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P Arner

Publications and source records attributed to P Arner.

At least 145 records · Page 8Linked to original sources

Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure.

OBJECTIVE: To compare the effect of bedtime NPH insulin or preprandial regular insulin combined with glibenclamide on metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure to sulfonylurea therapy. RESEARCH DESIGN AND METHODS: Eighty NIDDM patients were randomized to treatment with either three preprandial doses of regular insulin (daytime group D) or a bedtime dose of NPH insulin (nocturnal insulinization, group N), both regimens being combined with 10.5 mg of glibenclamide. Metabolic profiles were obtained at 0, 6, 16 weeks. RESULTS: Glycemic control had improved significantly in both groups after 4 months. Fasting blood glucose was significantly lower compared with baseline in both groups. The mean change +/- SD in group D was -2.8 +/- 3.5 mmol/l and in group N -6.4 +/- 3.0 mmol/L, the reduction being more pronounced in group N compared with group D (P < 0.0001). HbA1c was lowered similarly, from 9.2 +/- 1.4 to 7.1 +/- 1.2% in group D (P < 0.0001) and from 9.1 to 1.1 to 7.5 +/- 1.5% in group N (P < 0.0001). The total daily insulin doses were similar, 29 +/- 11 U in group D and 26 +/- 9 U in group N, and the circulating insulin levels during daytime were higher in group D than in group N. Total serum cholesterol and triglycerides were similarly and significantly lowered compared with baseline in both groups. Weight gain was more pronounced in group D (3.4 +/- 0.3 kg) than in group N (1.9 +/- 1.9 kg; D vs. N, P < 0.002), and the change was inversely correlated with initial eight but not with the improvement in HbA1c. CONCLUSIONS: The two insulin regimens exert similar effect on glucose metabolism and serum lipids in NIDDM patients on combination therapy. Weight gain is more pronounced in patients given insulin during the daytime when preprandial doses of short-acting insulin are used.

Adult↗

Differences in lipolysis between human subcutaneous and omental adipose tissues.

Hydrolysis of triglycerides to fatty acids and glycerol in fat cells (lipolysis) is of importance for the control of lipid and carbohydrate metabolism. This process is regulated by several hormones and parahormones acting on cyclic AMP formation or breakdown, which in turn influences the activity of hormone sensitive lipase. The latter enzyme stimulates hydrolysis of triglycerides in fat cells. It is well established through in vivo and in vitro investigations that there are regional variations in the lipolytic activity of human adipose tissue. The rate of lipolysis is low in the subcutaneous femoral/gluteal region, intermediate in the subcutaneous abdominal region and high in the visceral (i.e. omental) region. In non-obese subjects the differences between the subcutaneous and visceral fat depots may be explained by site variations in the function of receptors for insulin, catecholamines and adenosine. The lipolytic beta 1 and beta 2 adrenoceptors, as well as the newly discovered beta 3, are most active in the visceral fat cells. The antilipolytic insulin receptors, alpha 2 adrenoceptors and adenosine receptors are most active in the subcutaneous fat cells. In subjects with upper-body obesity the regional variations in the action of catecholamines on lipolysis are further enhanced. Decreased action of beta 2-adrenergic receptors and increased activity of alpha 2-adrenergic adrenoceptors in combination with defects in hormone sensitive lipase function inhibits the lipolytic effect of catecholamines in subcutaneous fat cells whereas increased activity of beta 3-adrenergic receptors and decreased activity of alpha 2 adrenoceptors augment the lipolytic response in visceral fat cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

Influence of local blood flow on glycerol levels in human adipose tissue.

DESIGN: The influence of blood flow on adipose tissue glycerol levels was investigated in human subcutaneous adipose tissue in situ, with the aid of microdialysis of the extracellular water space. The concentration of tissue-derived glycerol and the escape of ethanol from the dialysis solvent into the extracellular space were simultaneously monitored; the latter was used as an index of local blood flow around the probe. RESULTS: Selective vasodilation with nitroprusside or hydralazine rapidly reduced the concentration of glycerol by 50% and at the same time increased the escape of ethanol (P < 0.001). Stimulation of local blood flow and lipolysis with the beta-adrenoceptor agonist isoprenaline caused an increase in ethanol escape (P = 0.01) and a 100% rise in the dialysate glycerol level (P = 0.001). When vasodilation was first induced by nitroprusside, the subsequent addition of isoprenaline to the microdialysate perfusate caused no change in the concentration of glycerol in adipose tissue but a slight increase in ethanol escape. CONCLUSIONS: In conclusion, local blood flow plays an important role in the regulation of the glycerol level in human adipose tissue. Stimulation of blood flow may under certain conditions decrease the level of glycerol in the extracellular space of adipose tissue although the mobilization of glycerol from fat cells to this compartment is increased. Thus, changes in blood flow and glycerol should be considered together when adipose tissue lipolysis is investigated by microdialysis.

Adipose Tissue↗

Techniques for the measurement of white adipose tissue metabolism: a practical guide.

A number of old and new techniques to study various aspects of white adipose tissue metabolism in vivo and in vitro are discussed. It is possible to determine lipolysis rates in vivo with tracer techniques using glycerol or fatty acids labelled with stable or radioactive isotopes. These methods allow the determination of whole body lipolysis rates but are not valuable for the investigations of regional variations in lipolysis. When combined they permit a calculation of the rate of re-esterification of free fatty acids. The vein draining abdominal subcutaneous adipose tissue can be cannulated in humans. By this method substrate turnover can be determined in vivo over the cannulated adipose region. With microdialysis it is possible to study local metabolism in vivo in different adipose tissue regions. At the same time it is possible to locally manipulate the tissue with metabolically active pharmacological substances. A number of in vitro methods to determine glucose transport in isolated fat cells are developed. The most accurate one uses 3-O-methyl glucose as tracer. These methods can be combined with studies of the further metabolism of glucose to lipids, lactate and carbon dioxide using simple (usually radioactive) methods. Lipolysis as well as release and re-esterification of free fatty acids can be investigated in detailed in vitro with sensitive techniques based on luminescence. Finally, triglyceride turnover and partial metabolism of acylglycerols can be investigated in vitro with a double isotope technique.

Adipose Tissue↗

Impact of exercise on adipose tissue metabolism in humans.

Mobilization of lipids from adipose tissue during prolonged exercise is of key importance for the supply of energy to the working muscle. During exercise lipid mobilization is mainly stimulated by increased catecholamine production leading to acceleration of the beta-adrenoceptor mediated lipolysis rate in fat cells. This causes breakdown of triglycerides in fat cells to glycerol and free fatty acids, which then are delivered to the blood stream. Decreased insulin production, enhanced adipose tissue blood flow and decreased reesterification of free fatty acids in fat cells contribute to the enhancement of lipid mobilization during strenuous and long-term light exercise. Several additional factors modulate the lipolytic response to exercise as well. Endurance training increases the lipolytic action of catecholamine whereas the opposite occurs during ageing. These alterations are at least in part mediated by changes in the function of the final step in lipolysis activation, the protein kinase-hormone sensitive lipase complex. There are also gender and regional differences in the lipolytic response to exercise. Women mobilize more lipids from the subcutaneous abdominal area than men, whereas a low rate of lipid mobilization from the peripheral subcutaneous areas is observed in either sex. In pathophysiological states, which are associated with catabolism such as fasting and insulin dependent diabetes, there is an enhanced lipolytic response to exercise, because of increased beta-adrenoceptor function.

Adipose Tissue↗

Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta 2-adrenoceptors.

Upper-body obesity is an important risk factor for developing non-insulin dependent diabetes. To investigate the possibility that a lipolysis defect is present in this form of obesity, we examined the adrenergic regulation of lipolysis in abdominal subcutaneous fat cells from 25 women with upper-body obesity and 24 non-obese women. Lipolytic noradrenaline sensitivity (but not the maximum rate of lipolysis) was reduced by 10-fold in obese women (p < 0.01). The noradrenaline resistance could be ascribed to a 10-fold decrease in lipolytic beta 2-adrenoceptor sensitivity (p < 0.01). The lipolytic sensitivity of beta 1- and alpha 2-adrenergic receptors was normal in the obese women. A 70% reduction in the cell surface density of beta 2-adrenoceptors was observed compared to the control subjects (p < 0.01). However, beta 1-receptor density as well as steady-state mRNA levels for beta 1- and beta 2-receptors were normal in obese women. Lipolytic noradrenaline sensitivity correlated inversely with BMI (adjusted r2 = 0.76 together with fat cell volume in stepwise regression analysis). The fasting plasma level of free cortisol was 30% lower in obese compared to non-obese women (p < 0.05) but obesity did not influence resting plasma catecholamine levels. Thus, lipolytic catecholamine resistance is present in abdominal obesity, due to low density of beta 2-adrenoceptors, which in its turn may be caused by a post-transcriptional defect in beta 2-receptor expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗

Growth hormone regulation of lipid metabolism in cells transfected with growth hormone receptor cDNA.

The functional properties of the growth hormone (GH) receptor was studied using cellular transfection of GH receptor cDNA. GH treatment (1.5-2 h) of Chinese hamster ovary cells, stably transfected with GH receptor cDNA (CHO4), resulted in increased cellular lipid synthesis (240% of control). This effect was blocked by staurosporine, suggesting a dependence on cellular kinases. However, if GH treatment of CHO4 cells was prolonged (16 h), this instead stimulated lipolysis (128% of control). The GH receptor in CHO4 cells was also shown to be functional in terms of ligand internalization. A GH receptor mutant, in which 183 amino acids had been deleted in the carboxyterminal of the intracellular domain was functionally active, while a receptor without its intracellular domain was shown to be inactive. In conclusion, GH receptors expressed in CHO cells are functional and GH was also shown to have both an acute insulin-like effect, which was kinase dependent, and a long-term anti-insulin-like effect on the lipid metabolism. This suggests that an approach using GH receptor cDNA transfected cells can be of value in understanding the mechanism of GH action.

Alkaloids↗

Lipolytic and cardiac responses to various forms of stress in humans.

The lipolytic and the cardiac responses to 30 min of two different forms of stress--a standardized mental stress test and submaximal bicycle exercise--were investigated in non-obese healthy subjects. This was done by microdialysis of the extracellular space in the abdominal subcutaneous adipose tissue in order to determine lipolysis and electrocardiographic recordings of the heart rate. Glycerol concentrations (lipolysis index) in venous plasma and in adipose tissue dialysate as well as plasma catecholamines and determinations of the heart rate showed marked increases during mental stress (p < 0.001) and physical exercise (p < 0.001), but the patterns of response differed during the two forms of stress. All parameters rose gradually during exercise and decreased continuously in the post-exercise period. During mental stress, however, all parameters peaked within the first 20 min of stimulation and then remained at the same level until after the stress period, when they gradually declined. The maximal increase of glycerol in plasma and adipose tissue during mental stress correlated with the corresponding increase during exercise (r = 0.50-0.60). Such a relationship was not observed with plasma catecholamines or heart rate (r = 0.02-0.29). The peak level of plasma noradrenaline was an independent regressor for the peak levels of glycerol in plasma and adipose tissue as well as for the peak heart rate during mental stress and physical exercise (partial r from 0.35 to 0.64), while the peak level of adrenaline was a regressor for heart rate only during mental stress (partial r = 0.45), when multiple regression analysis was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

Multiple lipolysis defects in the insulin resistance (metabolic) syndrome.

Bearing in mind the importance of upper-body obesity for the insulin resistance (or metabolic) syndrome and the abnormalities in free fatty acid metabolism associated with this disorder, the regulation of lipolysis in isolated subcutaneous adipocytes was investigated in 13 72-yr old upper-body obese men with insulin resistance and glucose intolerance and in 10 healthy 72-yr-old men. There was a marked resistance to the lipolytic effect of noradrenaline in the metabolic syndrome due to defects at two different levels in the lipolytic cascade. First, an 80-fold decrease in sensitivity to the beta 2-selective agonist terbutaline (P < 0.001) which could be ascribed to a 50% reduced number of beta 2-receptors (P < 0.005) as determined with radioligand binding. The groups did not differ as regards dobutamine (beta 1) or clonidine (alpha-2) sensitivity, nor beta 1-receptor number. The mRNA levels for beta 1- and beta 2-receptors were similar in the two groups. Second, the maximum stimulated lipolytic rate was markedly reduced in the metabolic syndrome. This was true for isoprenaline (nonselective beta-agonist), forskolin (activating adenylyl cyclase), and dibutyryl cAMP (activating protein kinase). In regression analysis, the observed abnormalities in lipolysis regulation correlated in an independent way with the degree of glucose intolerance (r = -0.67) and beta 2-receptor number with insulin resistance (r = 0.67). In conclusion, the results of this study indicate the existence of lipolytic resistance to catecholamines in the adipose tissue of elderly men with the metabolic syndrome, which may be of importance for impaired insulin action and glucose intolerance. The resistance is located at a posttranscriptional level of beta 2-receptor expression and at the protein kinase-hormone sensitive lipase level.

Adipose Tissue↗

Lipolysis during abdominal surgery.

Subcutaneous adipose tissue lipolysis has been monitored with microdialysis during elective cholecystectomy by laparotomy in otherwise healthy nonobese subjects. Eight of the subjects received saline and seven received glucose iv during the operation. In both groups the glycerol level in the microdialysate (lipolysis index) started to increase steadily from the start of the general anesthesia until the abdominal wall was closed. Thereafter it leveled off and remained elevated until after extubation. Plasma glycerol started to rise after the surgical incision. The levels of noradrenaline and adrenaline, but not of insulin, glucagon, and cortisol in plasma, changed in parallel with that of glycerol in the microdialysate. The glycerol response in adipose tissue in the group receiving iv glucose was three times more marked than in the saline group (P = 0.01) in spite of marked hyperinsulinemia, but there was no difference between the groups in plasma glycerol response. The plasma noradrenaline response was 50% higher (P = 0.03) in the glucose group than in the saline group, but there was no difference between the groups in the plasma adrenaline, glucagon, or cortisol responses. Adipose tissue blood flow was measured by the escape of ethanol from the dialysis solvent into the extracellular space. It was constant throughout the experimental period in both groups. In conclusion, the lipolysis rate is accelerated during general anesthesia and abdominal surgery because of increased catecholamine production. Perioperative glucose infusion is associated with a further acceleration of the lipolytic rate in subcutaneous adipose tissue due to an additional activation of the sympathetic nervous activity that overrides the antilipolytic effect of the glucose-induced hyperinsulinemia. Other adipose regions may be less sensitive to glucose infusions and anesthesia.

Adipose Tissue↗

Insulin receptor ribonucleic acid levels and alternative splicing in human liver, muscle, and adipose tissue: tissue specificity and relation to insulin action.

The absolute levels and alternative splicing of insulin receptor RNA molecules were determined in samples from liver, muscle, and adipose tissue from 17 nondiabetic individuals. Both the absolute levels and alternative splicing varied in a tissue-specific manner. In all tissues, a majority of the insulin receptor RNA molecules contained exon 11. Liver tissue had a lower percentage of RNA molecules without exon 11 (Ex 11-) than muscle and adipose tissue, but the absolute number of Ex 11- RNA copies was higher due to higher overall levels of insulin receptor RNA. Insulin receptor RNA levels in adipose tissue showed significant correlation with obesity, expressed as body mass index (kilograms per m2) as well as with in vivo insulin action, as measured by the insulin tolerance test. In this study, obesity and insulin action were not correlated with insulin receptor RNA expression in liver or muscle. Within individuals, no relation was detected between the number of insulin receptor RNA copies in a tissue and the number or percent Ex 11- RNA in the same tissue. Also, the absolute levels or Ex 11- percentages in one tissue could not predict corresponding measurements in the other two investigated tissues from the same individual.

Adipose Tissue↗

Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients.

The influence of thyroid hormones on the adrenergic regulation of lipolysis was studied in isolated adipocytes removed from the gluteal region of hyper- and hypothyroid women and compared in adipocytes from euthyroid normal women. Noradrenaline significantly enhanced lipolysis in hyperthyroid patients, whereas noradrenaline inhibited lipolysis in hypothyroid patients compared to that in controls. Moreover, beta-adrenergic sensitivity and responsiveness were 10- and 2-fold increased, respectively, in hyperthyroid patients. In hypothyroid patients, beta-adrenoceptor responsiveness was reduced by 50%, whereas beta-adrenergic sensitivity remained unchanged compared with that in controls. Furthermore, the alpha 2-adrenergic and adenosine-induced antilipolytic effects were similar in all thyroid states. The lowered beta-adrenergic responsiveness seen in hypothyroidism could be mimicked by agents acting at the levels of phosphodiesterase (enprofylline), adenylate cyclase (forskolin) and protein kinase (dibutyryl cAMP). In hyperthyroidism, the increased beta-adrenergic sensitivity and responsiveness were not seen when lipolysis was stimulated at the adenylate cyclase, phosphodiesterase, or protein kinase levels. There was no change in the numbers of adipocyte beta- and alpha 2-adrenoceptors in hypothyroidism. However, the number of beta-adrenergic binding sites was doubled, whereas the fraction and affinities of isoprenaline high affinity sites remained unchanged in hyperthyroidism. Thus, the influence of thyroid hormone on catecholamine-stimulated lipolysis in man acts through different mechanisms when adipocytes are exposed to high or low levels of thyroid hormones. In hyperthyroidism, lipolysis adapts to increasing energy demands through an increase in the beta-adrenoceptor number and, thus, a more effective coupling of the adenylate-cyclase complex. In hypothyroidism, the low lipolytic effect of catecholamines seems to be mainly due to an impairment at the protein kinase level or to the hormone-sensitive lipase itself.

Adipocytes↗

Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension.

The new angiotensin-converting enzyme (ACE) inhibitor trandolapril 2 mg was administered daily for 10 consecutive days to young (mean age +/- SEM 44.1 +/- 2.3 years; n = 10) and elderly (mean age +/- SEM 69.3 +/- 0.9 years; n = 14) patients with mild-to-moderate hypertension. All groups had similar baseline blood pressures: mean 164/100 mm Hg. Maximal plasma ACE inhibition on day 10 and residual inhibition 24 h after the last dose was the same, irrespective of age: young, 85.2 and 57.4%; elderly 89.1 and 59.8%, respectively. There was no difference between the results on day 1 for the young and elderly groups. The absorption of trandolapril was rapid (< 1 h in all groups). The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were slightly higher in the older group, but the elimination half-life (t1/2) was the same, with no accumulation after repeat dosing. A steady-state plasma concentration of the active metabolite of trandolapril, trandolaprilat, was reached after 4 days in the two groups, with similar accumulation ratios (young, 1.48; elderly, 1.49). At steady state, the Cmax and AUC 0-24 h for trandolaprilat were similar in the two groups: young, 7.49 +/- 0.98 ng/ml and 82.27 +/- 6.95 ng/ml/h; elderly, 8.35 +/- 0.67 ng/ml/h and 96.75 +/- 5.67 ng/ml/h. Maximal reductions in systolic/diastolic blood pressures (at 6 h postdose) were -14.1%/-16.1% in young patients and -14.6%/-17.5% for the elderly. Significant blood pressure reduction persisted for 48 h after the last dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Influence of operation on glucose metabolism and lipolysis in human adipose tissue: a microdialysis study.

OBJECTIVE: To investigate the effect of an operation on metabolism in human adipose tissue. DESIGN: Open study. SETTING: Department of Surgery and the Research Centre at Huddinge Hospital. SUBJECTS: 13 non-obese patients who underwent elective cholecystectomy, and 5 control subjects. INTERVENTIONS: Microdialysis of the extracellular compartment of abdominal subcutaneous adipose tissue was done before, during and after a 45-minute intravenous infusion of 20 g glucose before, and one day after, the operation. MAIN OUTCOME MEASURES: Concentrations of glycerol, glucose, lactate and pyruvate in the tissue dialysate and in venous plasma. RESULTS: After operation, the baseline plasma insulin concentration doubled (p < 0.001) and the fasting glucose concentration rose from 4.4 (0.1) to 5.3 (0.2) mmol/l (p < 0.001). In response to the glucose infusion, the maximum increase in plasma insulin trebled (p < 0.01) and the integrated concentrations (area under the curve) of plasma glucose, lactate and pyruvate were significantly more pronounced (p < 0.02-p < 0.001) after than before operation. The suppression of plasma glycerol and free fatty acid concentrations was similar before and after operation (50-60%). The reduction in the concentrations of glycerol in adipose tissue, and the increases in the concentrations of glucose, lactate, and pyruvate, after intravenous infusion of glucose were not influenced by the operation. CONCLUSION: A moderately serious operation rapidly induces a deterioration in total body glucose homeostasis, partly as a result of peripheral insulin resistance. This does not affect the utilization of glucose by adipose tissue or the antilipolytic response to glucose infusion.

Adipose Tissue↗

Long-term continuous glucose monitoring with microdialysis in ambulatory insulin-dependent diabetic patients.

The glucose concentration in the extracellular space of subcutaneous adipose tissue closely mirrors the blood glucose concentration. With a microdialysis technique, we undertook continuous ambulatory monitoring of adipose tissue glucose in 17 insulin-dependent diabetic patients with labile glycaemic control. The aims of the study were to investigate performance of the microdialysis device and to evaluate whether consecutive 24 h glucose profiles could be used to adjust insulin therapy. A microdialysis probe was implanted subcutaneously, perfused by a portable microinfusion pump, and dialysate fractions were collected every 1 or 2 h for 75 h. The mean (SE) tissue dialysate glucose concentration was 93 (3)% of the concentration in venous plasma, and variations in adipose tissue glucose closely paralleled changes in plasma glucose. Mean 24 h tissue glucose concentration correlated significantly with glycosylated haemoglobin (HbA1c; r = 0.62, p < 0.01). Most patients had a reproducible daily pattern of glucose swings, and in more than half the patients consecutive ambulatory glucose profiles were almost superimposed. When patients' insulin therapy was adjusted on the basis of ambulatory glucose monitoring, HbA1c decreased by almost 2% (p < 0.01), and this decrease lasted for at least 9 months. Microdialysis of adipose tissue can be used for continuous long-term monitoring of glucose concentrations in diabetic patients during ordinary daily life. Daily glucose profiles are often reproducible and the recordings may thus be used for individual tailoring of insulin therapy to improve glycaemic control.

Adipose Tissue↗

Effect of glucocorticosteroid treatment on beta-adrenoceptor subtype function in adipocytes from patients with asthma.

1. Adrenoceptor subtype function was studied in isolated adipocytes obtained by subcutaneous fat biopsies from nine patients with mild asthma. The biopsies were taken before and after 7 days treatment with 25 mg of prednisolone given orally. Lipolytic activity after stimulation with various adrenergic agent was measured, using glycerol release as an index of lipolysis. The number of beta 1- and beta 2-adrenoceptor binding sites was determined in radioligand binding experiments and beta 1- and beta 2-adrenoceptor mRNA levels were measured with a solution hybridization assay. 2. Lipolytic sensitivity (ED50) to isoprenaline, a non-selective beta-adrenoceptor agonist, increased 50-fold after treatment (P = 0.04). Sensitivity to terbutaline, a selective beta 2-adrenoceptor agonist, increased 25-fold (P = 0.01), whereas the ED50 values for dobutamine, a selective beta 1-adrenoceptor agonist, did not change significantly. Likewise, the sensitivity to the alpha 2-adrenoceptor agonist, clonidine, and to the drugs acting at post-receptor levels did not change significantly. Basal and maximum lipolytic rates on stimulation were not altered by the treatment. 3. The number of beta 2-adrenoceptor binding sites increased by 60% after treatment (P < 0.05), whereas the beta 1-adrenoceptor binding sites were not affected. The affinity of each receptor subtype for the displacing ligand, ICI 118.551, was not significantly altered by steroids. No significant changes were demonstrated in either beta 1- or beta 2-adrenoceptor mRNA levels. 4. Thus, glucocorticoids selectively increase beta 2-adrenoceptor density and function in patients with asthma, studied by using subcutaneous fat cells as an experimental model.

Administration, Oral↗