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Biomedical subjects

U Smith

Publications and source records attributed to U Smith.

At least 109 records · Page 6Linked to original sources
PubMed1991

Measurements by microdialysis of free tissue concentrations of propranolol.

To determine the free concentration of a drug (propranolol) in the interstitial space in humans in vivo, seven male students were investigated by microdialysis of the periumbilical subcutaneous tissue. The microdialysis catheters were calibrated in vivo and the propranolol concentration was determined by high-performance liquid chromatography. Ten hours after intake of 80 mg of propranolol, the total plasma and free interstitial propranolol concentrations were 80 +/- 43 and 7 +/- 2 nM, respectively. After a second dose, maximum concentration was reached after 80 +/- 10 min and 98 +/- 12 min, in plasma, and the concentrations in the interstitial water were 594 +/- 138 and 27 +/- 7 nM, respectively. In a second study, microdialysis was performed on the left ventricular wall in six pigs receiving an intravenous injection of 5 mg of propranolol followed by a constant propranolol infusion for 40 min (5 mg propranolol per h). The maximum concentrations of propranolol were 97 +/- 29 and 6 +/- 2 nM in plasma and in interstitial water, respectively. The data suggest that microdialysis is a useful tool for recording the free concentrations of a drug in the interstitial space.

Adult↗
PubMed1991

Amiloride inhibits insulin sensitivity and responsiveness in rat adipocytes through different mechanisms.

To investigate the mechanisms by which amiloride inhibits insulin action rat adipocytes were treated with insulin and with amiloride added before or after energy depleting the cells with 2 mM KCN. Amiloride decreased the insulin response on 3-0-methylglucose transport, IGF-II- and insulin binding in both intact and energy depleted cells. In contrast, the sensitivity to insulin was inhibited by amiloride only when it was added before KCN. The effect of amiloride on insulin sensitivity was probably exerted through the impaired activation of the insulin receptor tyrosine kinase and the decreased insulin binding. However, insulin responsiveness was probably impaired through a direct effect on the plasma membrane proteins. In contrast to a recent report with pituitary cells, amiloride did not affect the activation of the inhibitory GTP-binding protein (Gi) in rat adipocytes.

Adipose Tissue↗
PubMed1991

The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man.

The present study was performed to elucidate the acute effect of insulin on levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor of endothelial cell type (PAI-1). Nine middle-aged, non-obese and non-smoking men were studied during a hyperinsulinemic, euglycemic glucose clamp for 2 h. Plasma insulin level during the clamp averaged 84 +/- 12 mU/l and euglycemia was maintained at 4.9 +/- 0.6 mmol/l. The t-PA activity gradually increased (75% mean increase after 2 h, p less than 0.001) and the PAI-1 activity decreased (49% mean decrease after 2 h, p less than 0.001) during the clamp. t-PA activity decreased and PAI-1 activity increased after the insulin infusion was ceased, but they were still 48% higher and 38% lower, respectively, after 60 min. PAI-1 and t-PA activities were not affected by saline infusion for 2 h. Thus, acute changes in the insulin levels lead to rapid alterations in the fibrinolytic system even when euglycemia is maintained. These effects may be induced by insulin itself or by the concomitant activation of the sympatho-adrenal system during the euglycemic clamp.

Blood Glucose↗
PubMed1991

Characterization of the insulin-antagonistic effect of growth hormone in man.

The insulin-antagonistic effect of growth hormone was characterized by infusing the hormone at three different infusion rates (6, 12 or 24 mU.kg-1.min-1) for one h in 11 healthy subjects. The insulin effect was measured with the euglycaemic clamp technique combined with D-(3-3H)-glucose infusion to evaluate glucose production and utilization. A control study with NaCl (154 mmol.l-1) infusion was also performed. The insulin levels during the clamps were similar in all studies (36 +/- 0.2 mU.l-1). Peak growth hormone levels were reached at 60 min (growth hormone 6 mU.kg-1.h-1: 31 +/- 5; growth hormone 12 mU.kg-1.h-1: 52 +/- 4 and growth hormone 24 mU.kg-1.h-1; 102 +/- 8 mU.l-1). The insulin-antagonistic effect of growth hormone started after approximately 2 h, was maximal after 4-5 h (approximately 39% inhibition of glucose infusion rate between control and growth hormone 24 mU.kg-1.h-1) and lasted for 6-7 h after peak levels. The resistance was due to a less pronounced insulin effect both to inhibit glucose production and to stimulate glucose utilization. Growth hormone infusion of 12 mU.kg-1.h-1 induced a similar insulin-antagonistic effect as the higher infusion rate whereas 6 mU.kg-1.h-1 induced a smaller response with a duration of 1 h between 3-4 h after peak levels of growth hormone. The present study demonstrates that growth hormone levels similar to those frequently seen in Type 1 (insulin-dependent) diabetic patients during poor metabolic control or hypoglycaemia, have pronounced insulin-antagonistic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors.

Insulin resistance and hyperinsulinaemia may play an important role in both the development of hypertension and its accompanying metabolic aberrations. In order to investigate this possibility, nine non-obese, non-diabetic, non-smoking, middle-aged men with untreated hypertension were treated with metformin 850 mg b.i.d. for 6 weeks as a pilot study and within-patient comparison. Metformin decreased total and LDL-cholesterol (P less than 0.01), triglyceride (P less than 0.01), fasting plasma insulin (P less than 0.01) and C-peptide levels (P less than 0.02). Glucose disposal, an indicator of insulin action measured by means of the euglycaemic clamp technique, increased (P less than 0.001). Tissue plasminogen activator (t-PA) activity increased (P less than 0.02), and t-PA antigen decreased (P less than 0.01), whereas plasminogen activator inhibitor (PAI-1) and fibrinogen were unaffected by metformin treatment. Body weight remained unchanged. Withdrawal of metformin was associated with the return of both blood pressure and metabolism towards the initial levels. In conclusion, metformin treatment increased insulin action, lowered blood pressure, improved the metabolic risk factor profile and tended to increase the fibrinolytic activity in these mildly hypertensive subjects. These results support the view that insulin resistance plays a role in hypertension, and may open up a new field for the alleviation of abnormalities associated with cardiovascular disease.

Blood Glucose↗
PubMed1991

Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

The effects of FFA on hepatic insulin clearance were studied in the in situ perfused rat liver. Clearance decreased with increasing body weight (age) of the rats. When FFA were added to the perfusate a 40% reduction of hepatic removal of insulin was found over the normal, physiological range (less than 1,000 mumol/liter), less pronounced in heavier rats. When perfusion was started with high concentrations of FFA, inhibition was rapidly reversible, a phenomenon again blunted in heavier rats. In contrast to FFA, different glucose concentrations in the perfusate did not affect the hepatic insulin uptake in the presence of FFA within physiological concentrations. Thus, hepatic clearance of insulin is proportional to rat weight (age) and portal FFA concentrations. Other studies have recently shown that fatty acids inhibit insulin binding, degradation, and function in isolated rat hepatocytes, and that hepatic clearance is inversely dependent on hepatic triglyceride concentrations, both inhibitions reversible by prevention of fatty acid oxidation. It is suggested that the diminished hepatic clearance of insulin in heavier (older) rats is at least partly due to their relative obesity and increased hepatic triglyceride contents. This effect as well as that of portal FFA is probably mediated via fatty acid oxidation in the liver. This mechanism may have implications for the regulation of hepatic metabolism, and peripheral insulin concentrations.

Animals↗
PubMed1991

Prevention of inhibitory effect of free fatty acids on insulin binding and action in isolated rat hepatocytes by etomoxir.

We recently demonstrated a marked inhibitory effect of high physiological concentrations of free fatty acids (FFAs) on insulin binding, degradation, and action in isolated rat hepatocytes. To elucidate the mechanism, male rats were treated for 3 days with saline (control) or etomoxir (ethyl 2-[6-(p-chlorophenoxy)hexyl]-glycidate), a prodrug, which in vivo is converted to a specific competitive inhibitor of carnitine palmitoyltransferase, and thus, lipid oxidation. Oleic acid (0.4 mM) reduced both 125-I-labeled insulin binding and insulin-stimulated [14C]aminoisobutyric acid transport approximately 40% in cells from control animals. However, this FFA concentration was without effect in cells from etomoxir-treated animals. Etomoxir increased EC50 for the inhibitory effect of oleic acid on insulin binding approximately threefold. The data indicate that the mitochondrial oxidation of fatty acids may be important for their inhibitory effect on insulin binding and action in isolated rat hepatocytes.

Aminoisobutyric Acids↗
PubMed1991

The skeletal muscle Na:K ratio is not increased in hypertension: evidence for the importance of obesity and glucose intolerance.

Several previous studies have suggested that hypertension is associated with altered sodium transport across the cell membrane. The aim of the present study was to study the skeletal muscle Na:K ratio in relation to blood pressure and glucose tolerance in obese and non-obese men. Muscle biopsies were taken from the femoral vastus lateralis muscle in men aged 52 +/- 5 years and the electrolytes were analyzed. Ten obese men with impaired glucose tolerance and hypertension, 10 obese normotensive controls, 10 lean men with hypertension and 10 lean normotensive controls participated in the study. Higher insulin levels were found in both hypertensive groups compared with the respective normotensive groups. Increased muscle Na:K ratio was found in obesity (P less than 0.01) and this was further enhanced when combined with hypertension and impaired glucose tolerance (P less than 0.001). However, hypertension in lean individuals was not associated with an increased muscle Na:K ratio. These data suggest that the increased muscle Na:K ratio in obese subjects and those with impaired glucose tolerance is not solely due to insulin resistance and hyperinsulinemia. Furthermore, the data clearly suggest that there is no important general perturbation of the Na-K pump in hypertension per se.

Biological Transport, Active↗
PubMed1991

Hypertension as a metabolic disorder--an overview.

Hypertension is related to several conditions with abnormalities in carbohydrate and lipid metabolism, such as obesity and impaired glucose tolerance. However, perturbed metabolism is also seen in non-obese hypertensive individuals. In addition, hypertension is linked to impaired fibrinolysis and elevated levels of the plasminogen activator inhibitor of endothelial type (PAI-1). Insulin resistance and hyperinsulinaemia in essential hypertension may be an important cause of these metabolic and fibrinolytic abnormalities. Whether hyperinsulinaemia is the cause of hypertension is currently unknown. However, it is clear that the relationship between hypertension and insulin is complex, and further studies are required to clarify this association. Based on the evidence states, it is suggested that insulin resistance and hyperinsulinaemia play a role in hypertension. However, it is also clear that hyperinsulinaemia occurs in the absence of hypertension, which suggests that other factors, such as genetic susceptibility, may be important.

Coronary Disease↗
PubMed1990

The insulin-like effect of growth hormone on insulin-like growth factor II receptors is opposed by cyclic AMP. Evidence for a common post-receptor pathway for growth hormone and insulin action.

The counter-regulatory effects of beta-adrenergic stimulation and cyclic AMP on the insulin-like action of growth hormone (GH) on the subcellular distribution of insulin-like growth factor II (IGF-II) receptors were studied in fat cells from hypophysectomized (Hx) and sham-operated rats. For comparison, the effect of insulin on this process was also studied. Basal IGF-II binding was increased by approx. 2-fold in cells from Hx as compared with sham-operated animals. The stimulatory effect of insulin was decreased in Hx cells, mainly due to a basal redistribution but also to a reduced total number of receptors. GH exerted an acute insulin-like effect in cells from Hx rats and stimulated the translocation of IGF-II receptors from an intracellular pool to the plasma membrane. beta-Adrenergic stimulation with isoprenaline or addition of the non-metabolizable cyclic AMP-analogue N6-monobutyryl cyclic AMP induced a cellular resistance to both GH and insulin and also reduced the responsiveness to these hormones. Adenosine exerted a modulatory effect on both hormones. Binding of 125I-labelled GH to its receptors was not significantly changed by any of these factors. It is concluded that: (1) beta-adrenergic stimulation and cyclic AMP induce a cellular GH resistance at a level distal to the GH-binding site, and (2) the insulin-like effect of GH shares a common pathway with insulin which occurs at the post-binding level.

Adenosine↗
PubMed1990

Probing the bacteriochlorophyll binding site by reconstitution of the light-harvesting complex of Rhodospirillum rubrum with bacteriochlorophyll a analogues.

Structural features of bacteriochlorophyll (BChl) a that are required for binding to the light-harvesting proteins of Rhodospirillum rubrum were determined by testing for reconstitution of the B873 or B820 (structural subunit of B873) light-harvesting complexes with BChl a analogues. The results indicate that the binding site is very specific; of the analogues tested, only derivatives of BChl a with ethyl, phytyl, and geranylgeranyl esterifying alcohols and BChl b (phytyl) successfully reconstituted to form B820- and B873-type complexes. BChl analogues lacking magnesium, the C-3 acetyl group, or the C-13(2) carbomethoxy group did not reconstitute to form B820 or B873. Also unreactive were 13(2)-hydroxyBChl a and 3-acetylchlorophyll a. Competition experiments showed that several of these nonreconstituting analogues significantly slowed BChl a binding to form B820 and blocked BChl a-B873 formation, indicating that the analogues may competitively bind to the protein even though they do not form red-shifted complexes. With the R. rubrum polypeptides, BChl b formed complexes that were further red-shifted than those of BChl a; however, the energies of the red shifts, binding behavior, and circular dichroism (CD) spectra were similar. B873 complexes reconstituted with the geranylgeranyl BChl a derivative, which contains the native esterifying alcohol for R. rubrum, showed in-vivo-like CD features, but the phytyl and ethyl B873 complexes showed inverted CD features in the near infrared. The B820 complex with the ethyl derivative was about 30-fold less stable than the two longer esterifying alcohol derivatives, but all formed stable B873 complexes.

Bacterial Proteins↗
PubMed1990

Evidence for lactate production by human adipose tissue in vivo.

Microdialysis of the abdominal subcutaneous tissue was performed in seven healthy normal weight subjects after an overnight fast and also after oral ingestion of 100g glucose. The lactate concentration in the interstitial water was compared with that in the venous and arterialized plasma from the cubital veins. In the postabsorptive state the lactate concentration in the subcutaneous tissue (1128 +/- 72 mumol/l, mean +/- SEM) was significantly higher (p less than 0.01) than that in both arterialized (722 +/- 72 mumol/l) and venous plasma (798 +/- 41 mumol/l). The oral glucose load further increased the lactate level in the subcutaneous tissue throughout the observation period of 2h. The kinetics for the increase in the lactate concentration was not apparently different in blood or tissue. The highest lactate levels were 1798 +/- 173 mumol/l in the subcutaneous tissue and 1199 +/- 150 mumol/l and 1275 +/- 123 mumol/l in arterialized and venous plasma, respectively. It is concluded that abdominal adipose tissue produces lactate both in the fasting state and after an oral glucose load. The data emphasize the importance of the adipose tissue as a significant source of lactate production in the body.

Adipose Tissue↗
PubMed1990

Characterization of the late posthypoglycemic insulin resistance in insulin-dependent diabetes mellitus.

The insulin effect (6.5 to 7.5 hours) following hypoglycemia was studied with the euglycemic clamp technique in eight patients with insulin-dependent diabeteses mellitus (IDDM). The results were compared with a control study with the same insulin infusion, but where hypoglycemia was prevented by a glucose infusion. Glucose production (Ra) and utilization (Rd) were evaluated with D-(3-3H) glucose infusion. Hypoglycemia (glucose nadir, 1.5 +/- 0.1 mmol/L) caused a marked increase in cortisol and growth hormone, whereas the release of adrenaline and, in particular, glucagon was low. The plasma free insulin levels were similar in the studies, including during the clamp periods. The glucose infusion rates (GIR) were significantly lower after the hypoglycemia as compared with the control study (control, 2.4 +/- 0.3; hypoglycemia, 1.5 +/- 0.3 mg/kg x min; P less than .05). Thus, hypoglycemia induces prolonged insulin resistance. The posthypoglycemic insulin resistance during a moderate hyperinsulinemic (approximately 30 mU/L) clamp was mainly due to a decreased insulin effect on glucose utilization (control, 2.9 +/- 0.2; hypoglycemia, 2.2 +/- 0.2 mg/kg x min; P less than .02), whereas the insulin effect on glucose production was not significantly different after hypoglycemia.

Adult↗
PubMed1990

Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1.

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.

Cardiovascular Diseases↗
PubMed1990

Increased insulin resistance and fat cell lipolysis in obese but not lean women with a high waist/hip ratio.

Increased lipolysis in abdominal adipocytes has been suggested to be of importance for the insulin resistance typical for abdominal obesity. In order to differentiate between fat distribution, measured as waist/hip ratio (WHR), and amount of body fat, glucose disposal during a euglycaemic clamp as well as lipolysis in isolated cells from abdominal and gluteo-femoral regions were studied in 20 obese and 20 lean postmenopausal women with a high (n = 10) and low (n = 10) WHR, respectively. The lipolytic response was increased in cells from obese women irrespective of region. Furthermore, lipolysis was enhanced in abdominal compared with the gluteo-femoral cells in obese women with a high WHR. Fasting blood glucose and insulin were increased in both groups of obese women while the degree of insulin resistance was most pronounced in the obese women with a high WHR. It is concluded that increased body fat is associated with both insulin resistance and increased lipolysis, and that this relationship is stronger in the presence of a high WHR. A high WHR may increase the expression of obesity as a risk for insulin resistance and this may be mediated through an increased lipolytic rate.

Adipose Tissue↗
PubMed1990

Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease.

The relationship between hypertension, glucose metabolism, fibrinogen and plasminogen activator inhibitor of endothelial cell type (PAI-1) was studied under conditions in which the influence of obesity and adipose tissue distribution (waist/hip ratio) were controlled. Twenty-two non-obese, middle-aged men with normal blood pressure (n = 11) and untreated mild hypertension (n = 11), respectively, participated in the study. Cholesterol, triglyceride and insulin levels were higher in hypertensive men than in the control group. Glucose disposal was studied as an indicator of insulin sensitivity using the euglycaemic clamp technique. The insulin effect tended to be less marked in men with hypertension. PAI-1 was higher in hypertensive men compared to the controls. A strong positive correlation was observed between PAI-1 and insulin levels as well as blood pressure. PAI-1 and fibrinogen levels correlated negatively with the rate of glucose disposal. Thus, even in these non-obese and mildly hypertensive individuals, an enhanced metabolic risk factor profile for cardiovascular disease was found. The metabolic aberrations were related to elevated fibrinogen and PAI-1 levels which, in turn, increase the risk of thrombus formation.

Anthropometry↗
PubMed1990

Microdialysis--a novel technique for clinical investigations.

Microdialysis is a novel, non-traumatic technique which, when properly performed, allows continuous direct measurements of substances in the interstitial space of a tissue or organ. It also makes it possible to obtain protein-free fluid for analyses, while contaminating bacteria or viruses are excluded. The measurements provide us with an insight into metabolic and pharmacological events at the cellular level in a target organ. Apart from its usefulness for experimental work, it is likely to become an important tool for defined areas in clinical practice.

Animals↗