Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes.

Transcription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, primarily through impairing the insulin secretion by pancreatic ß cells. However, the exact in vivo mechanisms remain poorly understood. We performed a family study and determined if the T risk allele of the rs7903146 in the TCF7L2 gene increases the risk of type 2 diabetes based on real-time stable isotope measurements of insulin synthesis during an Oral Glucose Tolerance Test. In addition, we performed oral minimal model (OMM) analyses to assess insulin sensitivity and ß cell function indices. Compared to unaffected relatives, individuals with type 2 diabetes had lower OMM indices and a higher level of insulin synthesis. We found a T allele-dosage effect on insulin synthesis and on glucose tolerance status, therefore insulin synthesis was higher among T-allele carriers with type 2 diabetes than in wild-type individuals. These results suggest that hyperinsulinemia is not only an adaptation to insulin resistance, but also a direct cause of type 2 diabetes.

A stable isotope method for in vivo assessment of human insulin synthesis and secretion.

AIMS: In vitro, beta cells immediately secrete stored but readily releasable insulin in response to a rise of glucose. During a prolonged insulin response, this is followed by newly synthesized insulin. Our aim was to develop an in vivo test to determine the ratio between readily available and newly synthesized insulin after a stimulus in humans by labelling newly synthesized insulin. METHODS: A stable isotope tracer of 1.0 g 13C leucine with C-peptide as target peptide was administered 45 min prior to 75 g glucose load of a frequently blood sampled 210-min oral glucose tolerance test (OGTT). Our OGTT also encompassed collection of urine, which has a high content of C-peptide. Prior, the optimal conditions under which the tracer 13C leucine was administered for enrichment of (pre) proinsulin were established. Also, techniques to obtain urinary C-peptide under highly purified circumstances were set up. Our main outcome measure was the stable isotope enrichment of de novo C-peptide, which we related to early plasma insulin and glucose AUC. Twelve healthy Caucasian individuals (M4F8, age 41.8 ± 2.3, BMI 28.3 ± 1.7) with normal glucose tolerance underwent our OGTT. RESULTS: We found that during a 75-g OGTT, newly synthesized insulin contributed approximately 20 % of total insulin secretion. The pattern of isotope enrichment obtained by collecting multiple urine voids was suggestive that the newly synthesized insulin contributes to the late phase of insulin secretion. De novo C-peptide correlated negatively with both early plasma insulin AUC (r = -0.629, P = 0.028) and early plasma glucose AUC (r = -0.605, P = 0.037). CONCLUSIONS: With stable isotope technique added to OGTT, we were able to measure newly synthesized insulin in healthy individuals. This new technique holds the promise that it is feasible to develop a direct in vivo beta cell function test.

Familial hypercholesterolaemia: cholesterol efflux and coronary disease.

BACKGROUND: Coronary heart disease (CHD) risk inversely associates with levels of high-density lipoprotein cholesterol (HDL-C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux. MATERIALS AND METHODS: We compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non-FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM). RESULTS: Seven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non-FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower (P = 0·03, CHD vs. non-CHD). Compared to their non-FH brothers, FH patients without CHD displayed significantly higher levels of HDL-cholesterol, HDL-S1P and apoM, while FH patients with CHD displayed lower levels than their non-FH brothers. CONCLUSIONS: A higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD.

Post-glucose-load urinary C-peptide and glucose concentration obtained during OGTT do not affect oral minimal model-based plasma indices.

The purpose of this study was to investigate how renal loss of both C-peptide and glucose during oral glucose tolerance test (OGTT) relate to and affect plasma-derived oral minimal model (OMM) indices. All individuals were recruited during family screening between August 2007 and January 2011 and underwent a 3.5-h OGTT, collecting nine plasma samples and urine during OGTT. We obtained the following three subgroups: normoglycemic, at risk, and T2D. We recruited South Asian and Caucasian families, and we report separate analyses if differences occurred. Plasma glucose, insulin, and C-peptide concentrations were analyzed as AUCs during OGTT, OMM estimate of renal C-peptide secretion, and OMM beta-cell and insulin sensitivity indices were calculated to obtain disposition indices. Post-glucose load glucose and C-peptide in urine were measured and related to plasma-based indices. Urinary glucose corresponded well with plasma glucose AUC (Cau r = 0.64, P < 0.01; SA r = 0.69, P < 0.01), S I (Cau r = -0.51, P < 0.01; SA r = -0.41, P < 0.01), Φ dynamic (Cau r = -0.41, P < 0.01; SA r = -0.57, P < 0.01), and Φ oral (Cau r = -0.61, P < 0.01; SA r = -0.73, P < 0.01). Urinary C-peptide corresponded well to plasma C-peptide AUC (Cau r = 0.45, P < 0.01; SA r = 0.33, P < 0.05) and OMM estimate of renal C-peptide secretion (r = 0.42, P < 0.01). In general, glucose excretion plasma threshold for the presence of glucose in urine was ~10-10.5 mmol L(-1) in non-T2D individuals, but not measurable in T2D individuals. Renal glucose secretion during OGTT did not influence OMM indices in general nor in T2D patients (renal clearance range 0-2.1 %, with median 0.2 % of plasma glucose AUC). C-indices of urinary glucose to detect various stages of glucose intolerance were excellent (Cau 0.83-0.98; SA 0.75-0.89). The limited role of renal glucose secretion validates the neglecting of urinary glucose secretion in kinetic models of glucose homeostasis using plasma glucose concentrations. Both C-peptide and glucose in urine collected during OGTT might be used as non-invasive measures for endogenous insulin secretion and glucose tolerance state.

Discriminative Ability of Plasma Branched-Chain Amino Acid Levels for Glucose Intolerance in Families At Risk for Type 2 Diabetes.

BACKGROUND: Insulin resistance and glucose intolerance have been associated with increased plasma levels of branched-chain amino acids (BCAA). BCAA levels do not predict T2DM in the population. We determined the discriminative ability of fasting BCAA levels for glucose intolerance in nondiabetic relatives of patients with T2DM of two different ethnicities. METHODS: Based on oral glucose tolerance test (OGTT), first-degree relatives of patients with T2DM were categorized as normal glucose tolerance, prediabetes, or T2DM. Included were 34, 12, and 18 Caucasian and 22, 12, and 23 Asian Indian participants, respectively. BCAA levels were measured in fasting plasma together with alanine, phenylalanine, and tyrosine. Insulin sensitivity and beta-cell function were assessed by indices derived from an extended OGTT and their relationship with plasma BCAA levels was assessed in multivariate regression analysis. The value of the amino acids for discriminating prediabetes among nondiabetic family members was determined with the area under the curve of receiver-operated characteristics (c-index). RESULTS: BCAA levels were higher in diabetic than in normoglycemic family members in the Caucasians (P = 0.001) but not in the Asian Indians. In both groups, BCAA levels were associated with waist-hip ratio (ß = 0.31; P = 0.03 and ß = 0.42; P = 0.001, respectively) but not with indices of insulin sensitivity or beta-cell function. The c-index of BCAA for discriminating prediabetes among nondiabetic participants was 0.83 and 0.74 in Caucasians and Asian Indians, respectively, which increased to 0.84 and 0.79 by also including the other amino acids. The c-index of fasting glucose for discriminating prediabetes increased from 0.91 to 0.92 in Caucasians and 0.85 to 0.97 (P = 0.04) in Asian Indians by inclusion of BCAA+alanine, phenylalanine, and tyrosine. CONCLUSIONS: Adding fasting plasma BCAA levels, combined with phenylalanine, tyrosine and alanine to fasting glucose improved discriminative ability for the prediabetic state within Asian Indian families at risk for T2DM. BCAA levels may serve as biomarkers for early development of glucose intolerance in these families.

Failing beta-cell adaptation in South Asian families with a high risk of type 2 diabetes.

We performed an extended oral glucose tolerance test (OGTT) to investigate the relationship between early and late beta-cell response and type 2 diabetes (T2D) in families of South Asian origin and indigenous Dutch, burdened by T2D. Based on the OGTT, 22 individuals were normoglycemic, 12 glucose intolerant and 23 had T2D in the South Asian families; these numbers were 34, 12 and 18 in the Caucasian families, respectively. The OGTT had 11 blood samplings in 3.5 h for glucose, insulin and C-peptide measurements. Through early and late insulin secretion rate (ISR), the above basal glucose area-under-the-curve after glucose load (glucose disposal) and insulin sensitivity index (ISI), we obtained early and late disposition indices (DI). South Asians on average had lower ISI than Caucasians (3.8 ± 2.9 vs. 6.5 ± 4.7, respectively, P < 0.001), with rapid decline of their early and late DI between normal glucose tolerance versus impaired fasting glucose/impaired glucose tolerance (late DI; P < 0.0001). Adjusted for ISI, age, gender and waist-to-hip ratio, early ISR was significantly associated with glucose disposal in South Asians (ß = 0.55[0.186; 0.920]), but not in Caucasians (ß = 0.09[-0.257; 0.441]). Similarly, early ISR was strongly associated with late ISR (ß = 0.71[0.291; 1.123]; R (2) = 45.5 %) in South Asians, but not in Caucasians (ß = 0.27[-0.035; 0.576]; R (2) = 17.4 %), with significant interaction between ethnicity and early ISR (ß = 0.341[0.018; 0.664]). Ordinal regression analyses confirmed that all South Asian OGTT subgroups were homogenously resistant to insulin and solely predicted by early ISR (ß = -0.782[-1.922; 0.359], ß = -0.020[-0.037; -0.002], respectively), while in Caucasian families both ISI and early ISR were related to glucose tolerance state (ß = -0.603[-1.105; -0.101], ß = -0.066[-0.105; -0.027], respectively). In South Asian individuals, rapid beta-cell deterioration might occur under insulin resistant conditions. As their early insulin response correlates strongly with both glucose disposal and late insulin response, alterations in beta-cell dynamics may give an explanation to their extreme early onset of T2D, although larger prospective studies are required.

Bioactive rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients.

BACKGROUND: Inadequate food intake plays an important role in the development of malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients. Aim of the study. The aim of the study was to investigate in CAPD patients whether circulating insulin-like growth factor-I (IGF-I) bioactivity may offer a more sensitive index to acute nutritional interventions than total IGF-I. METHODS: An open-label, randomized, crossover study of 2 days-with a 1-week interval-was performed in 12 CAPD patients in the fed state to compare a mixture of amino acids (Nutrineal 1.1%) plus glucose (AA plus G) (Physioneal 1.36% to 3.86%) dialysate versus G only as control dialysate. Fed-state conditions were created by identical liquid hourly meals. IGF-I bioactivity was measured by the kinase receptor activation assay (IGF-I KIRA); total IGF-I was measured by immunoassay. RESULTS: In the fed state, both after AA plus G as well as after G dialysis IGF-I bioactivity increased compared to baseline, while no changes in circulating total IGF-I levels were observed in both treatment arms. However, the increase in IGF-I bioactivity was only significant after AA plus G dialysis (P = 0.02). CONCLUSIONS: Our results provide evidence that in CAPD patients changes in circulating IGF-I bioactivity are associated with nutrient intake and that IGF-I bioactivity rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients.

Human fetal albumin synthesis rates during different periods of gestation.

BACKGROUND: Despite nutritional intervention, albumin concentrations are often low in critically ill premature neonates. OBJECTIVE: Our aim was to quantify albumin synthesis rates during early life under physiologic circumstances. Human fetuses thereby reflect the developmentally related optimal condition. DESIGN: Pregnant women undergoing elective cesarean delivery received 3 different labeled amino acid infusions starting at different times before surgery. With the use of mass spectrometry techniques, this novel model enabled us to quantify fetal albumin synthesis from a single blood sample taken from the umbilical cord after cesarean delivery. The fractional synthesis rate reflects the fraction of the albumin pool that is daily renewed. The absolute synthesis rate is the absolute amount of albumin that is daily synthesized. Results are expressed as medians (25th-75th percentile). RESULTS: We studied 8 fetuses at 29.9 (28.4-35.4) weeks of gestation and 8 fetuses around term. Fractional synthesis rates in premature fetuses [17.5 (12.1-24.4) %/d] were higher (P = 0.02) than in mature fetuses [10.4 (9.1-13.7) %/d]. Absolute synthesis rates were also higher (P = 0.02) in premature than in mature fetuses: 280 (227-365) versus 205 (184-238) mg . kg(-1) . d(-1). CONCLUSIONS: On a weight basis, albumin synthesis rates in premature fetuses were higher than in fetuses at term and were higher than the rates previously found in neonates after preterm birth. Considering that the premature fetal liver can synthesize albumin at a high rate, the observed hypoalbuminemia in premature infants therefore seems to suggest that current (nutritional) therapies fail to meet requirements necessary to sustain optimum albumin synthesis rates.

Whole-body protein turnover in peritoneal dialysis patients: a comparison of the [15N]glycine end product and the [13C]leucine precursor methods.

BACKGROUND: Two well-described methods for measuring whole-body protein turnover (WBPT) are the precursor method using a primed continuous infusion of [1-(13)C]leucine and the end-product method with a single oral dose of [(15)N]glycine. We previously measured the effects of amino acid (AA)-containing dialysate on protein anabolism in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) using the [1-(13)C]leucine technique. Here, we examine whether the less invasive [(15)N]glycine method could also be appropriate for studying nutritional interventions. METHODS: We compared the results of WBPT measurements using a single oral dose of [(15)N]glycine with those obtained with the primed continuous infusion of [1-(13)C]leucine during AA and glucose (G) dialysis and G-only dialysis in 12 CAPD patients in the fed state. RESULTS: The end-product method showed a wide variation for protein synthesis and breakdown measurements. It did not detect a small but significant increase in protein synthesis with AA-containing dialysate as shown by the precursor method. However, a significant relation was found between both methods for net protein synthesis (i.e. protein synthesis minus breakdown) during AA and G (r = 0.75, P = 0.005) or during G-only dialysis (r = 0.86, P < 0.001). The agreement between the two methods for the net protein balance was good [intra-class correlation coefficient (ICC) = 0.88] with G-only dialysate and moderate (ICC = 0.70) with AA and G dialysate. CONCLUSION: While the precursor method shows less variation, the more convenient end-product method may be useful in larger groups of selected patients including those on PD.

Albumin synthesis in premature neonates is stimulated by parenterally administered amino acids during the first days of life.

BACKGROUND: We recently showed that parenteral administration of amino acids to premature infants immediately after birth is safe and results in a positive nitrogen balance and increased whole-body protein synthesis. However, we did not determine organ-specific effects; albumin, produced by the liver, is an important protein, but its concentration is often low in premature neonates during the first few days after birth. OBJECTIVE: The objective of the study was to test the hypothesis that the fractional and absolute albumin synthesis rates would increase with the administration of amino acids after birth, even at low nonprotein energy intake. DESIGN: Premature infants (<1500 g birth weight), who were on ventilation, received from birth onward either glucose only (control group, n = 7) or glucose and 2.4 g amino acid kg(-1) d(-1) (intervention group, n = 8). On postnatal day 2, all infants received a primed continuous infusion of [1-(13)C]leucine, and mass spectrometry techniques were used to determine the incorporation of the leucine into albumin. Results are expressed as medians and 25th and 75th percentiles. RESULTS: Albumin fractional synthesis rates in the intervention group were significantly higher than those in the control group [22.9% (17.6-28.0%)/d and 12.6% (11.0-19.4%)/d, respectively; P = 0.029]. Likewise, the albumin absolute synthesis rates in the intervention group were significantly higher than those in the control group [228 (187-289) mg kg(-1) d(-1) and 168 (118-203) mg kg(-1) d(-1), respectively; P = 0.030]. CONCLUSION: Amino acid administration increases albumin synthesis rates in premature neonates even at a low energy intake.

Peritoneal dialysis with solutions containing amino acids plus glucose promotes protein synthesis during oral feeding.

Inadequate food intake plays an important role in the development of malnutrition. Recently, an increased rate of protein anabolism was shown in fasting state in patients who were on automated peritoneal dialysis with combined amino acids (AA) and glucose (G) dialysate serving as a source of both proteins and calories. This study investigated the effects of such a dialysis procedure in the daytime in the fed state in patients who were on continuous ambulatory peritoneal dialysis (CAPD). A crossover study was performed in 12 CAPD patients to compare, at 7-d intervals, a mixture of AA (Nutrineal 1.1%) plus G (Physioneal l.36 to 3.86%) versus G only as control dialysate. Whole-body protein turnover was studied by primed constant intravenous infusion of (13)C-leucine during the 9-h dialysis. For meeting steady-state conditions during whole-body protein turnover, frequent exchanges with a mixture of AA plus G were done using an automated cycler. Fed-state conditions were created by identical liquid hourly meals. Using AA plus G dialysate, as compared with the control, rates of protein synthesis increased significantly (2.02 +/- 0.08 versus 1.94 +/- 0.07 mumol leucine/kg per min [mean +/- SEM]; P = 0.039). Rates of protein breakdown and net protein balance did not differ significantly between AA plus G and G. In conclusion, dialysate that contains AA plus G also improves protein synthesis in fed CAPD patients. The use of such a mixture may contribute to long-term improvement of the nutritional status in malnourished CAPD patients with deficient food intake.

Albumin synthesis in preterm infants on the first day of life studied with [1-13C]leucine.

Albumin is the major binding protein in the human neonate. Low production of albumin will lower its transport and binding capacity. This is especially important in preterm infants, in whom albumin binds to potentially toxic products such as bilirubin and antibiotics. To study the metabolism of plasma albumin in preterm infants, we administered a 24-h constant infusion of [1-(13)C]leucine to 24 very low birth weight (VLBW) infants (28.4 +/- 0.4 wk, 1,080 +/- 75 g) on the first day of life. The caloric intake consisted of glucose only, and therefore amino acids for albumin synthesis were derived from proteolysis. The fractional synthesis rate (FSR) of plasma albumin was 13.9 +/- 1.5%/day, and the absolute synthesis rate was 148 +/- 17 mg x kg(-1) x day(-1). Synthesis rates were significantly lower (P<0.03) in infants showing intrauterine growth retardation. Albumin synthesis increased with increasing SD scores for gestation and weight (P<0.05). The FSR of albumin tended to increase by 37% after administration of antenatal corticosteroids to improve postnatal lung function (P=0.09). We conclude that liver synthetic capacity is well developed in VLBW infants and that prenatal corticosteroids tend to increase albumin synthesis. Decreased weight gain rates in utero have effects on protein synthesis postnatally.

Dialysate as food: combined amino acid and glucose dialysate improves protein anabolism in renal failure patients on automated peritoneal dialysis.

Protein-energy malnutrition as a result of anorexia frequently occurs in dialysis patients. In patients who are on peritoneal dialysis (PD), dialysate that contains amino acids (AA) improves protein anabolism when combined with a sufficient oral intake of calories. It was investigated whether protein anabolism can be obtained with a mixture of AA plus glucose (G) as a source of proteins and calories during nocturnal automated PD (APD). A random-order cross-over study was performed in eight APD patients to compare in two periods of 7 d each AA plus G dialysate obtained by cycler-assisted mixing of one bag of 2.5 L of AA (Nutrineal 1.1%, 27 g of AA) and four bags of 2.5 L of G (Physioneal 1.36 to 3.86%) versus G as control dialysate. Whole-body protein turnover was determined using a primed continuous infusion of L-[1-13C]leucine, and 24-h nitrogen balance studies were performed. During AA plus G dialysis, when compared with control, rates of protein synthesis were 1.20 +/- 0.4 and 1.10 +/- 0.2 micromol/kg per min leucine (mean +/- SD), respectively (NS), and protein breakdown rates were 1.60 +/- 0.5 and 1.72 +/- 0.3 micromol/kg per min (NS). Net protein balance (protein synthesis minus protein breakdown) increased on AA plus G in all patients (mean 0.21 +/- 0.12 micromol leucine/kg per min; P < 0.001). The 24-h nitrogen balance changed by 0.96 +/- 1.21 g/d, from -0.60 +/- 2.38 to 0.35 +/- 3.25 g/d (P = 0.061, NS), improving in six patients. In conclusion, APD with AA plus G dialysate improves protein kinetics. This dialysis procedure may improve the nutritional status in malnourished PD patients.

Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial.

OBJECTIVE: To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery. SUMMARY BACKGROUND DATA: Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability, attenuate nitrogen loss, improve survival, and lower the incidence of nosocomial infections. Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results. METHODS: Eighty newborns and infants were included in a double-blind, randomized trial comparing standard parenteral nutrition (sPN; n = 39) to glutamine-supplemented parenteral nutrition (GlnPN; glutamine target intake, 0.4 g kg day; n = 41), starting on day 2 after major digestive-tract surgery. Primary endpoints were intestinal permeability, as assessed by the urinary excretion ratio of lactulose and rhamnose (weeks 1 through 4); nitrogen balance (days 4 through 6), and urinary 3-methylhistidine excretion (day 5). Secondary endpoints were mortality, length of stay in the ICU and the hospital, number of septic episodes, and usage of antibiotics and ICU resources. RESULTS: Glutamine intake plateaued at 90% of the target on day 4. No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints. Glutamine supplementation was not associated with adverse effects. CONCLUSIONS: In newborns and infants after major digestive-tract surgery, we did not identify beneficial effects of isonitrogenous, isocaloric glutamine supplementation of parenteral nutrition. Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise.

Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes.

BACKGROUND: Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38. METHODS: Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided. RESULTS: CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006). CONCLUSION: CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.

Clinical relevancy of nonurinary nitrogen excretion in newborns and infants after digestive tract surgery.

BACKGROUND: Whether the contribution of nonurinary nitrogen excretion (N2nu) to total nitrogen excretion (N2tot) is clinically relevant has not been tested in children in an intensive care unit. Particularly after digestive tract surgery, fecal nitrogen losses, and losses via nasogastric tubes, enterostomies and wound drains may be large. METHODS: We prospectively measured urinary nitrogen excretion (N2u) and N2nu 4 to 6 days after digestive tract surgery in 78 newborns and infants who were given total parenteral nutrition. RESULTS: Two hundred seven collections of excreta, each representing one 24-hour period, were obtained. Median N2nu was 15 mg/kg/24 hours (range, 0.4-153), median N2u 153 mg/kg/24 hours (range, 57-558), median N2tot 179 mg/kg/24 hours (range, 72-577), and the median ratio of N2nu and N2u 9.9% (range, 0.2-110). The observed variations could not be attributed to differences in the severity of the underlying disease or the surgical stress. The mean difference between N2tot and N2u was 21 mg/kg/24 hours (95% prediction interval -20 to +63). Use of a linear regression equation that predicts N2tot according to N2u and the weights of other excreta eliminated bias and improved precision (95% prediction interval -34 to +34 mg/kg/24 hours). For individual measurements, however, considerable imprecision remained. CONCLUSIONS: In newborns and infants, receiving parenteral nutrition 4 to 6 days after digestive tract surgery, N2nu is variable and not to be neglected. The only way to accurately assess N2tot in individual patients is by measuring the nitrogen content of all excreta.

Feasibility and image quality of dual-isotope SPECT using 18F-FDG and (99m)Tc-tetrofosmin after acipimox administration.

UNLABELLED: Currently, with the rapidly increasing number of patients with heart failure due to chronic coronary artery disease, the need for viability studies to guide treatment in these patients is increasing. The most accurate method for viability assessment is metabolic imaging with (18)F-FDG with PET or SPECT. To obtain excellent image quality in all patients, the (18)F-FDG studies should be performed during hyperinsulinemic euglycemic clamping. However, this approach is time-consuming and is not feasible in busy nuclear medicine laboratories. Recently, the use of a nicotinic acid derivative, acipimox, has been suggested, but limited data are available on the image quality of the (18)F-FDG studies using this approach. METHODS: We evaluated the feasibility and image quality of (18)F-FDG SPECT (with dual-isotope simultaneous acquisition (DISA) using (99m)Tc-tetrofosmin to assess perfusion) after acipimox administration in 50 nondiabetic patients. The image quality of both (18)F-FDG and (99m)Tc-tetrofosmin was assessed visually and quantitatively using myocardium-to-blood-pool (M/B) ratios as a measure of target-to-background ratio. The image quality and diagnostic value of DISA (99m)Tc-tetrofosmin SPECT was compared with standard (99m)Tc-tetrofosmin SPECT at baseline. RESULTS: After acipimox administration, the plasma levels of free fatty acids were extremely low (68 +/- 89 nmol/L). No severe side effects were observed, only paroxysmal flushing. The (18)F-FDG image quality was good in 46 patients (92%) and moderate but still interpretable in the other 4 patients (8%). The clinical information of the baseline (99m)Tc-tetrofosmin SPECT was retained in the DISA (99m)Tc-tetrofosmin SPECT images because we did observe no substantial fill-in of perfusion defects by high (18)F-FDG uptake in the same segment. CONCLUSION: Cardiac (18)F-FDG SPECT after acipimox is safe and resulted consistently in good image quality; this simple approach may be the method of choice for routine cardiac metabolic imaging.

Fatty acid composition of plasma lipids in patients with pancreatic, lung and oesophageal cancer in comparison with healthy subjects.

BACKGROUND & AIMS: Despite the general notion of impaired nutritional status in cancer patients, studies on fatty acid status in cancer patients are limited. The aim of the present study was to investigate whether plasma n-3 fatty acids concentrations are reduced in patients with different tumour types. METHODS: We measured fatty acid composition in plasma phospholipids (PLs) and cholesteryl esters (CEs) in 71 newly diagnosed, untreated cancer patients of three tumour types: oesophageal or cardia cancer (n = 35), non-small cell lung cancer (n = 22) and pancreatic cancer (n = 15) and in 45 healthy subjects. RESULTS: In pancreatic cancer, plasma n-3 fatty acids showed a substantial reduction in both plasma PLs and CES. Although n-3 fatty acids in lung cancer also tended to be reduced, this difference failed to reach statistical significance. n-3 Fatty acid levels were especially reduced in pancreatic cancer patients without diabetes mellitus, and in lung cancer patients with weight loss. In oesophageal cancer, n-3 fatty acid concentrations were comparable to those in healthy subjects. CONCLUSION: We conclude that plasma n-3 fatty acid levels were reduced in pancreatic cancer, tended to be reduced in lung cancer, but were not altered in oesophageal cancer. Further studies are needed to assess the mechanisms underlying the observed changes in n-3 fatty acid concentrations.

Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: a randomized clinical trial.

PURPOSE: In a randomized clinical trial in patients with advanced non-small-cell lung cancer (NSCLC), infusion with adenosine 5'-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expenditure as secondary outcome measures in the same patients are reported. PATIENTS AND METHODS: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 intravenous, 30-hour ATP infusions every 2 to 4 weeks or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expenditure (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance. RESULTS: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas, per 4 weeks, the control group lost 0.6 kg of FM (P =.004), 0.5 kg of FFM (P =.02), 1.8% of arm muscle area (P =.02), and 0.6% of BCM/kg body weight (P =.054) and decreased 568 KJ/d in energy intake (P =.0001). Appetite also remained stable in the ATP group but decreased significantly in the control group (P =.0004). No significant differences in REE between the ATP and control groups were observed. CONCLUSION: The inhibition of weight loss by ATP infusions in patients with advanced NSCLC is attributed to counteracting the loss of both metabolically active and inactive tissues. These effects are partly ascribed to maintenance of energy intake.