Reduced plasma glycine concentration in healthy and chronically diseased older adults: a marker of visceral adiposity?

BACKGROUND: Previous studies have shown that a reduced plasma concentration of the amino acid glycine (Gly) is associated with intra-abdominal obesity, but the mechanism remains unclear. OBJECTIVES: This study aimed to investigate whether lower plasma Gly concentrations in older adults are independently associated with (visceral) adiposity, age, sex, presence of chronic disease, and glucose intolerance, and whether they are caused by a reduced Gly whole-body production (WBP) and/or increased Gly disposal capacity. METHODS: We studied 102 older adults (47 males/55 females, 68.5 ± standard deviation 6.4 y) without comorbidities and 125 older adults with chronic obstructive pulmonary disease (COPD) (58 males/67 females, 69.7 ± 8.6 y). We assessed body composition and visceral adipose tissue (VAT) by dual-energy x-ray absorptiometry and muscle function by dynamometry. We measured postabsorptive plasma amino acid profile and glucose, followed by pulse administration of stable isotope-labeled Gly ([2,2-2H2]), and blood sampling was performed to measure the WBP of Gly. Results are expressed as means and 95% confidence intervals (CIs). RESULTS: We found a lower plasma Gly concentration in healthy males and males with COPD than in females (Healthy: 211; 95% CI: 193,230 compared with 248; 95% CI: 225,271; COPD: 200; 95% CI: 186,215 compared with 262: 95% CI: 241, 283; P < 0.0001, respectively), with no difference between healthy and COPD groups. A negative relationship was found between unadjusted plasma Gly and VAT mass (R2: 0.16; slope: -1.7; 95% CI: -2.4, -1.2; P < 0.0021), but not with total body fat or fasting glucose. The strong association between lower plasma Gly and increased VAT mass in older adults was independent of age, sex, body weight, lean mass or body mass index, and the presence of COPD. Inclusion of these covariates increased the R2 to 0.783. We found no relation between the VAT and WBP of Gly (P = 0.35) or Gly clearance (P = 0.187) when lean mass was considered. CONCLUSIONS: Reduced plasma Gly in older adults can be considered a marker of visceral adiposity, independent of sex, age, body composition, presence of chronic disease, and whole-body Gly production or clearance. This study was registered on clinicaltrials.gov as NCT01787682, NCT02082418, NCT02157844, NCT02770092, NCT02780219, NCT03796455, and NCT04461236.

Total energy expenditure assessed by 24-h whole-room indirect calorimeter in patients with colorectal cancer: baseline findings from the PRIMe study.

BACKGROUND: Total energy expenditure (TEE) determines energy requirements, but objective data in patients with cancer are limited. OBJECTIVES: We aimed to characterize TEE, investigate its predictors, and compare TEE with cancer-specific predicted energy requirements. METHODS: This cross-sectional analysis included patients with stages II-IV colorectal cancer from the Protein Recommendation to Increase Muscle (PRIMe) trial. TEE was assessed by 24-h stay in a whole-room indirect calorimeter before dietary intervention and compared with cancer-specific predicted energy requirements (25-30 kcal/kg). Generalized linear models, paired-samples t tests, and Pearson correlation were applied. RESULTS: Thirty-one patients (56 ± 10 y; body mass index [BMI]: 27.9 ± 5.5 kg/m2; 68% male) were included. Absolute TEE was higher in males (mean difference: 391 kcal/d; 95% CI: 167, 616 kcal/d; P < 0.001), patients with colon cancer (mean difference: 279 kcal/d; 95% CI: 73, 485 kcal/d; P = 0.010), and patients with obesity (mean difference: 393 kcal/d; 95% CI: 182, 604 kcal/d; P < 0.001). Appendicular lean soft tissue (ß: 46.72; 95% CI: 34.27, 59.17; P < 0.001) and tumor location (colon-ß: 139.69; 95% CI: 19.44, 259.95; P = 0.023) independently predicted TEE when adjusted for sex. Error between measured TEE and energy requirements predicted by 25 kcal/kg (mean difference: 241 kcal/d; 95% CI: 76, 405 kcal/d; P = 0.010) or 30 kcal/kg (mean difference: 367 kcal/d; 95% CI: 163, 571 kcal/d; P < 0.001) was higher for patients with obesity, and proportional error was observed (25 kcal/kg: r = -0.587; P < 0.001; and 30 kcal/kg: r = -0.751; P < 0.001). TEE (mean difference: 25 kcal/kg; 95% CI: 24, 27 kcal/kg) was below predicted requirements using 30 kcal/kg (-430 ± 322 kcal/d; P < 0.001). CONCLUSIONS: This is the largest study to assess TEE of patients with cancer using whole-room indirect calorimeter and highlights the need for improved assessment of energy requirements in this population. Energy requirements predicted using 30 kcal/kg overestimated TEE by 1.44 times in a controlled sedentary environment and TEE was outside of the predicted requirement range for most. Special considerations are warranted when determining TEE of patients with colorectal cancer, such as BMI, body composition, and tumor location. This is a baseline cross-sectional analysis from a clinical trial registered at clinicaltrials.gov as NCT02788955 (https://clinicaltrials.gov/ct2/show/NCT02788955).

Tolerance to increased supplemented dietary intakes of methionine in healthy older adults.

Background: l-Methionine (Met) is an essential amino acid for humans and is important for protein synthesis and the formation of polyamines and is involved in the synthesis of many metabolites, including homocysteine. Free-Met supplements have been claimed to have multiple positive effects; however, it remains unclear what the exact tolerance level is. With aging, Met metabolism changes, and increased plasma homocysteine is more apparent. High plasma concentrations of homocysteine are assumed to be associated with a high risk of developing atherosclerosis.Objective: We estimated the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL) of supplemented, oral, free Met in healthy older adults by examining the increase in plasma homocysteine as the primary determinant.Design: We provided capsules with free Met to 15 healthy older adult subjects for 4 wk at climbing dosages of, on average, 9.2, 22.5, 46.3 and 91 mg · kg body weight-1 · d-1 with washout periods of 2 wk between each intake. Before, at 2 and 4 wk during, and 2 wk after each dosage, we studied a complete panel of biochemical blood variables to detect possible intolerance to increased Met intake. Plasma homocysteine and body composition were measured, and tolerance, quality of life, and cognitive function were assessed via questionnaires.Results: Plasma homocysteine was elevated with the highest dose of supplemented Met. The estimated NOAEL of supplemented Met was set at 46.3 mg · kg body weight-1 · d-1, and the estimated LOAEL of supplemented Met was set at 91 mg · kg body weight-1 · d-1 (on the basis of the actual intakes) in subjects independent of sex. No signs of intolerance were observed via questionnaires or other blood variables at the LOAEL. There were no meaningful changes in body composition.Conclusions: On the basis of plasma homocysteine, the NOAEL of supplemented Met intake is 46.3 and the LOAEL is 91 mg · kg body weight-1 · d-1 in healthy older adults. Both the NOAEL and LOAEL are not associated with meaningful effects on health and wellbeing. This trial was registered at clinicaltrials.gov as NCT02566434.

Effectiveness of essential amino acid supplementation in stimulating whole body net protein anabolism is comparable between COPD patients and healthy older adults.

BACKGROUND: The development of effective nutritional strategies in support of muscle growth for patients with chronic obstructive pulmonary disease (COPD) remains challenging. Dietary essential amino acids (EAAs) are the main driver of postprandial net protein anabolism. In agreement, EAA supplements in healthy older adults are more effective than supplements with the composition of complete proteins. In patients with COPD it is still unknown whether complete protein supplements can be substituted with only EAAs, and whether they are as effective as in healthy older adults. METHODS: According to a double-blind randomized crossover design, we examined in 23 patients with moderate to very severe COPD (age: 65±2 years, FEV1: 40±2% of predicted) and 19 healthy age-matched subjects (age: 64±2 years), whether a free EAA mixture with a high proportion (40%) of leucine (EAA mixture) stimulated whole body net protein gain more than a similar mixture of balanced free EAAs and non-EAAs as present in whey protein (TAA mixture). Whole body net protein gain and splanchnic extraction of phenylalanine (PHE) were assessed by continuous IV infusion of L-[ring-2H5]-PHE and L-[ring-2H2]-tyrosine, and enteral intake of L-[15N]-PHE (added to the mixtures). RESULTS: Besides an excellent positive linear relationship between PHE intake and net protein gain in both groups (r=0.84-0.91, P<0.001), net protein gain was 42% higher in healthy controls and 49% higher in COPD patients after intake of the EAA mixture compared to the TAA mixture (P<0.0001). These findings could not be attributed to the high LEU content, as in both groups net protein gain per gram EAA intake was lower for the EAA mixture (P<0.0001). Net protein gain was higher in COPD patients for both mixtures due to a 40% lower splanchnic extraction (P<0.0001), but was similarly related to dietary PHE (i.e. EAA) plasma appearance. CONCLUSIONS: In COPD patients, similarly to healthy older adults, free EAA supplements stimulate whole body protein anabolism more than free amino acid supplements with the composition of complete proteins. Therefore, free EAA supplements may aid in the prevention and treatment of muscle wasting in this patient population.

Presence of early stage cancer does not impair the early protein metabolic response to major surgery.

BACKGROUND: Combined bilateral mastectomy and reconstruction is a common major surgical procedure in women with breast cancer and in those with a family history of breast cancer. As this large surgical procedure induces muscle protein loss, a preserved anabolic response to nutrition is warranted for optimal recovery. It is unclear whether the presence of early stage cancer negatively affects the protein metabolic response to major surgery as this would mandate perioperative nutritional support. METHODS: In nine women with early stage (Stage II) breast malignancy and nine healthy women with a genetic predisposition to breast cancer undergoing the same large surgical procedure, we examined whether surgery influences the catabolic response to overnight fasting and the anabolic response to nutrition differently. Prior to and within 24 h after combined bilateral mastectomy and reconstruction surgery, whole body protein synthesis and breakdown rates were assessed after overnight fasting and after meal intake by stable isotope methodology to enable the calculation of net protein catabolism in the post-absorptive state and net protein anabolic response to a meal. RESULTS: Major surgery resulted in an up-regulation of post-absorptive protein synthesis and breakdown rates (P < 0.001) and lower net protein catabolism (P < 0.05) and was associated with insulin resistance and increased systemic inflammation (P < 0.01). Net anabolic response to the meal was reduced after surgery (P < 0.05) but higher in cancer (P < 0.05) indicative of a more preserved meal efficiency. The significant relationship between net protein anabolism and the amount of amino acids available in the circulation (R2 = 0.85, P < 0.001) was independent of the presence of non-cachectic early stage breast cancer or surgery. CONCLUSIONS: The presence of early stage breast cancer does not enhance the normal catabolic response to major surgery or further attenuates the anabolic response to meal intake within 24 h after major surgery in patients with non-cachectic breast cancer. This indicates that the acute anabolic potential to conventional feeding is maintained in non-cachectic early stage breast cancer after major surgery.

Alterations in whole-body arginine metabolism in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a condition characterized by systemic low-grade inflammation that could increase the production of nitric oxide (NO), of which arginine is the sole precursor. Arginine is derived from the breakdown of protein and through the conversion of citrulline to arginine (de novo arginine production). OBJECTIVE: Our objective was to study whole-body arginine and citrulline and related metabolism in stable COPD patients. DESIGN: With the use of stable isotope methodology, we studied whole-body arginine and citrulline rates of appearance, de novo arginine (citrulline-to-arginine flux) and NO (arginine-to-citrulline flux) production, protein synthesis and breakdown rates, and plasma amino acid concentrations in a heterogeneous group of patients with moderate-to-severe COPD [n = 23, mean ± SE age: 65 ± 2 y, forced expiratory volume in 1 s (FEV1): 40% ± 2% of predicted], and a group of healthy older adults (n = 19, mean ± SE age: 64 ± 2 y, FEV1: 95% ± 4% of predicted). RESULTS: Although plasma arginine and citrulline concentrations were comparable between COPD patients and controls, whole-body arginine (P = 0.015) and citrulline (P = 0.026) rates of appearance were higher in COPD patients and related to a 57% greater de novo arginine production (P < 0.0001). Despite a higher whole-body arginine clearance in COPD patients (P < 0.0001), we found no difference in NO production. CONCLUSION: In stable patients with moderate-to-severe COPD, endogenous arginine production is upregulated to support a higher arginine utilization that is unrelated to whole-body NO production. This trial was registered at clinicaltrials.gov as NCT01173354 and NCT01172314.

Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients.

BACKGROUND: Pancreatic cancer is often accompanied by cachexia, a syndrome of severe weight loss and muscle wasting. A suboptimal response to nutritional support may further aggravate cachexia, yet the influence of nutrition on protein kinetics in cachectic patients is poorly understood. METHODS: Eight cachectic pancreatic cancer patients and seven control patients received a primed continuous intravenous infusion of l-[ring-(2)H5]phenylalanine and l-[3,3-(2)H2]tyrosine for 8 h and ingested sips of water with l-[1-(13)C]phenylalanine every 30 min. After 4 h, oral feeding was started. Whole body protein breakdown, protein synthesis, and net protein balance were calculated. Results are given as median with interquartile range. RESULTS: Baseline protein breakdown and protein synthesis were higher in cachectic patients compared with the controls (breakdown: 67.1 (48.1-79.6) vs. 45.8 (42.6-46.3) µmol/kg lean body mass/h, P = 0.049; and synthesis: 63.0 (44.3-75.6) vs. 41.8 (37.6-42.5) µmol/kg lean body mass/h, P = 0.021). During feeding, protein breakdown decreased significantly to 45.5 (26.9-51.1) µmol/kg lean body mass/h (P = 0.012) in the cachexia group and to 33.7 (17.4-37.1) µmol/kg lean body mass/h (P = 0.018) in the control group. Protein synthesis was not affected by feeding in cachectic patients: 58.4 (46.5-76.1) µmol/kg lean body mass/h, but was stimulated in controls: 47.9 (41.8-56.7) µmol/kg lean body mass/h (P = 0.018). Both groups showed a comparable positive net protein balance during feeding: cachexia: 19.7 (13.1-23.7) and control: 16.3 (13.6-25.4) µmol/kg lean body mass/h (P = 0.908). CONCLUSION: Cachectic pancreatic cancer patients have a higher basal protein turnover. Both cachectic patients and controls show a comparable protein anabolism during feeding, albeit through a different pattern of protein kinetics. In cachectic patients, this is primarily related to reduced protein breakdown, whereas in controls, both protein breakdown and protein synthesis alterations are involved.