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Biomedical subjects

O Pedersen

Publications and source records attributed to O Pedersen.

At least 235 records · Page 13Linked to original sources
PubMed1988

Characterization of the insulin resistance of glucose utilization in adipocytes from patients with hyper- and hypothyroidism.

UNLABELLED: Insulin action on glucose utilization was characterized in adipocytes from 10 thyrotoxic patients, 6 hypothyroid patients and 10 age- and sex-matched control subjects. In thyrotoxic patients insulin binding at low insulin concentrations was reduced (P less than 0.05) and accompanied by impaired insulin sensitivity of glucose transport (P less than 0.02), glucose oxidation (P less than 0.05) and lipogenesis (P less than 0.05). Glucose transport and glucose oxidation rates also exhibited depressed maximal insulin responsiveness (P less than 0.05). In hypothyroid patients insulin binding was reduced, too, (P less than 0.05) and associated with impaired sensitivity to insulin of glucose transport (P less than 0.05). Both glucose transport and lipogenesis rates showed decreased maximal insulin responsiveness (P less than 0.05). IN CONCLUSION: In man, both hyper- and hypothyroidism are characterized by insulin resistance of adipocyte glucose utilization localized to insulin binding as well as to insulin-stimulated glucose transport and metabolism.

Adipose Tissue↗
PubMed1988

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion.

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1988

In vivo action of glibenclamide in obese subjects with mild type 2 (non-insulin dependent) diabetes.

In order to evaluate whether the hypoglycaemic action of glibenclamide during chronic treatment of obese subjects with NIDDM is primarily due to changes in the daytime insulin level, in insulin secretion or to changes in tissue sensitivity to insulin, we studied eight NIDD's (age 43 +/- 3 years, body mass index 31.4 +/- 2.6 kg/m2) inappropriately controlled by dietary treatment alone. Before and after three months of glibenclamide treatment, plasma glucose, insulin and C-peptide were measured hourly (0800 to 1600 hours) and in vivo insulin sensitivity was evaluated using the sequential euglycaemic clamp (insulin infusion: 0, 0.8, 3.2 mU/kg/min) in combination with 3-3H-glucose tracer technique. During glibenclamide treatment the mean daytime glucose level was reduced (11.2 +/- 0.5 versus 7.1 +/- 0.4 mmol/l, p less than 0.001) but not to normal (5.2 +/- 0.2 mmol/l, p less than 0.001). Before treatment the mean daytime insulin level was higher than normal (38 +/- 58 versus 24 +/- 2 microU/ml, p less than 0.05) and was increased by 79% (67 +/- 8 microU/ml, p less than 0.001) after three months of treatment. In contrast the mean C-peptide level was unchanged (1.40 +/- 0.13 versus 1.30 +/- 0.17 nmol/l, p = NS), although it was higher than normal on both occasions (0.84 +/- 0.09 nmol/l, p less than 0.05). The basal hepatic glucose production rate was normal before treatment (86 +/- 4 versus 82 +/- 3 mg.m-2.min-1 in normals, p = NS), and unchanged after glibenclamide treatment (80 +/- 3 mg.m-2.min-1, p = NS versus pretreatment level).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Multiple insulin injections using a pen injector versus insulin pump treatment in young diabetic patients.

Continuous subcutaneous insulin infusion (CSII) of 6 months duration was compared with 6 months of multiple insulin injections (MII) using a pen injector (NovoPen) in a prospective cross-over study with 20 young insulin dependent diabetics by evaluating metabolic control, insulin requirements and patient acceptability. Following both intensified regimens (CSII/MII) serum fructosamine declined significantly from 4.1 +/- 0.7 to 3.4 +/- 0.5 mmol/l and 3.6 +/- 0.7 mmol/l respectively (normal range: 2.2 +/- 0.2 mmol/l). When comparing CSII and MII no significant differences could be demonstrated in mean blood glucose (MBG), fasting plasma ketone bodies, fasting plasma free fatty acids (FFA), fasting plasma human growth hormone (HGH), fasting plasma glucagon or serum fructosamine. Mean insulin requirement was 11.4% higher during MII and glucose instability--demonstrated by the M-values and by the frequency of blood glucose values below 4 mmol/l--was significantly (p less than 0.02) higher during the MII treatment. All of the patients reported a better well-being on both treatment regimens and none of them wanted to go back to conventional therapy (CT). In conclusion, on a long-term basis both regimens result in identical metabolic control, but due to physical discomfort during pump treatment, the insulin pen injector was preferred by the majority (80%) of the patients.

Adult↗
PubMed1986

Reduced binding and antilipolytic effect of prostaglandin E2 in adipocytes from patients with hyperthyroidism.

The present study was undertaken to evaluate the effect of thyroid hormones on prostaglandin E2 (PGE2) binding and action in human adipocytes. The study consisted of 12 patients with hyperthyroidism and 20 normal subjects. In adipocytes from hyperthyroid patients, there was a 32% decrease in [3H]PGE2-binding sites (P less than 0.01). This reduced binding was accompanied by a 46% reduction in the relative antilipolytic effect of PGE2 in adipocytes from patients with hyperthyroidism. These changes might, then, account for some of the enhanced lipolysis that occurs in hyperthyroid patients. Thyroid hormones significantly increased the lipolytic effect of isoproterenol (P less than 0.01). However, the lipolytic effect of theophylline plus adenosine deaminase and basal lipolysis also were increased in adipocytes from hyperthyroid subjects. The latter findings indicate that thyroid hormones induce a state of increased activation of lipolysis under both basal and stimulated conditions. It is concluded that thyroid hormones reduce the binding and action of PGE2 in human adipocytes, possibly via a cAMP dependent mechanism. These alterations will contribute to accelerated lipid metabolism in the hyperthyroid state.

Adipose Tissue↗
PubMed1986

Impaired insulin receptor binding and postbinding defects of adipocytes from normal and diabetic pregnant women.

To evaluate the relative contribution of insulin binding and postbinding defects of glucose utilization in peripheral tissue during normal and diabetic pregnancy, we have studied the in vitro insulin action of isolated adipocytes from eight nondiabetic pregnant women and nine pregnant women with insulin-dependent diabetes mellitus who were undergoing cesarian section. The pregnant women were compared with a matched group of normal nonpregnant women undergoing gynecologic surgery. Insulin binding to adipocytes measured at tracer insulin concentration was reduced by 45% (P less than 0.01) in normal pregnant women and by 30% (P less than 0.02) in pregnant women with diabetes. In contrast, no changes were found between the three groups in insulin binding to pure monocytes and erythrocytes. The glucose transport system in fat cells from both groups of pregnant women was characterized by impaired maximal (P less than 0.05) and half-maximal (P less than 0.05) response to insulin. When fat cell glucose metabolism was studied, pregnant diabetic women exhibited decreased basal lipogenesis (P less than 0.05) and decreased maximal responses of lipogenesis and glucose oxidation to insulin stimulation (P less than 0.05). Similar but less pronounced abnormalities were seen in glucose metabolism of adipocytes from nondiabetic pregnant women. In conclusion, both in late normal and diabetic pregnancy, insulin binding to adipocytes is significantly reduced and accompanied by decreased insulin sensitivity and reduced maximal insulin responsiveness of glucose transport and by impaired basal and maximally insulin-stimulated glucose metabolism.

Adipose Tissue↗
PubMed1986

Continuous subcutaneous insulin infusion fails to correct impaired basal glucose metabolism and impaired insulin sensitivity of adipocytes from patients with type 1 (insulin-dependent) diabetes.

Studies of the in vivo insulin action in conventionally treated Type 1 diabetic patients have shown insulin resistance, especially in poorly controlled patients. We reported previously on impaired basal and insulin-stimulated glucose utilization in adipocytes from Type 1 diabetic subjects. In this study we have examined whether a near-normalization of glycaemia and plasma levels of metabolites in Type 1 diabetic patients induced by continuous subcutaneous insulin infusion might reverse abnormalities of adipose tissue metabolism. 11 Type 1 diabetic subjects who had been treated conventionally with diet and insulin for 11 yr were studied before and after continuous subcutaneous insulin infusion for 6 months. In Type 1 diabetic patients before insulin pump treatment we found decreased adipocyte insulin binding (p less than 0.01), normal insulin binding to monocytes and erythrocytes, impaired insulin sensitivity of the adipocyte glucose transport (p = 0.02) and reduced basal and maximally insulin-stimulated rates of adipocyte glucose oxidation and lipogenesis (all p less than 0.05). After pump therapy for 6 months we found a further reduction of basal and maximal adipocyte glucose oxidation and lipogenesis (all p less than or equal to 0.05), whereas we found no significant changes of insulin receptor binding or insulin sensitivity of adipocyte glucose utilization. We conclude that continuous subcutaneous insulin infusion of Type 1 diabetic patients for 6 months aggravates the defects in basal (non-insulin-stimulated) and maximally insulin-stimulated glucose utilization of isolated adipocytes despite an optimization of glycaemic control and a near-normalization of plasma metabolites.

Adipose Tissue↗
PubMed1985

Alpha 2-adrenergic binding and action in human adipocytes. Comparison between binding to plasma membrane preparations and to intact adipocytes.

Binding of the alpha 2-adrenoceptor antagonist [3H]yohimbine was demonstrated on intact human adipocytes and on human adipocyte membranes. Specific binding was rapid, reversible, saturable and of high affinity in both preparations. [3H]Yohimbine binding was inhibited by various adrenergic agents in a manner which suggests that the labeled sites probably represent the alpha 2-receptor both in intact adipocytes and in the membrane fraction. In adipocyte membranes the maximal binding capacity (Bmax) was 463 +/- 38 fmol/mg protein and the binding was of high affinity with a Kd of 2.1 +/- 0.4 nM. In intact human adipocytes, Bmax was 903 +/- 139 fmol/10(6) cells (or 342 +/- 21 fmol/100 cm2) and the binding affinity was 6.6 +/- 0.8 nM. Adrenergic antagonists bound to a homogeneous class of receptors (linear Scatchard plots) both in isolated membranes and in intact adipocytes. However, agonist binding was heterogeneous in both preparations. The affinity of agonist binding was 5-10 times higher in membranes than in intact adipocytes. The physiological relevance of the binding data was evaluated by correlating the binding of yohimbine with the antilipolytic effect of clonidine. A positive and significant correlation was found between Bmax and maximal antilipolytic effect of clonidine (r = 0.70) in membranes. Furthermore, the binding affinity (Kd) was positively correlated to the sensitivity (IC50) of the clonidine-induced antilipolysis (r = 0.65). A positive and significant correlation was also found in intact adipocytes between Bmax and the maximal antilipolytic effect of clonidine (r = 0.79). However, there was no significant correlation between Kd in intact adipocytes and the IC50 of clonidine. It is concluded that both intact human adipocytes and membrane fractions are useful models to investigate the properties and regulation of alpha 2-adrenoceptors. However, it appears from our correlation studies that the binding data obtained with the membranes are the best related to the physiological effects mediated by alpha 2-receptors in human adipocytes.

Adipose Tissue↗
PubMed1985

Effects of prostaglandin E2, indomethacin and adenosine deaminase on basal and insulin-stimulated glucose metabolism in human adipocytes.

The effects of prostaglandin E2 were studied on glucose metabolism (3-O-methylglucose transport, CO2 production and lipogenesis) in human adipocytes. Initially, the effects of endogenously produced adenosine and prostaglandins were indirectly demonstrated by using adenosine deaminase and indomethacin in the incubations. From these studies it was found that adenosine deaminase (5 micrograms/ml) had a pronounced effect on adipocyte glucose metabolism in vitro. In the basal (nonhormonal-stimulated) state, glucose transport, CO2 production and lipogenesis were inhibited by about 30% (P less than 0.05). Furthermore, adenosine deaminase significantly inhibited the isoproterenol- and insulin-stimulated CO2 production and lipogenesis (P less than 0.01). Indomethacin (50 microM) had a consistently inhibitory effect on the insulin-stimulated CO2 production (P less than 0.05), whereas indomethacin had no significant effects on basal or isoproterenol-stimulated glucose metabolism. In contrast to the relatively minor effect of endogenous prostaglandins, the addition of exogenous prostaglandin E2 significantly stimulated the glucose transport, glucose oxidation and lipogenesis in human adipocytes, especially in the presence of adenosine deaminase. Half-maximal stimulation was obtained at prostaglandin E2 concentrations of 2.2, 0.8 and 0.8 nM, respectively. The effect of prostaglandin E2 was specific, since the structurally related prostaglandin, prostaglandin F2 alpha, had practically no effect on glucose metabolism. The maximal effect of prostaglandin E2 (1 microM) on glucose metabolism was 30-35% of the maximal insulin (1 nM) effect. When insulin and prostaglandin E2 were added together, the effect of prostaglandin E2 on glucose metabolism was additive at all insulin concentrations tested.

3-O-Methylglucose↗
PubMed1985

Postbinding defects of insulin action in human adipocytes from uremic patients.

It is now well established that longstanding human uremia is associated with impaired in vivo insulin action on glucose utilization of peripheral target tissues. In an attempt to define the cellular basis of the uremic insulin resistance we studied insulin action in adipocytes from eight patients with undialyzed chronic uremia and from eight matched healthy controls. (125I)-Insulin binding to fat cells from uremic patients was normal. In contrast (14C)-D-glucose transport exhibited decreased sensitivity to insulin. The concentrations of insulin that elicited half-maximal response was 422 +/- 95 pmoles/liter in uremic patients and 179 +/- 38 pmoles/liter in normal subjects (P less than 0.01). The noninsulin- and the maximal insulin-stimulated glucose transport of adipocytes from uremic patients with normal. (14C)-D-glucose conversion to total lipids was also measured in these cells in the absence and presence of various insulin concentrations. Similar to the findings in transport studies the lipogenesis of fat cells from uremic patients had depressed sensitivity to insulin (half-maximal stimulation at 38 +/- 8 pmoles/liter in uremic patients and at 11 +/- 3 pmoles/liter in normal subjects, P less than 0.01) with unchanged noninsulin and maximal insulin-stimulated lipogenesis. Taken together these results suggest that the insulin resistance of adipocytes from patients with chronic uremia may be accounted for primarily by postbinding defects localized to glucose transport and metabolism.

Adipose Tissue↗
PubMed1985

Defective non-insulin-mediated and insulin-mediated glucose transport and metabolism in adipocytes from obese and lean patients with untreated type 2 diabetes mellitus.

Insulin binding, glucose transport, and glucose metabolism were investigated in isolated adipocytes from 11 lean and 13 obese patients with non-insulin-dependent diabetes mellitus. Insulin binding at 15 degrees C was reduced by 35% (p less than 0.01) in both lean and obese diabetic patients, whereas insulin binding (or uptake) at 37 degrees C was similar in diabetic patients and healthy controls. In lean diabetic patients both non-insulin-mediated (basal) and maximally insulin-stimulated glucose transport and metabolism were significantly reduced (all p less than 0.01). The percentage responses to insulin were also markedly reduced (p less than 0.05, p less than 0.02). In obese diabetic patients basal glucose transport was reduced (p less than 0.01) but basal glucose metabolism was not. Insulin-stimulated glucose transport and metabolism were significantly reduced (p less than 0.01, p less than 0.05). The percentage responses were reduced compared to healthy controls (p less than 0.05, p less than 0.05) but higher than in lean diabetic patients (p less than 0.05). We conclude that adipocytes isolated from both lean and obese patients with non-insulin-dependent diabetes mellitus are characterized by severely depressed non-insulin-mediated and insulin-mediated glucose transport and depressed insulin-mediated glucose metabolism. The major defect seems to be a reduced maximal effect of insulin on glucose metabolism, suggesting post-binding and post-transport abnormalities.

Adipose Tissue↗
PubMed1985

Glucose transport and metabolism in adipocytes from newly diagnosed untreated insulin-dependent diabetics. Severely impaired basal and postinsulin binding activities.

Previous studies have shown cellular insulin resistance in conventionally treated insulin-dependent diabetics. To determine whether insulin resistance is also present in insulin-dependent diabetics before the commencement of insulin therapy, we studied nine newly diagnosed untreated insulin-dependent diabetics and nine control subjects. Insulin binding to adipocytes, monocytes, and erythrocytes was normal in the diabetic individuals. Basal (noninsulin stimulated) glucose transport rate was normal, whereas the maximal insulin responsiveness of glucose transport was severely impaired (P less than 0.02). Insulin sensitivity as judged by left or rightward shifts in the insulin dose-response curves was unchanged. Moreover, the basal lipogenesis rate measured at a glucose concentration of 0.5 mmol/liter was decreased in the diabetics (P less than 0.05), and the maximal insulin responsiveness of lipogenesis was also reduced (P less than 0.05). We conclude that fat cells from untreated insulin-deficient diabetics are insulin resistant. The major defects are (1) reduced maximal insulin responsiveness of glucose transport and conversion to lipids that are postbinding abnormalities, and (2) reduced basal glucose conversion to lipids.

Adipose Tissue↗
PubMed1985

Beta-adrenergic regulation of prostaglandin E2 receptors in human and rat adipocytes.

Incubation of intact human and rat adipocytes with isoproterenol (10(-6) M) inhibits the specific binding of [3H] prostaglandin E2 (PGE2) by about 25% in human adipocytes and 50% in rat adipocytes. Scatchard analysis of [3H]PGE2 binding demonstrated that the isoproterenol-induced decrease in receptor activity may be due to a decrease in the apparent number of PGE2-binding sites, while the receptor affinity was unaltered. The inhibitory effect of isoproterenol on [3H]PGE2 binding was already seen after 10 min of isoproterenol treatment, and the maximal effect was obtained after 30-60 min. Half-maximal inhibition of binding occurred at a concentration of 5 X 10(-8) M isoproterenol. The effect of isoproterenol could be mimicked by epinephrine, theophylline, and (Bu)2-cAMP, indicating that elevated levels of cAMP are the common mechanism by which these agents affect PGE2 binding. Furthermore, the isoproterenol-induced inhibition of PGE2 binding was completely blocked by propranolol. The effects of some FFA and indomethacin were studied on PGE2 receptor binding, too. From the results of the latter studies, we suggest that endogeneously released arachidonic acid could account for some of the reduction in PGE2 binding. In conclusion, a beta-adrenergic receptor-mediated cAMP-dependent mechanism for the regulation of PGE2 receptor binding is demonstrated in both human and rat adipocytes.

Adipose Tissue↗
PubMed1985

Characterisation of mechanisms responsible for uraemic insulin resistance: in vitro experiments.

In an attempt to define the cellular basis of the uraemic insulin resistance we studied insulin action in adipocytes from eight patients with undialysed chronic uraemia and from eight matched healthy controls. (125I)-insulin binding to fat cells from uraemic patients was normal. In contrast (14C)-D-glucose transport exhibited decreased sensitivity to insulin. The concentrations of insulin that elicited a half-maximal response were 422 +/- 95 pmol/L in uraemic patients and 179 +/- 38 pmol/L in normals (p less than 0.01). The non-insulin and the maximally insulin stimulated glucose transport of adipocytes from uraemic patients was normal. The lipogenesis of fat cells from uraemic patients had depressed sensitivity to insulin (half-maximal stimulation at 38 +/- 8 pmol/L in uraemic patients and at 11 +/- 3 pmol/L in normals, p less than 0.01) with unchanged non-insulin and maximally insulin stimulated lipogenesis. Taken together these results suggest that the insulin resistance of adipocytes from patients with chronic uraemia may be primarily accounted for by post-binding defects localised to glucose transport and metabolism.

Adipose Tissue↗
PubMed1984

Prostaglandin E2 receptor binding and action in human fat cells.

The prostaglandin E2 (PGE2) receptor in human adipocytes was identified by the use of [3H]PGE2. The receptor binding at physiological temperature and pH was specific, saturable, and slowly reversible. Half-maximal displacement for [3H]PGE2 binding occurred with 2.5 nmol/liter. Half-maximal inhibition of isoproterenol-induced lipolysis was achieved at a concentration of PGE2 of 3.8 nmol/liter and half-maximal inhibition of basal lipolysis was achieved at a concentration of PGE2 of 0.9 nmol/liter. The order of potency for prostaglandin inhibition of receptor binding and antilipolytic effect was the same, with PGE2 greater than PGF2 alpha much greater than arachidonic acid. Scatchard analysis of the binding data revealed a nonlinear plot indicating the existence of two or more binding sites with different affinities. The binding sites of high affinity had an equilibrium constant (Kd) of 2 nmol/liter and a total binding capacity of 58 fmol/10(6) adipocytes which corresponds to about 33,000 binding sites per adipocyte. The binding sites of low affinity had a Kd of 56 nmol/liter and a total binding capacity of 700 fmol/10(6) adipocytes. We conclude that [3H]PGE2 binds to receptors in isolated human adipocytes and that their antilipolytic effects are mediated by this binding.

Adipose Tissue↗