings or reincubation of the isolated fat cells did not restore the PDE activity. A purified collagenase with low specific protease activity reduced the PDE activity in isolated fat cells to a lesser extent than did a collagenase with high specific protease activities. Collagen and several protease inhibitors were ineffective in preventing the reduction of PDE after exposure to collagenase. It is concluded that nonspecific proteases in the collagenase preparations used for fat cell isolation interact with particulate and soluble PDE causing an irreversible inhibition of PDE activity in isolated fat cells. Of the various forms of PDE, plasma membrane-associated PDE seems most sensitive to collagenase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Effect of glucose on beta-adrenergic induced downregulation of insulin receptor binding in human fat cells.

The effect of beta-adrenergic stimulation on specific insulin binding to isolated human fat cells was investigated at 24 degrees C and 37 degrees C. In the absence of glucose isoprenaline caused a 40% decrease in high affinity insulin binding at both temperatures. At 37 degrees C the reduction in binding was completely offset by the addition of glucose to the medium. A maximum effect of glucose occurred at 5 mmol/l. At 24 degrees C, however, there was no effect of glucose on insulin binding. The effects of glucose and isoprenaline on insulin binding were not related to the lipolytic activities these two agents. In conclusion, low amounts of glucose prevent catecholamine induced down-regulation of insulin receptor binding in human fat cells at physiological temperature.

Adipose Tissue↗
PubMed1984

Binding and molecular weight properties of the insulin receptor from omental and subcutaneous adipocytes in human obesity.

The insulin binding properties and the molecular weights of the insulin receptor and its insulin binding subunit were studied in omental and subcutaneous adipocytes prepared from obese- and normal-weight subjects. Insulin binding by such adipocytes was decreased in obesity when the binding activity was expressed per unit of cell surface area. No significant difference from the lean controls was evident, however, when binding was calculated on a per cell basis, indicating that the total receptor content of the cells from the obese subjects was not altered. In addition, the normal difference in the receptor binding affinities previously reported between omental and subcutaneous cells from lean individuals was unaffected by the obese condition. Studies of the molecular weight of the non-reduced insulin receptor in fat cell membranes prepared from pieces of omental and subcutaneous fat demonstrated a major receptor species of 390-425K Mr. In contrast, adipocytes isolated by collagenase treatment of the fat had heterogeneous non-reduced receptor species of Mr 355K, 285K and small amounts of 427K and 182K. Although different non-reduced receptor species were evident depending on the adipocyte receptor preparation (e.g. isolated adipocytes or fat cell membranes), no differences were found between obese and lean controls or between subcutaneous and omental receptors when the appropriate comparisons were made. Upon sulphydryl reduction, all receptor preparations had a major binding subunit of 125K Mr. In conclusion, obesity is characterized by a dilution of the insulin receptor over the adipocyte cell surface in the absence of a change in total cellular content of receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1984

Site differences in human subcutaneous adipose tissue metabolism in obesity.

The results of several recent studies indicate that there are regional differences in the metabolism of subcutaneous fatty depots in obesity. Fat cells are larger in the femoral than in the abdominal region. Lipids are mobilized at a slower rate but synthesized at a higher rate in the former than the latter region. Fasting is accompanied by an increased rate of fat mobilization and a decreased rate of fat synthesis in all fat depots. These changes are, however, more pronounced in abdominal than in femoral fat. There are also regional differences in the hormonal regulation of fat metabolism in obesity. The action of insulin is most pronounced in the femoral region whereas that of catecholamines is most marked in the abdominal area. The regional differences in hormone action are further enhanced during therapeutic fasting. These differences may partly explain why adiposity is more catching in some fatty regions than in others and also why some obese areas are resistant to slimming.

Adipose Tissue↗
PubMed1984

Influence of fasting on lipolytic response to adrenergic agonists and on adrenergic receptors in subcutaneous adipocytes.

The influence of 1 week's total fasting on the lipolytic effect of adrenergic agonists and on the binding of adrenergic antagonists was examined in isolated adipocytes of subcutaneous specimens removed from the hypogastric and the femoral sites in seventeen obese women. In the femoral adipocytes the lipolytic sensitivity to isopropyl noradrenaline decreased 30-fold (P less than 0.01) during fasting. The specific binding of the radioligands (-)-[3H]-dihydroalprenolol and (-)-[125I]-cyanopindolol decreased significantly during fasting, essentially owing to a reduction in the receptor density. In adipocytes from the hypogastric region no such changes were found. For both tissue regions fasting induced a right-ward shift in the dose-response curve for the inhibitory effect of the alpha 2 agonist, clonidine, on theophylline-induced lipolysis, corresponding to a 10-fold decrease in sensitivity. There was also a significant decrease of about 20% in the alpha 2-adrenoceptor density, as estimated with the radioligand [3H]-yohimbine. The results suggest that the regulation of the lipid mobilization in man by the sympathetic nervous system during fasting occurs not only through an increase in the level of circulating noradrenaline but also through changes in the adrenergic receptor density of the adipocytes.

Adipose Tissue↗
PubMed1984

Influence of obesity on the antilipolytic effect of insulin in isolated human fat cells obtained before and after glucose ingestion.

The antilipolytic effect of insulin was studied in 9 obese and 10 age- and sex-matched subjects of normal weight. Isolated fat cells were taken before and 1 h after an 100 g oral glucose load. Insulin inhibition of basal and isoprenaline-induced rates of lipolysis were determined by using a sensitive bioluminescent glycerol assay. When compared with the controls, the obese group showed a lower glucose tolerance, a higher insulin secretion, and a lower specific insulin receptor binding per adipocyte surface area, which would suggest an insulin-resistant state. Before oral glucose, however, the sensitivity of the antilipolytic effect of insulin was enhanced 10-fold in obesity (P less than 0.01), but the maximum antilipolytic effect was not altered. Glucose ingestion induced a 10-25-fold increase in insulin sensitivity (P less than 0.01) and a 10% but not significant increase in specific adipocyte insulin receptor binding in the nonobese group. In the obese group, however, neither the insulin binding nor the antilipolytic effect of the hormone was increased by oral glucose. After oral glucose, insulin sensitivity was similar in the two groups. The concentration of the hormone which produced a half maximum effect was about 1 microU/ml. Similar results were obtained with insulin inhibition of basal and isoprenaline-stimulated glycerol release. It is concluded that, after an overnight fast, the sensitivity of the antilipolytic effect of insulin is markedly enhanced in adipocytes of "insulin-glucose resistant" obese subjects, presumably because of alterations at postreceptor levels of insulin action. In obesity, the antilipolytic effect of insulin seems normal after glucose ingestion. Furthermore, in adipocytes of subjects of normal weight, oral glucose rapidly stimulates the sensitivity of the antilipolytic effect of insulin, apparently because of changes at postreceptor sites. This short-term regulation of insulin action following the ingestion of glucose does not seem to be present in obesity.

Adipose Tissue↗
PubMed1984

Influence of thyroid hormone level on insulin action in human adipose tissue.

The relationship between the levels of circulating thyroid hormones and the action of insulin on adipose tissue was investigated in 6 hypothyroid patients and 6 hyperthyroid patients, all untreated, and 8 healthy control subjects. All were matched for age, body weight, and fat cell size. Gluteal s.c. adipose tissue was used. The insulin receptor number in isolated adipocytes was increased by 70% in hypothyroidism and decreased by 40% in hyperthyroidism. The sensitivities of the effects of insulin on lipolysis and glucose oxidation were increased fourfold in hypothyroidism and decreased fivefold in hyperthyroidism. The maximum insulin-induced glucose oxidation (insulin responsiveness) was inhibited by 60% in hypothyroidism and enhanced by 180% in hyperthyroidism. The thyroid hormone concentration was significantly correlated with insulin receptor number (r = -0.72), insulin responsiveness (r = 0.71), and insulin sensitivity (r = -0.75). It is suggested that thyroid hormones regulate the effect of insulin on adipose tissue, which occurs at the receptor and postreceptor levels of insulin action.

Adipose Tissue↗
PubMed1983

Glucose stimulation of the antilipolytic effect of insulin in humans.

Dose-response studies of the inhibition of lipolysis by insulin in isolated human adipocytes were conducted with the use of a sensitive bioluminescent assay of glycerol release. The addition of glucose to the incubation medium was associated with an increase in insulin sensitivity and an increase in the maximum insulin effect. The results suggest that glucose plays an important role in regulating the antilipolytic action of insulin in humans.

Adipose Tissue↗