Metabolism in adipose tissue in response to citalopram and trimipramine treatment--an in situ microdialysis study.

The intake of antidepressants is often accompanied by weight gain. Antidepressants may influence lipid and carbohydrate metabolism that can result in metabolic changes and obesity. We investigated the effect of citalopram and trimipramine on interstitial glycerol, glucose and lactate concentration and blood flow in subcutaneous adipose tissue of obese subjects by means of the microdialysis technique. In addition, the effect of stimulation with norepinephrine on metabolic response was investigated. Each subject was compared to a control subject matched for BMI and age. Each group comprised 10 subjects. Circulating plasma triglyceride concentrations were higher in drug-treated groups. In subcutaneous adipose tissue, microdialysis experiments revealed a higher and prolonged glycerol release in the presence of norepinephrine, but not under basal conditions. In citalopram treated subjects, basal glucose and lactate concentrations were higher compared with controls or with the trimipramine treated group. Local administration of norepinephrine induced a decrease in glucose levels and an increase in lactate levels, but without significant differences between groups. Local adipose tissue blood flow decreased in control groups following norepinephrine application, but remained constant in the antidepressant groups. In conclusion, citalopram and trimipramine affected glucose and lipid metabolism in adipose tissue and resulted in enhanced release of glycerol and free fatty acids into the circulation.

Effect of low-dose somatostatin infusion on pancreatic and gastric endocrine function in lean and obese nondiabetic human subjects.

The present study was designed to compare, in lean and obese nondiabetic subjects, basal and postprandial levels of peripheral venous plasma insulin, glucagon, gastrin, pancreatic polypeptide (PP), glucose, triglycerides, and somatostatin-like immunoreactivity (SLI) during the infusion of synthetic somatostatin-14 or saline. Thirty-five minutes before the ingestion of the test meal, an infusion of synthetic somatostatin-14 was started at a rate of 0.5 ng/kg X min and was increased to 1.0 ng/kg X min 30 min after consumption of the meal and lasted for another 90 min. During the infusion of saline, basal peripheral vein levels of insulin, gastrin, and triglycerides were elevated in obese subjects, whereas basal plasma SLI levels were significantly lower compared with the lean controls. Basal glucagon and PP levels were similar in both groups. After the ingestion of the meal, augmented concentrations of insulin and gastrin were observed in the obese subjects, whereas postprandial SLI and PP levels were reduced. Chromatography of fasting plasma revealed all measurable SLI to be confined to the void volume fractions of a Bio-Gel P-10 column. The rise in SLI after the meal was due to an increase of SLI co-eluting with somatostatin-28 and somatostatin-14. During the infusion of somatostatin, only basal insulin levels were significantly lower in the obese subjects, whereas no change of any basal hormone level was observed in the lean group. During the infusion of somatostatin, SLI levels were elevated by 20-30 pg/ml in both groups compared with the saline controls. During the infusion rate of 0.5 ng/kg X min, only postprandial PP levels were reduced significantly in the obese group, while all the other parameters were unaffected in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of phosphodiesterase effects on adipose tissue metabolism in obese subjects by the microdialysis technique.

The effect of non-selective (theophylline) inhibition of cyclic AMP breakdown on norepinephrine stimulated lipolysis rate was investigated in subcutaneous adipose tissue of obese subjects. In addition, changes in interstitial glucose and lactate concentration were assessed by means of the microdialysis technique. The interaction of endogenous released insulin and theophylline on adipocyte metabolism was determined. Theophylline and norepinephrine alone increased glycerol outflow significantly. When both agents were perfused in combination, interstitial glycerol concentration increased further. The enhanced glycerol level due to theophylline application was slightly decreased by insulin. In the presence of theophylline, extracellular glucose concentration increased, in contrast to the catecholamine. Norepinephrine decreased interstitial glucose level. When both drugs were added in combination, the level of interstitial glucose increased to about 1 mM, greater than with theophylline alone. With each intervention, lactate was synthesized. Local adipose tissue blood flow was increased by theophylline and theophylline plus norepinephrine. In conclusion, post-receptor mechanisms increased norepinephrine maximal stimulated lipolysis rate in subcutaneous adipose tissue. Glucose uptake was inhibited by the non-specific inhibitor of phosphodiesterase. The effect of insulin on inhibition of lipolysis was modest but sustained in the presence of high theophylline (10(-4) M) concentration. Phosphodiesterase activity may be relatively low in obese subjects in comparison with lean subjects. In lean subjects theophylline caused a transient reversal of the antilipolytic effect of insulin.

Potency of biosynthetic human insulin determined in vitro.

Biosynthetic human insulin (BHI) obtained from separately synthesized A- and B-chains by recombinant DNA technology with Escherichia coli fermentation was compared with human and pork insulin of high purity in vitro. Applying four biologic tests (glucose oxidation and glucose incorporation into the lipids by rat epididymal fat pads, inhibition of lipolysis, and ATP depletion of isolated fat cells) and three receptor assays (binding competition with human fat cells, IM-9 lymphocytes, and rat liver cell plasma membranes), we could not discern significant differences of the half-maximum response by these seven methods. The only variance occurred with the ATP-depletion assay. This method disclosed 10% greater maximum reversion of isoproterenol-induced ATP depletion by BHI when compared with pork insulin.

Somatostatin modulation of pancreatic glucagon, insulin, glucose and free fatty acids following beta-adrenergic stimulation.

This study was undertaken to determine the effect of somatostatin on acute, orciprenaline mediated, beta-adrenergic stimulation of free fatty acids, blood glucose, insulin, and glucagon in healthy subjects. After orciprenaline and somatostatin insulin and glucagon decreased, whereas blood glucose and free fatty acids increased, probably in part as a result of the lesser inhibition of glucagon (50%) than of insulin (83%). From these observations it is tentatively concluded that the inhibitory effects of somatostatin on insulin and glucagon release in man are a consequence of beta-adrenergic receptor involvement. These effects are possibly mediated through increased destruction of cAMP, blocking of camp dependent secretion or impairment of calcium uptake.

Blood pressure and plasma norepinephrine responses to dexfenfluramine in obese postmenopausal women.

Dexfenfluramine has been shown to reduce body weight and lower blood pressure in obese individuals. However. it is not clear whether the blood pressure-lowering effect is due to dexfenfluramine or to the loss of weight. This project was designed to study the effect of a 5-d treatment of dexfenfluramine on blood pressure changes in obese postmenopausal women. Twenty women aged 51-60 y matched for body mass index [BMI (in kg/m2) of 34.5-50.1] were assigned to either the dexfenfluramine group (15 mg orally twice a day for 5 d) or the control group. All subjects were instructed about an isoenergetic diet. Twenty-four-hour ambulatory blood pressure, plasma catecholamines, glucose, insulin, and lipids were measured at the beginning and repeated at the conclusion of the study. On day 5 the mean systolic (SBP) and mean diastolic blood pressures (DBP) in the dexfenfluramine group were lower than those of the control group (SBP: 114+/-7 mm Hg in the dexfenfluramine group compared with 124+/-12 mm Hg in the control group, P < 0.05; DBP: 70+/-9 mm Hg in the dexfenfluramine group compared with 76+/-10 mm Hg in the control group, P < 0.05). The mean plasma norepinephrine concentration was lower in the dexfenfluramine group than in the control group (1.60+/-0.5 compared with 2.41+/-0.5 nmol/L, respectively, P < 0.05). No differences were noted in epinephrine, glucose, insulin. and lipid concentrations between the two groups. We showed that a 5-d treatment of dexfenfluramine decreases blood pressure and reduces heart rate in obese postmenopausal women. Our data suggest that these effects are results of the direct action of dexfenfluramine.

Metabolic and weight-loss effects of a long-term dietary intervention in obese patients.

BACKGROUND: Obesity is a chronic disease that has become one of the most serious health problems in Western society. OBJECTIVE: We assessed the long-term effects of an energy-restricted diet combined with 1 or 2 daily meal replacements on body weight and biomarkers of disease risk in 100 obese patients. DESIGN: Phase 1 consisted of a 3-mo, prospective, randomized, parallel intervention study of 2 dietary interventions to reduce weight. The energy-restricted diet (5.2-6.3 MJ/d) consisted of conventional foods (group A) or an isoenergetic diet with 2 meals and 2 snacks replaced daily by energy-controlled, vitamin-and-mineral-supplemented prepared foods (group B). Phase 2 consisted of a 24-mo, case-control, weight-maintenance study with an energy-restricted diet and 1 meal and 1 snack replaced daily for all patients. RESULTS: Total weight loss (as a percentage of initial body weight) was 5.9+/-5.0% in group A and 11.3+/-6.8% in group B (P < 0.0001). During phase 1, mean weight loss in group B (n = 50) was 7.1+/-3.5 kg, with significant reductions in plasma triacylglycerol, glucose, and insulin concentrations (P < 0.0001). Group A patients (n = 50) lost an average of 1.3+/-2.2 kg with no significant improvements in these biomarkers. During phase 2, both groups lost on average an additional 0.07% of their initial body weight every month (P < 0.01). During the 27-mo study, both groups experienced significant reductions in systolic blood pressure and plasma concentrations of triacylglycerol, glucose, and insulin (P < 0.01). CONCLUSION: These findings support the hypothesis that defined meal replacements can be used for successful, long-term weight control and improvements in certain biomarkers of disease risk.

Fenofibrate treatment inhibits HMG-CoA reductase activity in mononuclear cells from hyperlipoproteinemic patients.

The effect of fenofibrate treatment on serum cholesterol levels was studied in relation to the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase in mononuclear cells from patients with hyperlipoproteinemia type IIa and IIb. When patients who had received fenofibrate (300 mg/day) for at least 8 weeks were given placebo during a subsequent 2-months period, both serum cholesterol concentration and mononuclear cell HMGR increased significantly in both types IIa and IIb. After reinstitution of fenofibrate treatment both parameters gradually declined and returned close to the initial level after another 28 weeks. It is concluded that a part of the lipid-lowering action of fenofibrate may be due to an inhibition of cholesterol synthesis.

Inhibition of HMG-CoA reductase in mononuclear cells during gemfibrozil treatment.

The effect of gemfibrozil treatment (900 mg/day) on serum levels of total cholesterol, HDL-cholesterol, triglyceride, apoproteins A-I, A-II and B as well as HMG-CoA reductase in mononuclear cells was studied in patients with hyperlipoproteinemia types IIa and IIb. After 4 weeks of treatment gemfibrozil reduced total serum cholesterol (IIa: -17%, IIb: -26%), triglyceride (IIa: -39%, IIb: -47%) and apoprotein B (IIa: -22%, IIb: -15%). HDL cholesterol was increased by 20-22% and apoproteins A-I and A-II by 4-11%. Concomitantly, HMG-CoA reductase activity in freshly isolated mononuclear cells was suppressed by 78% in type IIa and 51% in type IIb patients. Continuation of treatment for up to 16 weeks prompted a further decline to 8 and 5% of the initial values, respectively. However, gemfibrozil failed to affect HMG-CoA reductase directly in homogenized or cultured mononuclear cells and did not further promote the suppressive action of LDL when added to the culture medium. Similarly, preincubation with the drug did not significantly modulate the binding or degradation of LDL in the cultured cells. However, LDL from patients with hyperlipoproteinemia types IIa and IIb exhibited enhanced binding and more potent HMG-CoA reductase suppression when isolated after compared to before gemfibrozil treatment. It is suggested that the HMG-CoA reductase inhibition observed in mononuclear cells during gemfibrozil treatment is due to changes in LDL structure affecting LDL receptor binding rather than direct effects of the drug on cellular cholesterol metabolism.

Treatment of type II hyperlipoproteinemia with d-thyroxine.

The effectiveness of a new, almost l-thyroxine free preparation of d-thyroxine (Dynothel) was tested in 15 patients with Type IIa and 4 patients with Type IIb hyperlipoproteinemia. Eleven patients with Type IIa and 3 with Type IIb were responsive to treatment and showed an average 26% decrease in plasma TC. This decrement in plasma TC was mirrored in a significant reduction of LDL cholesterol in Type IIa and IIb. While VLDL cholesterol slightly decrease in Type IIb, it remained the same in Type IIa and so did the HDL cholesterol in both types. As neither VLDL nor LDL or HDL triglyceride levels changed very much in either type, the total plasma triglycerides remained the same. The plasma phospholipids were higher in Type IIa and lower in Type IIb on therapy. Thus, Dynothel seems to be a potent d-thyroxine preparation for lowering plasma cholesterol, this decrease being brought about by reduction of LDL cholesterol levels. The effect of the drug on plasma TG and PL is less certain.

Fat distribution, endocrine and metabolic profile in obese women with and without hirsutism.

The relationship between adipose tissue distribution, androgen levels, and metabolic complications of obesity was studied in 20 hirsute and 20 nonhirsute obese premenopausal women. The group of hirsute women showed preferentially an upper body type of obesity as assessed by the waist-to-hip ratio (0.902 + 0.017 v 0.778 +/- 0.015, P less than .01). They had higher serum concentrations of total testosterone (100.4 + 11.7 v 48.8 +/- 4.5 ng/dL, P less than .01) and lower levels of serum sex-hormone-binding globulin (28.1 +/- 3.6 v 44.0 + 4.2 nmol/L, P less than .05) exhibiting an increased androgenic activity as compared to the nonhirsute women. Serum glucose and insulin levels after an oral glucose load were significantly higher in the hirsute women. In addition, the group of hirsute females has significantly higher fasting concentrations of total cholesterol (5.82 +/- 0.28 v 4.75 +/- 0.14 mmol/L, P less than .05) and triglycerides (2.51 +/- 0.38 v 1.14 +/- 0.10 mmol/L, P less than .01). The hirsute group also showed higher systolic (166.7 +/- 5.1 v 142.1 +/- 4.5 mm Hg, P less than .01) and diastolic (100.9 +/- 3.6 v 85.2 +/- 2.5 mm Hg, P less than .01) blood pressure values than the nonhirsute women. Analysis of correlation revealed that an increasing waist-to-hip ratio was accompanied by increasing testosterone levels (r = .39, P less than .05) and by decreasing sex-hormone-binding globulin levels (r = .37, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Lovastatin alters blood rheology in primary hyperlipoproteinemia: dependence on lipoprotein(a)?

As part of a randomized, single-blind, comparative study evaluating the efficacy of lovastatin and bezafibrate retard in the treatment of primary hypercholesterolemia, hemorheologic parameters (whole blood viscosity, hematocrit, plasma viscosity, red blood cell aggregation and deformability, and fibrinogen) were studied in 35 patients. Whole blood viscosity and plasma viscosity improved significantly after 3 months of treatment with lovastatin, whereas other hemorheologic variables remained unchanged. Stratifying 24 patients by their lipoprotein Lp(a) levels showed that in those with low Lp(a) (less than or equal to 25 mg/dL) high-density lipoprotein cholesterol increased and red blood cell aggregation as well as deformability decreased considerably, whereas in the group with high Lp(a) levels (greater than 25 mg/dL), the opposite behavior was observed. Treatment of primary hypercholesterolemia with lovastatin may not only reduce the risk for atherosclerotic complications by its pronounced decrease of low-density lipoprotein cholesterol, but also may favorably alter blood rheology, and may decrease insudation of plasmatic components into the arterial wall and improve tissue perfusion, in particular on the microcirculatory level. The possible relevance of Lp(a) levels for the hemorheologic effects of lovastatin remains to be elucidated.

Lipoprotein responses to weight loss and weight maintenance in high-risk obese subjects.

OBJECTIVE: To examine changes in plasma lipids and lipoproteins after 51 months of reduced energy intake and sustained weight loss. METHODS: One-hundred patients were randomized to one of two dietary interventions for 3 months (weight loss period). Groups A and B received an energy-restricted diet plan of 5.2-6.3 MJ/day but group B was further instructed to replace two of three meals with a nutrient-fortified liquid meal replacement (MR). Upon completion of the weight loss period, all patients were given the same instructions regarding energy intake and were advised to use one MR daily. Body weight and 7 day food diaries were measured monthly or bimonthly and blood lipids at baseline, 3, 9 and 51 months. RESULTS: Of the original 100 patients 75 had completed 4 y. Of those 75, 73 had complete lipid records. Baseline body weights of Groups A and B were 90.7+/-14.0 and 91.6+/-9.8 kg, respectively. The percentage change in total cholesterol (%DeltaTC) decreased in a linear fashion with increasing weight loss, when all data was combined, but did not approach statistical significance (P< or =0.26, r=0.02). Further regression analysis found a significant negative linear relationship (P< or =0.0001, r=0.69) between initial total cholesterol (TC) concentrations and %DeltaTC. Hence, data from 27 of the 73 completers who exhibited an elevated serum total cholesterol (> or =6.2 mmol/l) were isolated and analyzed further. Baseline TC was 6.75+/-0.64, 5.85+/-0.63 at 9 months (P<0.05) and 5.76+/-0.52 mmol/l at 51 months (P<0.05). Similar values for VLDL-cholesterol were 1.33+/-0.80, 0.74+/-0.24 and 0.66+/-0.21 mmol/l by 51 months (P<0.05). Weight decreased by 5.2+/-5.1, 7.6+/-4.9 and 6.7+/-4.6% at 3, 9 and 51 months, respectively. CONCLUSION: Continuous energy restriction associated with a clinically meaningful weight loss significantly improved the lipid profile of high-risk patients. Similar weight and diet changes occurring in patients with normal plasma cholesterol were either increased or without affect.

Reduced epinephrine-stimulated lipolytic activity in male golden-mantled ground squirrel during hibernation: an in situ microdialysis study.

We studied lipolytic activities in vivo in golden mantle ground squirrels during pre-hibernation and hibernation using microdialysis technique. Microdialysis probes were inserted into the abdominal subcutaneous adipose tissues. Baseline lipolysis were assessed by measuring glycerol concentration. Epinephrine-stimulated lipolysis was also examined. Eight squirrels (four male, four female) were studied in each of the two stages. Basal glycerol concentrations were lower in the hibernating state than in the pre-hibernation state in male squirrels (P < 0.05). Epinephrine application induced glycerol release in male and female squirrels (P < 0.001) in both stages. Male squirrels demonstrated a reduced epinephrine-stimulated glycerol release in the hibernating state, which was not observed in female squirrels.

Blood rheology after LDL apheresis using dextran sulfate cellulose absorption--a case report.

The authors describe a thirty-eight-year-old woman with familial hypercholesterolemia treated by dextran sulfate cellulose adsorption apheresis. This technique and the selective extracorporeal LDL cholesterol elimination by immunoabsorption or heparin-induced precipitation not only dramatically decrease blood lipids but also result in a marked improvement in the rheologic profile. It is suggested that the amelioration of blood rheology by LDL apheresis may represent the cause for the early clinical improvement felt by most patients with severe coronary heart disease and hypercholesterolemia.

Postprandial lipoprotein metabolism in obese patients with moderate hypertriglyceridaemia: effects of gemfibrozil.

After an oral fat load of 1 g/kg body weight in 10 obese females with hyperlipoproteinaemia type IV, serum triglycerides concentrations were maximal at 4 h with a slight decline at 6 h, whereas serum cholesterol concentrations rose slightly at 4 h and 6 h. After 6 h, concentrations of triglycerides and cholesterol were significantly increased in chylomicrons and very low-density lipoprotein (VLDL), whereas cholesterol concentrations were decreased in high-density lipoprotein 2 (HDL2) plus HDL3. After oral treatment with 450 mg gemfibrozil twice daily for 28 days, triglyceride concentrations were reduced in serum, chylomicrons, VLDL and low-density lipoprotein, and total cholesterol concentrations were reduced in serum, chylomicrons and VLDL, and increased in HDL2 plus HDL3. At 6 h after a fat load following 28 days' gemfibrozil treatment, triglyceride and cholesterol concentrations were reduced in serum, chylomicrons and VLDL when compared with pretreatment results. It is concluded that gemfibrozil is effective in lowering triglycerides and cholesterol, particularly in triglyceride-rich particles, and raising the cholesterol content of HDL2 plus HDL3. After an oral fat load gemfibrozil inhibits the increase in serum cholesterol and partly prevents postprandial hypertriglyceridaemia.

[Pravastatin, cholestyramine and gemfibrozil in long-term therapy of primary hypercholesterolemia. An open randomized comparative study]. / Pravastatin, Colestyramin und Gemfibrozil in der Langzeittherapie der primären Hypercholesterinämie. Eine offene randomisierte Vergleichsstudie.

In this open controlled clinical trial the lipid-lowering effect, the tolerance and clinical safety of the new hydrophilic HMG-CoA reductase inhibitor pravastatin and cholestyramine were compared in the treatment of 45 patients with primary hypercholesterolaemia over a period of 16 weeks. Following a dietary lead-in of six weeks, patients were randomized at a ratio of 3:2 to receive either pravastatin 10 mg b.i.d. or cholestyramine 8 g b.i.d. The dose of pravastatin was increased to 40 mg per day after eight weeks of treatment and after 16 weeks cholestyramine 8 g b.i.d. was added. Two thirds of the patients in the cholestyramine group were switched to gemfibrocil 900 mg. At the end of the 48 week treatment period the mean reduction rates of total cholesterol, LDL-cholesterol and triglycerides for the pravastatin combination compared to cholestyramine (in brackets values for gemfibrocil) were -30, -35 and -17% versus -17 (-19), -25 (-22) and +27 (-24)%. Pravastatin lead to an increase of the HDL concentration of approximately 8%, gemfibrocil to approximately 13%, whilst cholestyramine alone did not change this lipid fraction. The reduction of total cholesterol and LDL-cholesterol was associated with a decrease in the apolipoprotein B concentration. However, the apolipoprotein AI and AII levels remained unchanged. Due to the absence of clinically relevant side effects and laboratory abnormalities coupled with the excellent compliance in this study, pravastatin proved to be a convincing therapeutic alternative to cholestyramine and gemfibrocil. The combination therapy of pravastatin and cholestyramine offers a potentially highly efficacious and safe therapeutic regimen for the future.

[Principles of dietary treatment of obesity]. / Grundlagen der Diättherapie der Adipositas.

One of the first steps in a clinical approach to any obese subject should be focused on the reduction and/or normalization of any potential or existing metabolic abnormality. Overeating and/or unbalanced food intake remains the major element in the origin and maintenance of obesity. The reduction of energy intake is the basis of successful weight loss. In obese subjects there are huge amounts of energy stored, mainly in the adipose tissue, which are mobilized according to the size and duration of an energy deficit. Considerable studies have been devoted to finding the optimal dietary approach that would promote rapid weight loss while maximizing the depletion of adipose tissue and conserving body protein. During fasting adipose tissue lipolysis rate increases and liberated unesterified fatty acids are oxidized in muscle and liver. The liver produces ketones which are oxidized in muscle and brain. The energy need of the brain is not sufficiently covered by ketone oxidation, therefore additional glucose must be provided. The liver produces glucose by gluconeogenesis using amino acids from muscle protein. Because of limited protein sources, protein must be given during energy restricted diet. Besides protein also vitamins, minerals, trace elements, fiber, and linoleic acid must be substituted during fasting and during treatment with very low calorie diets. Meal replacements are helpful to fulfil all the requirements. There is consensus that the first step in dietary treatment is an energy restricted diet with a calorie deficit of at least 600 Kcal/day, but more than 800 Kcal/day must be provided, with all essential nutrients. Observing the regulations, weight reduction with appropriate diet plans improves metabolic disturbances.