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Patients with cancer have an anabolic potential to be exploited early on in cachexia development. High-leucine and protein supplements are worth testing as part of a multimodal anabolic approach in long-term trials to confirm their efficacy to sustain anabolism, and attenuate or even reverse muscle wasting.

Context:Specific plasma amino acid (AA) profiles including elevated postabsorptive branched-chain amino acids (BCAAs) have been associated with insulin resistance (IR), mostly estimated by homeostatic model assessment. This study assessed the associations of postabsorptive AAs with IR directly measured by insulin-mediated glucose disposal and determined the quantitative value of AAs and conventional IR predictors.Design:Fifty-one healthy, 31 overweight or obese (Ow/Ob), and 52 men and women with type 2 diabetes (T2D) were studied retrospectively. The main outcome measures were the glucose disposal (M/I) index (using 3-[3H]-glucose) during a hyperinsulinemic–euglycemic clamp and whole-body protein turnover (using 1-[13C]-leucine).Results:Compared with healthy participants, M/I was lower in Ow/Ob participants and lowest in those with T2D. BCAAs, glutamate, and lysine were higher in the Ow/Ob and T2D groups than in healthy participants; glycine and threonine were lower. Most AAs were higher in men. Principal component analysis identified component 1 (C1: BCAAs, methionine) and C3 (glycine, threonine, serine). Glutamate, C1, ornithine, lysine, methionine, and tyrosine correlated negatively with M/I; C3 and glycine correlated positively. Waist circumference and sex strongly influenced AA–IR relationships; only glutamate correlated after these factors were controlled for. From regression analysis, waist circumference, fasting glucose, insulin, and free fatty acids (FFAs) negatively predicted 64% of the M/I variance; glutamate added 2% more. In nondiabetic participants, IR was predicted by waist circumference, insulin, and FFAs, without contribution from AAs.Conclusion:Several postabsorptive AAs correlated with IR but added limited predictive value to conventional markers because levels were determined largely by abdominal adiposity. Data suggest a sex-specific regulation of AA metabolism by excess adiposity, particularly the BCAAs, warranting investigation.

Cancer and aging are both accompanied by metabolic alterations leading to muscle loss that may result from an increased use of amino acids for gluconeogenesis (GNG).Methodswe measured the fractional contributions (%) of glycogen, glycerol and GNG from phosphoenolpyruvate (PEP) to 17h‐fasting endogenous glucose production (EGP), using oral 2H20 and deuterium enrichment of plasma glucose, by NMR spectroscopy. Whole‐body protein and glucose kinetics (1‐13C‐leucine and 3H3‐glucose) were measured fasting and during a subsequent hyperinsulinemic, euglycemic, isoaminoacidemic clamp in: young (Y, n=11; 27±3 y), older (O, n=13; 65±2 y) and older men with lung cancer (CA, n=9; 66±2 y).ResultsMen with CA had greater serum CRP levels and resting energy expenditure (REE) than Y and O, and a lesser clamp glucose disposal, indicating insulin resistance. EGP was elevated with aging and cancer with greater contribution from GNG: Y:37±2, O:43±2 and CA:48±4% (ANOVA p<0.05); % contribution from glycogen and glycerol did not differ. The resulting GNG flux (EGP × %GNG) correlated positively with CRP (r=0.69) and REE (r=0.61), and negatively with fat‐free mass index (r=−0.41), all p<0.05. GNG flux was related to lesser glucose uptake and protein anabolic response (r= −0.54, p=0.001) in response to insulin.ConclusionsInflammation may underlie the greater production of glucose from GNG and blunted protein anabolism. (CIHR)

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