Energy, substrate and protein metabolism in morbid obesity before, during and after massive weight loss.

OBJECTIVE: To investigate the effect of surgically induced weight loss on energy, substrate and protein metabolism of morbidly obese patients. DESIGN: A prospective, clinical intervention study of morbidly obese patients before and after surgical treatment. SUBJECTS: Eight morbidly obese patients (BMI 47.88+/-7.03). METHODS: Total energy expenditure (TEE; doubly labeled water method), sleeping metabolic rate (SMR; respiration chamber), body composition (deuterium oxide component of doubly labeled water), substrate metabolism (48 h dietary records, 48 h urine collection and gaseous exchange in the respiration chamber) and whole body protein turnover (primed-continuous infusion of L-[1-13C]-leucine) were measured before, 3 and 12 months after vertical banded gastroplasty (VBG). RESULTS: The TEE decreased as a result of a decreased SMR (64%) and non-SMR (36%; P=0.001). SMR as a function of fat-free mass (FFM) decreased after weight loss (P<0.05). The physical activity index (PAI), defined as TEE/SMR, was low and was not influenced by weight loss. Protein and carbohydrate oxidation decreased significantly after VBG (P<0.05), although 3 months after VBG protein oxidation did not decrease enough to prevent loss of FFM. The energy used for protein turnover was approximately 24% of SMR and did not change after weight loss. CONCLUSIONS: Compensatory processes that oppose weight loss of morbidly obese patients exist, as demonstrated by the disproportional reduction of SMR, and a low PAI. Protein turnover is not a major contributor to the disproportional reduction of SMR.

Glutamine appearance rate in plasma is not increased after gastrointestinal surgery in humans.

The metabolic response to surgical stress is characterized by muscle protein breakdown and mobilization of amino acids and has been postulated to furnish glutamine and other amino acids to the immune system, gut and liver. The present study was undertaken to investigate whether the whole body appearance rate (R(a))(3) of glutamine in plasma is increased after major elective surgery. Fourteen patients (8 males, 6 females) were measured prior to laparotomy and on the second postoperative day. Patients received a primed continuous 6-h infusion of L-[5-(15) N]glutamine and L-[1-(13)C]leucine, and arterial blood samples and muscle biopsies were taken for concentration and enrichment measurements. As expected, the metabolic response to surgery was characterized by a rise in whole body protein breakdown (n = 14, P < 0.001) and a decreased concentration of glutamine in plasma (n = 14, P < 0.001) and muscle (n = 8, P < 0.01). However, these catabolic changes were not reflected by an increase in the plasma R(a) of glutamine: 246 +/- 8 micromol. kg(-1). h(-1) before surgery vs. 241 +/- 10 micromol. kg(-1). h(-1) on the second postoperative day. We conclude that the whole body R(a) of glutamine in plasma is not increased 2 d after elective gastrointestinal surgery. Further studies are warranted to establish whether the lack of an increase in plasma glutamine R(a) provides a rationale for glutamine supplementation.

Nutritional depletion and dietary manipulation: effects on the immune response.

The association between nutritional depletion and the increased susceptibility for infectious diseases has been recognized for a long time. The complexity of the immune system, however, makes it difficult to unravel the underlying mechanisms. It appears that depletion adversely affects virtually all components of the immune system. This review provides an overview over the specific requirements of substrates by immune cells and the effects of nutritional depletion on various components of the immune response, with special attention to gut-associated lymphoid tissue. The literature concerning effects of dietary interventions with specific nutrients on the immune response is also discussed. Finally, we offer a hypothesis with regard to the improvement of composition of "trauma" nutrition solutions.

Absence of glutamine isotopic steady state: implications for the assessment of whole-body glutamine production rate.

1. During infusion of [5-15N]glutamine in patients with gastrointestinal cancer we unexpectedly observed a gradual decrease in time of the appearance rate (Ra) of glutamine in plasma. Here we investigate whether the failure to achieve a plateau isotopic enrichment in plasma is, among other factors, due to incomplete equilibration of the glutamine tracer with the large intramuscular free glutamine pool.2. Plasma and intramuscular glutamine enrichment were measured during 6-11 h infusions of L-[5-15N]glutamine and L-[1-13C]glutamine in post-absorptive patients admitted to hospital for elective abdominal surgery. L-[1-13C]Leucine and L-[ring-2H5]phenylalanine were infused to measure the proportion of glutamine appearing in plasma directly due to its release from protein.3. The glutamine tracer entered muscle, but the rise in intramuscular glutamine enrichment was small, presumably as a result of the enormous size of the intramuscular glutamine pool and the limited speed of entry of glutamine into muscle. In each patient the intramuscular glutamine enrichment was lower than that in plasma (P<0.001), and both increased with tracer infusion time (P<0.001), indicating incomplete equilibration of the glutamine tracer.4.A comparison of the results obtained by the two glutamine tracers indicated that recycling of the nitrogen label contributed to about 15% of the decrease in Ra.5. There was a gradual reduction in the glutamine release from proteolysis, which contributed to 16-21% of the decline in Ra.6. We conclude that slow equilibration of the glutamine tracer with the large muscle glutamine pool significantly contributes to the absence of isotopic steady state. Consequently, the appearance rate of glutamine in plasma measured during short tracer infusion periods (hours) considerably overestimates the whole-body glutamine flux.

Contribution of tubular anion and cation secretion to residual renal function in chronic dialysis patients.

The clearance of organic ions by the tubules may contribute to the removal of uremic waste products in dialysis patients. The renal excretion of an exogenous anion p-aminohippurate (PAH) was investigated in 10 peritoneal dialysis patients and 10 hemodialysis patients during one clearance period and compared with the clearance of creatinine (Ccr) and inulin (CIn). The clearance period was 24 hours in the peritoneal dialysis patients and one interdialytic interval of 3 days divided in 4 parts [CPA-D] in hemodialysis patients. In peritoneal dialysis patients the renal clearance of total PAH (median 14.3 ml/min, range 3.8-33.0) exceeded the CIN (median 3.2 ml/min, range 1.6-11.2, p < 0.005) and Ccr (median 4.0 ml/min, range 1.7-15.0, p < 0.005). A positive correlation was found between the tubular clearances of creatinine (cationic pathway) and of total PAH (anionic pathway, r: 0.72, p <0.02). In hemodialysis patients the clearance of total PAH (CPA: median 2.0, range 0.8-9.6; CPD: median 3.8, range 1.7-15.4) also exceeded the clearance of inulin (CPA: median 1.5, range 0.2-3.4; CPD: median 2.7, range 0.9-4.4) in the beginning and the end of the interdialytic interval (p < 0.005). The CIN and the clearance of total PAH increased during the interdialytic interval, but the Ccr (CPA: median 2.2, range 0.4-8.9, CPD: median 2.9, range 1.2-4.6) remained stable. Thus, the change in tubular clearance of creatinine and PAH was opposite during the interdialytic interval: it increased for total PAH and decreased for creatinine. The CTPAH/CIN ratio in hemodialysis patients was lower than in peritoneal dialysis patients. In CPA it was median 1.6 (range 1.1-5.6, p < 0.05) and in CPD it was median 1.7 (range 1.1-5.0, p < 0.02) and in the peritoneal dialysis patients it was median 3.6 (range 1.5-9.1). We conclude that tubular clearances contribute to the residual renal function in dialysis patients, but the tubular handling of anions and cations in relation to the residual GFR is different between peritoneal and hemodialysis patients. A difference in clearance of organic acids caused by the dialysis techniques may be an explanation for the differences in clinical outcome between the two dialysis modalities.

In vivo inter-organ protein metabolism of the splanchnic region and muscle during trauma, cancer and enteral nutrition.

The study of protein kinetics has entered a new era by the recognition that whole body protein turnover only poorly reflects the true events occurring in several organs and with regard to the multitude of proteins present in the body. It is also increasingly recognized that the simultaneous synthesis and degradation of proteins is important in regulation and adaptation during several metabolic conditions like starvation, feeding, after trauma, and during exercise. Especially important is the recognition that the kinetics of individual proteins may change in opposite directions, thereby leading to fluxes of alpha-amino-nitrogen that serve to adapt to and survive a changing environment. At present, much emphasis is put upon molecular biological regulation. However, it is important that the metabolic processes that occur in the intact organism are still poorly defined. New technology allows the exploration of these processes, which should therefore prompt the initiation of further research in this area.

Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09.

BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.

Effect of prednisone on renal function in man.

To clarify the rise in plasma creatinine concentration previously observed during prednisone treatment, we studied changes in renal function in Graves' ophthalmopathy patients before and after 2 weeks of either prednisone 60 mg/day or retrobulbar radiotherapy (controls). Compared to retrobulbar radiotherapy, prednisone treatment was associated with an increase in: (a) plasma creatinine concentration (from 68 +/- 4 to 76 +/- 4 mumol/l), (b) glomerular filtration rate (GFR, from 93 +/- 4 to 102 +/- 5 ml/min/1.73 m2), and (c) urinary creatinine excretion rate (from 510 +/- 40 to 570 +/- 40 mumol/h). We conclude that GFR rises during 2 weeks of high-dose prednisone administration, a rise that is not reflected by a decrease in plasma creatine concentration. On the contrary, both plasma creatinine concentration and urinary creatinine excretion increase, probably as a result of the catabolic effect of prednisone. As established by the present study, prednisone 60 mg/day is associated with protein wasting, also after 14 days of treatment.

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate.

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/Cll) ranged from 1.14 to 2.27. With cimetidine, ClC/Cll approached unity in 8 patients (mean 1.02 [SD 0.03]), but considerably exceeded unity in 8 others (1.33 [0.14]). Plasma cimetidine/creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p = 0.01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibited previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures GFR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

The effect of fish oil on lipid profile and viscosity of erythrocyte suspensions in CAPD patients.

In this study we investigated the effects of a daily supplementation of 6 g Super-EPA containing 3 g of the marine fatty acids eicosapentaenoic acid (EPA, C 20:5 omega-3) and docosahexaenoic acid (DHA, C 22:6 omega-3) for a period of 8 weeks in nine patients on continuous ambulatory peritoneal dialysis. The concentrations of both HDL2 cholesterol and total HDL cholesterol increased (P less than 0.05) and there was a marked reduction in triglycerides (P less than 0.05). The viscosity of erythrocyte suspensions at a haematocrit of 0.80 decreased at most shear rates, suggesting an increased erythrocyte deformability. Mean corpuscular volume decreased (P less than 0.05) and total cholesterol and phospholipids in the erythrocyte membrane increased. We conclude that the daily use of 3 g of omega-3 polyunsaturated fatty acids by CAPD patients produces favourable effects on lipid profile and viscosity of erythrocyte suspensions, which may be of importance in protecting these patients against a further progression of atherosclerosis.