Energy Expenditure, Substrate Oxidation, and Body Composition in Subjects with Chronic Alcoholism: New Findings from Metabolic Assessment

There is some controversy as to the effect of ethanol on body weight and alcohol energy contribution to body mass. The aim of this study was to evaluate the effect of alcohol addiction on resting energy expendhrre (REE) and body composition. Twelve patients with current alcoholism (A) without severe liver disease or lipid and carbohydrate malabsorption were compared with a group of healthy social drinkers (B) matched for sex, age, and height. Their caloric intake was computed on the basis of a food diary. REE was measured with indirect calorimetry, and body composition was assessed by both anthropometry and bioimpedance. A significant decrease in fat mass in A compared with B was found (14.8 ± 5.39 vs. 19.0 ± 3.50 kg; p < 0.05). No significant differences were observed in fat-free mass (FFM) or in total body water between the two groups. A showed higher REE values normalized by FFM than B (35.5 ± 2.97 vs. 33.0 ± 2.95 kcal/kg_FFM; p < 0.05). The nonprotein respiratory quotient was significantly lower in A than in B (0.76 ± 0.03 vs. 0.86 ± 0.03; p < 0.001), and A showed significantly higher lipid oxidation and lower carbohydrate oxidation than B (p < 0.05). The daily caloric intake provided only by food ingestion was found to be significantly higher in controls, but because the percentage of alcohol calories of total energy intake was 46.3 ± 6.80 in alcoholics and 13.6 ± 3.59 in controls (p < 0.0001), the total caloric intake, computed as food intake plus alcohol intake, was higher in alcoholics than in control subjects. No statistical differences were found in urinary nitrogen excretion and fecal loss between groups. Patients with alcoholism showed an increased REE over predicted values and a preferential lipid oxidation with respect to controls; these findings could be related to induction of microsomal ethanol oxidizing system and to mitochondrial function adaptation secondary to chronic alcohol abuse. In either case, the effects of such changes in energy metabolism may contribute to alcohol associated hepatic injury.     

Diminished energy requirements in reduced-obese patients

In assessing the reasons for the frequent regaining of weight by reduced-obese patients, we examined retrospectively the seven-day energy intake requirements for weight maintenance of 26 obese patients (12 males, 14 females) at maximum weight (152.5 ± 8.4 kg) and after weight loss (100.2 ± 5.7 kg). These results were compared with those obtained in 26 age- and sex-matched control patients who had never been obese (62.6 ± 2.3 kg). The obese and control subjects required comparable caloric intakes: 1432 ± 32 kcal/m²/d vs 1341 ± 33 kcal/m²/d, respectively. Following weight loss, the reduced-obese subjects required only 1021 ± 32 kcal/m²/d, a 28% decrease (P < 0.001) in requirements relative to their obese state and a 24% decrease relative to the control patients (P < 0.001). The mean individual energy requirement of the reduced-obese subjects (2171 kcal/d) was less than that for the control subjects (2280 kcal/d) despite the fact that they still weighed 60% more than the controls. In order to maintain a reduced weight, some reduced-obese or even partially reduced patients must restrict their food intake to approximately 25% less than that anticipated on the basis of metabolic body size. The reasons why this finding is unlikely to be an artifactual consequence of changes in lean body mass or body water content are discussed. This finding has implications with regard to the pathophysiology and treatment of obesity in humans.     

Energy Expenditure in Type 2 Diabetic Patients on Metformin and Sulphonylurea Therapy

Insulin and sulphonylurea therapies have both been reported to cause weight gain in Type 2 diabetic patients whereas metformin does not have this adverse effect. The mechanism for this difference is unclear. We have investigated in a cross-over study the effect of sulphonylurea and metformin therapy on energy expenditure and body composition in 10 Type 2 diabetic patients (7 females, 3 males) of various weights (mean body mass index 33.4 (SD 7.6 kg m^?2)). Free living total energy expenditure was measured over 14 days by the doubly labelled water method adjusted for urinary glucose energy losses and resting energy expenditure by ventilated hood indirect calorimetry. Overall, total energy expenditure (12.88 ± 4.17 vs 13.1 ± 3.69 MJ 24 h^?1) and resting metabolic rate (7.30 ± 1.75 vs 7.23 ± 1.74 MJ 24 h^?1) were similar on metformin and sulphonylurea therapy, respectively. When adjusted for differences in fat free mass, resting metabolic rate on sulphonylurea therapy was slightly but significantly lower (mean difference ?5.5 kJ 24 h^?1 kg^?1, 95% CI ?1.2, ?9.9 kJ 24 h^?1 kg^?1, p < 0.05). Fat free mass also increased significantly by 1.3 kg (95% CI 0.4, 2.4 kg, p < 0.05) when on sulphonylurea therapy, thus compensating for the lower resting metabolic rate per kg fat free mass to leave overall resting metabolic rate unchanged compared to metformin therapy. We also investigated the effect of adding metformin to six Type 2 diabetic patients already on insulin. This did not lead to any measurable changes in any of the components of energy expenditure. Our results suggested that the weight gain of 0.8 kg with sulphonylurea was secondary to a relatively greater energy intake and/or metabolizable energy availability, possibly augmented by a slightly lower resting metabolic rate when adjusted for differences in fat free mass.     

Exenatide has a pronounced effect on energy intake but not energy expenditure in non-diabetic subjects with obesity: A randomized,double-blind,placebo-controlled trial

AimsExenatide is a glucagon-like peptide 1 (GLP-1) mimetic which induces weight loss predominantly, it is presumed, via decreased food intake. However, circulating GLP-1 is also a determinant of energy expenditure. We sought to quantify the effect of exenatide on energy expenditure (EE) and energy intake.Materials and MethodsIn this single-center, randomized double-blind placebo controlled trial, we randomized 80 healthy, non-diabetic volunteers with obesity (46 women, age: 34.4 ± 8.7 y, body fat by DXA: 44.2 ± 7.8%) to subcutaneous exenatide 10 μg twice daily or placebo. Subjects were admitted to our clinical research unit for measurement of 24 h-EE in a whole-room indirect calorimeter and ad libitum food intake using an automated vending machine paradigm before and after randomization. Furthermore, energy expenditure and ad libitum food intake measures were repeated at 24-week after readmission for 7-day inpatient stay. Body weight was obtained weekly for up to 5 weeks and was recorded at each monthly follow up visit up to 24 weeks.ResultsPrior to randomization, participants over ate during the 3-day vending machine period in the whole study group (114.6 ± 35.2%), expressed as percentage of weight maintaining energy needs (WMEN) with those who were eventually randomized to exenatide overeating more (121.6 ± 37.7%) compared to placebo group (107.6 ± 31.5%). In the exenatide group, ad libitum absolute energy intake decreased by 1016.1 ± 724.5 kcal/day (95% CI: −1250.9 to −781.2) versus a 245.1 ± 710.5 kcal/day (95% CI: −475.4 to −14.7) decrease in placebo (Δ = −624.8 Kcal/day, p < 0.0001) whereas the reduction in ad libitum caloric intake relative to WMEN was a more modest 366.8 ± 752.1 kcal/day (95% CI: −614.0 to −119.6) decrease compared to 8.0 ± 860.1 kcal/day (95% CI: −286.8 to 270.8) reduction in placebo (Δ = −382.3 Kcal/day, p = 0.03). The decrease was uniform across all macronutrients groups.No differences in 24hEE or substrate oxidation rates were found. In the exenatide group, body weight decreased more over the 5 weeks (β = −0.039 kg/week, p = 0.02) and was lower compared to placebo at the end of fifth week (−1.48 ± 0.77 kg; 95% CI: −3.02 to 0.05, p = 0.06).At the 24-week follow up, there was no difference in energy intake between exenatide group and placebo group and the treatment group decreased 24-h EE more compared to placebo (β = −160.6 Kcal/day, 95% CI: −307.6 to 13.6, p = 0.03) compared to their pre-randomization measurement. However, this reduction was not present after adjustment for changes in FM and FFM (β = −87 kcal/day, p = 0.14). No difference was observed in body weight (Δ = −1.72 kg, 95% CI: −5.77 to 2.30, p = 0.39) in exenatide versus placebo over 24 weeks.ConclusionCompared with placebo, exenatide decreased early ad libitum energy intake but did not change 24 h-EE. However, the reduction was more modest in relative versus absolute terms (i.e. below that needed for WMEN). Thus, although rate of weight change was greater in the exenatide treated subjects at 5 weeks, the absolute difference in weight was not significant. These findings indicate that although exenatide reduces food intake, it may be more beneficial in blunting overeating and thus may serve to more prevent weight regain following initial weight loss.     

Influence of age in estimating maximal oxygen uptake

Objective To assess the influence of age on the error of estimate (EE) of maximal oxygen uptake (VO₂max) using sex and population specific-equations in cycle ergometer exercise testing, since estimated VO₂max is associated with a substantial EE, often exceeding 20%, possibly due to intrinsic variability of mechanical efficiency. Methods 1850 adults (68% men), aged 18 to 91 years, underwent maximal cycle ergometer cardiopulmonary exercise testing. Cardiorespiratory fitness (CRF) was assessed relative to sex and age [younger (18 to 35 years), middle-aged (36 to 60 years) and older (> 60 years)]. VO₂max [mL?(kg?min)^?1] was directly measured by assessment of gas exchange and estimated using sex and population specific-equations. Measured and estimated values of VO₂max and related EE were compared among the three age- and sex-specific groups. Results Directly measured VO₂max of men and women were 29.5 ± 10.5 mL?(kg?min)^?1 and 24.2 ± 9.0 mL?(kg?min)^?1 (P < 0.01). EE [mL?(kg?min)^?1] and percent errors (%E) for men and women had similar values, 0.5 ± 3.2 and 0.4 ± 2.9 mL?(kg?min)^?1, and ?0.8 ± 13.1% and ?1.7 ± 15.4% (P > 0.05), respectively. EE and %E for each age-group were, respectively, for men: younger = 1.9 ± 4.1 mL?(kg?min)^?1 and 3.8 ± 10.5%, middle-aged = 0.6 ± 3.1 mL?(kg?min)^?1 and 0.4 ± 10.3%, older = ?0.2 ± 2.7 mL?(kg?min) ^?1 and ?4.2 ± 16.6% (P < 0.01); and for women: younger = 1.2 ± 3.1 mL?(kg?min) ^?1 and 2.7 ± 10.0%, middle-aged = 0.7 ± 2.8 mL?(kg?min)?1 and 0.5 ± 11.1%, older = -0.8 ± 2.3 mL?(kg?min)^?1 and ?9.5 ± 22.4% (P < 0.01). Conclusion VO₂max were underestimated in younger age-groups and were overestimated in older age groups. Age significantly influences the magnitude of the EE of VO₂max in both men and women and should be considered when CRF is estimated using population specific equations, rather than directly measured.     

Weight maintenance after a very low calorie diet (VLCD) weight reduction period and the effects of VLCD supplementation: A prospective,randomized, comparative,controlled long-term trial

Abstract. Objectives . To evaluate the efficacy of a structured very low calorie diet (VLCD) weight reduction/weight maintenance behaviour programme on weight maintenance in obese patients (BMI ≥ 30 kg/m²). Design . Prospective, randomized, controlled intervention trial. Setting . University out-patient obesity clinic. Subjects . A total of 114 obese patients from the waiting list were invited to participate in the structured weight reduction/weight maintenance programme lasting for 64 weeks. Sixty patients agreed to participate. Intervention . All 60 patients were placed on a Cambridge 330 kcal day^-1diet during the first 12 weeks. Fifty-two were subsequently randomized to either a well balanced hypocaloric diet (1600 kcal day^-1), of which 220 kcal were provided by two sachets of Cambridge diet (group 1), or the same energy provided by the same principal diet (group 2) during the following 52-week weight maintenance period. Main outcome measures . During the VLCD period, the mean body weight decreased significantly from 112.4 ± 19.8 to 91.6 ± 17.7 kg (P < 0.0001). Seventy-one per cent of the weight loss was fat. During the weight maintenance period the average body weight increased significantly in group 1: 8.0 ± 8.2 vs. 12.3 ± 9.7 kg in group 2 (P < 0.0001). After the 64-week treatment period the mean body weight in group 1 was 93.7 ± 18.1 kg and significantly lower compared to 109.9 ± 23.8 kg in group 2 (P = 0.008). Compliance was high: 87% completed the VLCD period and 75% completed the whole 64-week treatment programme. Conclusion . Very low calorie diet as part of the dietary allowance during the weight maintenance programme partly prevents weight regain. This finding can be translated into practical treatment recommendations.     

Similarity in Gallstone Formation from 900 kcal/day Diets Containing 16 g vs 30 g of Daily Fat (Evidence that Fat Restriction Is Not the Main Culprit of Cholelithiasis During Rapid Weight Reduction)

Diets containing essentially no fat, 1-2 g fatper day, have resulted in cholesterol gallstones.Greater fat may result in less gallbladder stasis. Dogallstones form with greater fat content? We studied 272 moderately obese subjects who had normalgallbladder ultrasonograms. The 900 kcal/day liquiddiets contained either 16 g fat (N = 94) or 30 g fat (N= 178) each day for 13 weeks. A second gallbladderultrasound was performed. Sixteen of 94 (17.0%) of the16-g fat group developed stones with a weight loss of 18(±7) kg and a body mass index (BMI) decrease of6 (±2) kg/m². Twenty of 178 (11.2%) ofthe 30-g fat group developed stones (P = 0.18, no differencein stone formation) with similar weight loss of 20(±7) kg (P = 0.08) and BMI decrease of 7(±2) kg/m² (P = 0.04). Substantial fatfor rapid weight-reducing diets resulted in gallstone formation. Sinceexperiments have shown that our higher fat diet,containing 10 g fat per meal, results in maximalgallbladder emptying, cholelithiasis from rapid weightloss may not be solely attributable to gallbladderstasis.     

Role of sympathetic cardiovascular tone in control of arterial pressure in rats with cirrhosis

Abstract: Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg · kg^-1 · min^-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356±50 vs 166±30 pg/ml, p=0.04) than in normal rats (186±23 vs 86±31 pg/ml, p=0.06) and rats with portal vein stenosis (103±37 vs 93±5 pg/ml, p=0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg · kg^-1 · min^-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25±2%) than in normal rats (-11±1%) and in rats with portal vein stenosis (-13±2%) (p=0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.     

Proof-of-concept trial on the efficacy of sodium tungstate in human obesity

Aim: Considering the poor long‐term success of current dietary and pharmacological interventions, we aimed to evaluate the potential effect of sodium tungstate in the treatment of grade I and II obesity ( ClinicalTrials.gov identifier: NCT00555074). Methods: Prospective, randomized, placebo‐controlled, double‐blind, proof‐of‐concept study was carried out. Following a 2‐week lead‐in period, 30 obese (body mass index, BMI 30.0–39.9 kg/m²), non‐diabetic subjects were randomized to receive either sodium tungstate (100 mg bid) or placebo for 6 weeks. The primary study endpoint was the absolute change in body weight relative to the time of randomization. Results: Treatment with sodium tungstate [?0.135 ± 0.268 kg (95% CI ?0.686 to +0.416 kg)] was not associated with a significant weight loss compared to placebo [?0.063 ± 0.277 kg (95% CI ?0.632 to +0.507 kg)] (p = 0.854). Likewise, treatment with sodium tungstate was not associated with significant changes in fat mass (DEXA), resting energy expenditure (indirect calorimetry) or caloric consumption (3‐day food records). Conclusion: Our data do not support sodium tungstate as a pharmacological agent in the treatment of human obesity.     

Increase in skeletal muscle fatty acid binding protein (FABPC) content is directly related to weight loss and to changes in fat oxidation following a very low calorie diet

Aims/hypothesis: There is increasing evidence that intracellular fatty acid binding proteins (FABPc's; 15 kD) function as vehicles of cytosolic fatty acid transport. We studied skeletal muscle cytosolic FABPc, and enzymes reflecting β-oxidation and oxidative capacity (3-hydroxyacyl-CoA dehydrogenase, HAD, and citrate synthase, CS) in relation to weight loss and changes in substrate utilisation in a group of 35 obese women and obese men with Type II (non-insulin-dependent) diabetes mellitus (women = 27, men = 8). Methods: Muscle biopsies (vastus lateralis), and measurements of body composition, resting energy expenditure and respiratory exchange ratio were taken before and after dietary intervention (by means of a very low calorie diet). Results: Muscle FABPc tended to increase after diet (178 ± 13 vs 204 ± 12 mg^.gww^–1, p = 0.06), whereas there were no changes in CS (10.5 ± 0.7 vs 11.1 ± 0.6 U^.gww^–1) and HAD (11.2 ± 0.7 vs 11.7 ± 0.6 U^.gww^–1). There was a positive relation between the increase in FABPc as result of diet and the amount of weight lost (p < 0.01; adjusted R², 15.4 %), even when adjusted for mean body weight, and changes in CS and in HAD by partial regression analysis. Interestingly, the increase in FABPc was positively related to increases in resting fat oxidation (adjusted R², 24 %), even when adjusted for mean resting fat oxidation, and changes in CS and in HAD. Conclusion/interpretation: In conclusion, the ability to increase muscle FABPc could be directly related to weight loss and to changes in fat oxidation following dietary intervention in obesity and Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2001) 44: 2013–2017] Received: 4 May 2001 and in revised form: 17 July 2001     

Influence of weight loss on myocardial performance index

Obese patients may have a phase of asymptomatic left ventricular dysfunction. A combined myocardial performance index (MPI) has been demonstrated to be a useful index to estimate left ventricular function and to predict the prognosis of patients with heart failure. The objective of the study was to determine the influence of weight loss on MPI. A total of 18 obese patients (3 men, 15 women, mean age 49.6 ± 5.5 years, body mass index [BMI] >30 kg/m²) were investigated in the study. All patients were treated with a multidisciplinary approach consisting of a hypocaloric diet and orlistat therapy (120 mg three times daily), and all of them underwent two-dimensional and Doppler echocardiographic examination two times before starting the study and after a period of weight loss. Using echo-Doppler methods, ejection fraction, peak velocities of early (E) and late (A) diastolic filling, the E/A ratio, deceleration time (DT), isovolumic contraction time (IVCT), isovolumic relaxation time, ejection time, and MPI were measured. The MPI was obtained by subtraction ejection time from the interval between cessation and onset of the mitral flow. All patients lost at least 10% of their initial body weight, with a mean decrease of 10.8 ± 3.7 kg. This was associated with significant reductions in BMI with a mean decrease 4.5 ± 1.4 kg/m². Compared with baseline, after weight loss the E/A ratio of 1.01 ± 0.22 before treatment increased to 1.17 ± 0.26 (P = 0.012), left ventricular mass index decreased from 88 ± 23 to 82 ± 19 g/m² (P = 0.028), IVCT from 71 ± 20 to 53 ± 30 ms (P = 0.004), DT from 233.65 ± 38.14 to 196.72 ± 47.73 s (P = 0.004), and MPI from 0.63 ± 0.13 to 0.50 ± 0.13 (P = 0.0001). Weight loss ameliorates MPI and seems to be a clinically relevant measurement of left ventricular global function, and may prove to be a valuable tool in assessing the risk of developing heart failure.     

The effect of metabolic control on leucine metabolism in Type 1 (insulin-dependent) diabetic patients

Summary Leucine production rate, metabolic clearance rate and oxidation rate were measured in 10 Type 1 (insulin-dependent) diabetic patients after (1) 24 h insulin withdrawal, (2) conventional insulin therapy and (3) an overnight insulin infusion to maintain normoglycaemia, and in 10 control subjects. In the insulin-withdrawn patients, leucine concentration (259 ± 17 μmol/1), production rate (2.65 ± 0.29 p mol·min⁻¹ kg⁻¹) and oxidation rate (0.69 ± 0.10 μmol · min⁻¹ · kg⁻¹) were significantly greater (p < 0.001;p < 0.05;p < 0.005 respectively) than corresponding values in control subjects (127±6; 1.81 ± 0.12; 0.19 ± 0.02). Following conventional insulin therapy, leucine concentration (162 ± 12 μmol/1) and oxidation rate (0.43 ± 0.05 μmol · min⁻¹ · kg⁻¹) were lower than after insulin withdrawal but were still significantly greater than in control subjects (p<0.05;p<0.005). Although leucine concentration, production rate and metabolic clearance rate were normal after an overnight insulin infusion, leucine oxidation rate was still greater than normal (0.34 ± 0.06 μmol · min⁻¹ kg⁻¹;p<0.05). These results suggest that increased leucine concentration in insulin deficiency is due to elevated leucine production rate caused by increased proteolysis, and that leucine concentration is restored to normal by insulin treatment.     

Hypertension in cyclosporin A-treated patients is independent of circulating endothelin levels

Abstract. Objectives. To measure blood pressure (BP), plasma endothelin-1 (ET-1), atrial natriuretic peptide (ANP), antidiuretic hormone (ADH) and aldosterone (ALDO) concentration, and plasma renin activity (PRA) in patients treated with a low-dose cyclosporin A (CyA). Design. An open study of patients with rheumatoid arthritis (RA) or palmoplantar pustulosis (PPP). Setting. Out-patient clinics at the Central Hospital of Jyväskylä and Helsinki University Central Hospital. Subjects. CyA was given to 25 patients with RA and to 10 patients with PPP. Intervention. RA patients were given CyA at a dose of 2.5±0.13 mg kg^?1 body weight (BW) to 3.47±0.79 mg kg^?1 BW (mean values±SD) at the start of the study and after 6 months, respectively, and the CyA dose was 2.67±0.13 mg kg^?1 BW decreasing to 2.07±0.96 mg kg^?1 (P < 0.001) after 4 months in PPP subjects. Results. Systolic (sBP) and diastolic blood pressure (dBP) increased from 127.8±13.6/79.7±8.4 mmHg to 140.0±19.8/83.8±9.7 mmHg during the study (P < 0.03). Plasma ET-1, ANP, ALDO and ADH concentration and PRA did not change during 4 to 6 months of CyA treatment. The plasma ANP concentration was constantly higher in CyA-treated RA patients (112±87 ng l^?1) to 118±78 ng l^?1) than in PPP patients (37.3±26 ng l^?1 to 47.7±39.9 ng l^?1; P < 0.02). The serum creatinine concentration remained within the normal range, but increased from baseline (76.7±11.9 μmol l^?1), to 90±15.4 μmol l^?1 (P < 0.001). The serum magnesium concentration decreased significantly (P < 0.005) after 6 months of CyA treatment in RA patients. No correlation was found between serum creatinine and plasma ET-1 concentration. Conclusions. Increased blood pressure during CyA treatment was independent of circulating ET-1 levels. A low dose of CyA did not induce increased ET-1 synthesis as judged from plasma samples. The high plasma ANP level observed in RA patients could be due to fluid retention caused by concomitant treatment with non-steroid anti-inflammatory drugs. Fluid retention and decreased magnesium levels could also be involved in the development of hypertension in CyA-treated subjects.     

Reductions in Blood Pressure Following Energy Restriction for Weight Loss Do Not Rebound after Re-Establishment of Energy Balance in Overweight and Obese Subjects

Objective.?The objective of the present study was to elucidate the separate effects of energy restriction and weight loss on blood pressure (BP) and to assess the relationship between sodium intake, weight loss, and BP.?Methods.?Two hundred and eight overweight and obese subjects (age: 52.4 ± 0.8 yrs; BMI 33.6 ± 0.3 kg/m²) completed a weight loss diet program consisting of 8–12 weeks of moderate energy restriction (ER; ～30% energy deficit, unrestricted salt intake) and four weeks of energy balance (EB). Body weight and BP were measured at baseline, the midpoint, and the end of ER and after EB. 24-hr Na+ excretion was measured at baseline and at the end of EB.?Results. Overall, body weight reduced progressively by 7.0 ± 0.2 kg (7.5%; p?<?0.001) with the hypocaloric diet. BP fell substantially during the first phase of ER (?5.7 ± 0.7/?2.6 ± 0.4 mmHg, p = 0.001), corresponding to a 4.5 ± 0.2 kg weight reduction, with no further BP changes during the second phase of ER, despite further weight loss (2.4 ± 0.1 kg). During EB, BP remained stable. The hypotensive effects of caloric restriction and weight loss were similar across clinical subgroups defined by age, sex, diabetes, insulin sensitivity, and hypertensive status. BP responses to weight loss were independent of 24-hr urinary Na+ excretion. 24-hr urinary Na+ excretion was similar at baseline and at the end of EB (146.5 ± 5.3 vs. 146.9 ± 5.3 mmol/24-hr).?Conclusion.?The hypotensive effects of caloric restriction do not rebound upon return to eucaloric intake at a reduced body weight, and a high sodium intake does not appear to alter the hypotensive effects of weight loss. This reinforces the clinical importance of weight loss and supports the recommendation that strategies for promoting long-term weight loss should become the primary focus of dietary efforts to control BP in overweight patients.     

Protein intake during aggressive calorie restriction in obesity determines growth hormone response to growth hormone-releasing hormone after weight loss

OBJECTIVE We evaluated the influence of two types of calorie restriction, total fast or very low calorie diet, on GH responsiveness to GHRH in severely obese patients. DESIGN Twenty patients with massive obesity underwent one of two types of calorie restriction, total fast (10 patients) or very low calorie diet (10 patients). MEASUREMENTS Fasting GH, IGF-I, glucose, insulin and GH secretion after GHRH (100 ug i.v.) were assessed in all patients before and after diet therapy. RESULTS Both types of diet produced similar weight reduction (total fast, 5.6 ± 1.6 kg/m²vs very low calorie diet, 5.6 ± 1.5 kg/m² mean ± SD). A significant increase in the integrated GH secretion was observed after weight-loss with very low calorie diet (17 ± 9 vs27 ± 12mU/l min; P < 0.05). However, no change was found in GH response after weight loss with total fast (13 ± 5 vs 15 ± 7 μ/l min). Glucose, insulin and IGF-I levels showed a significant decrease with weight reduction which was similar for both groups. CONCLUSION These findings suggest that the type of dietary manipulation during calorie restriction in obese patients may influence the changes in GH response to GHRH after weight loss.     

Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs

Aims/hypothesis In non-diabetic people, insulin levels in the liver are two-fold higher than those in the systemic circulation. In contrast, patients with type 1 diabetes have similar hepatic and systemic insulin levels because insulin is administered peripherally. The aim of this study was to compare the effects of systemic (SI) and pre-portal (PI) insulin administration on energy, glucose and protein metabolism in chronic insulin-dependent ketosis-prone diabetic dogs. Materials and methods We applied glucose-controlled insulin infusion, indirect calorimetry and stable isotope and radioisotope techniques to measure energy, protein and glucose metabolism. We maintained near-normoglycaemia at identical levels under both study conditions for 20 h. Results SI was associated with lower oxygen consumption (130±13 vs 161±8 ml/min), CO₂ production (99±10 vs 130±8 ml/min), respiratory quotient (0.76±0.02 vs 0.81±0.01) and energy expenditure (870±90 vs 1089±60 kcal/24 h) (p<0.05 for all differences). PI increased the respiratory quotient from the insulin-deprived state, whereas SI did not. Glucose kinetics were similar for SI and PI, whereas leucine oxidation (36±4 vs 54±5 μmol kg⁻¹ min⁻¹) and the fractional synthesis rates of liver tissue protein (0.68±0.6 vs 0.83±0.07%/h), albumin (0.55±0.06 vs 0.68±0.4%/h), and fibrinogen (1.73±0.23 vs 2.59±0.25%/h) were all lower during SI than PI (p<0.05). Conclusions/interpretation The route of insulin administration did not alter glucose metabolism but did affect protein synthesis in the liver. The potential impact of this altered liver protein metabolism on chronic complications needs careful evaluation. A similar decrease in energy expenditure resulting from systemic insulin administration during tight glycaemic control is a potential cause of weight gain.     

Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice

Summary. N8 is a new recombinant factor VIII (rFVIII) compound produced and formulated without human‐ or animal‐derived protein. The aims of the present studies were to evaluate the pharmacokinetics and pharmacodynamics properties of N8 and to compare with a commercially available rFVIII product (Advate^®) in haemophilia A mice. The pharmacokinetics were evaluated after single i.v. administration of 80, 120 and 280 IU kg^?1 of N8 and Advate^® and measurements of FVIII blood concentrations as a function of time. The efficacy and dose response curves of N8 and Advate^® (1–200 IU kg^?1) were evaluated in a tail bleeding model. Furthermore, the effects in a newly developed haemophilia knee joint haemarthrosis model were investigated. No significant differences were found in the pharmacokinetic parameters between N8 and Advate^®. The clearances were 11 ± 1 vs. 10 ± 2 mL h^?1 kg^?1 (P = 0.14) and the half‐lives 7.2 ± 0.9 vs. 7.7 ± 1.4 h (P = 0.31) after administration of N8 and Advate^® respectively. Dose‐independent pharmacokinetics was shown, and comparable efficacy and potency were shown between N8 and Advate^® in the tail bleeding model. Both compounds normalized the bleeding at the dose of 200 IU kg^?1, and for blood loss ED₅₀ values of 27 IU kg^?1 (N8) and 28 IU/kg (Advate^®) were found (P = 0.97). In the haemarthrosis model, treatment with N8 and Advate^® at 200 IU kg^?1 reduced the mean increase in the joint diameter significantly from 1.23 ± 0.19 to 0.32 ± 0.08 mm (P < 0.01) and 0.25 ± 0.08 mm (P < 0.001) respectively. Pharmacokinetics and pharmacodynamics of N8 and Advate^® were comparable after i.v. administration to haemophilia A mice.     

Tonic and Phasic Pyloric Activity in Response to CCK-Octapeptide

Background The purpose of this study was to determine whether a high-resolution solid-state catheter system could detect regional pressure changes within the antrum and pylorus in response to CCK-octapeptide. Methods Subjects received a 30 min infusion of CCK-octapeptide at either 0.02 or 0.06 μg kg⁻¹ h⁻¹. Results Five males and two females were studied. Mean antral pressure during phase I MMC increased from 5.3 ± 2.1 to 9.9 ± 2.4 mmHg (P = 0.028) after infusion. At the pylorus, only the 0.06 μg kg⁻¹ h⁻¹ dose increased tonic pressure (8.8 ± 1.4 to 17.6 ± 2.0 mmHg; P = 0.01) as compared with the 0.02 μg kg⁻¹ h⁻¹ dose (4.7 ± 0.7 to 7.3 ± 0.4 mmHg; P = NS). The peak pressure of pyloric phasic pressure waves was 153 ± 28.4 mmHg and their frequency was 4.9 ± 1.1 contractions min⁻¹. Conclusions CCK-octapeptide elicits both tonic and phasic activity of the pyloric sphincter. The contractile response to a dose of 0.06 μg kg⁻¹ h⁻¹ is greater than the response to 0.02 μg kg⁻¹ h⁻¹.     

The effect of anti‐inflammatory (aspirin and/or statin) therapy on body weight in Type 2 diabetic individuals: EAT,a retrospective study

Aims Obesity is associated with inflammation. Anti‐inflammatory interventions such as aspirin and statins (anti‐IFRx) might be a novel approach to the treatment of obesity and Type 2 diabetes mellitus (T2DM). The present study was designed to determine whether exposure to anti‐IFRx is associated with weight loss in T2DM patients. Methods Exposure to anti‐IFRx was compared between T2DM patients with a history of weight loss (n = 100) and those with no weight loss or with weight gain (n = 102) during a 1‐year follow‐up period. Logistic regression was used to develop odds ratios for weight loss status. Results Subjects who lost weight were more frequently exposed to anti‐IFRx (85.0 vs. 71.5%, P = 0.018) than subjects who maintained or gained weight during follow‐up. The 158 subjects exposed to anti‐IFRx were older (64.2 ± 9.4 vs. 60.6 ± 11.2 years, P = 0.04), had longer duration T2DM (14.5 ± 9.5 vs. 9.0 ± 9.4 years, P = 0.001), had greater prevalence of dyslipidaemia (72 vs. 19%, P < 0.0001) hypertension (57.3 vs. 38.1%, P = 0.03) and cardiovascular disease (37.7 vs. 9.5%, P < 0.0001) than subjects not exposed to anti‐IFRx. In a logistic regression model for weight change status, anti‐IFRx exposure was significantly associated with weight status (odds ratio = 2.3, 95% confidence interval 1.1–4.8, P = 0.02, an association that persisted), even after controlling for age, sex, baseline body mass index, years since diagnosis, OHA therapy and co‐morbidities. Conclusions Exposure to anti‐IFRx more than doubled the odds of weight loss in T2DM patients. Results of this study justify a randomized clinical trial to determine definitively the role of anti‐IFRx in weight loss in subjects with T2DM.