Nonoxidative Disposal Research Articles

The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic β-oxidation, and induces ketosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10-3H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and nonoxidative disposal (Rst). In the liver, clearance (Kβ-ox) and flux (Rβ-ox) of FFA into β-oxidation were estimated using [9,10-3H]-(R)-bromopalmitate/[U-14C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, Ra, Rox, and Rst with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to β-oxidation, with increased Kβ-ox, Rβ-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma β-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward β-oxidation.

Physiological responses to carbohydrate overfeeding.

To consider emerging research into the physiological effects of excessive dietary carbohydrate intake, with a particular focus on interactions with physical activity. A single episode of massive carbohydrate overload initiates physiological responses to stimulate additional peptide hormone secretion by the gut and the conversion of carbohydrate into lipid by the intestine, liver and adipose tissue. These acute responses maintain glycaemic control both via increased oxidation of carbohydrate (rather than lipid) and via nonoxidative disposal of surplus carbohydrate into endogenous glycogen and lipid storage depots. Sustained carbohydrate overfeeding therefore results in a chronic accumulation of lipid in the liver, skeletal muscle and adipose tissue, which can impair insulin sensitivity and cardiometabolic health in general. Beyond any direct effect of such lipid deposition on body mass/composition, there is not yet clear evidence of physiologically meaningful metabolic or behavioural adaptations to carbohydrate overfeeding in terms of other components of energy balance. However, regular physical exercise can mitigate the negative health effects of carbohydrate overfeeding, independent of any effect on the net carbohydrate surplus. Research in this area has advanced understanding regarding the mechanisms of weight gain and associated health outcomes within the modern context of an abundant supply of dietary carbohydrate.

Branched-Chain Amino Acid Oxidation Is Elevated in Adults with Morbid Obesity and Decreases Significantly after Sleeve Gastrectomy

Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. Ten morbidly obese [BMI (in kg/m2)≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI <25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. Data were analyzed by nonparametric methods and presented as median (IQR). Participants with obesity had IR with an HOMA-IR (4.89; 4.36-8.76) greater than that of healthy-weight participants (1.32; 0.99-1.49; P <0.001) and had significantly faster leucine flux [218; 196-259 compared with 145; 138-149 μmol · kg fat-free mass (FFM)-1 · h-1], oxidation (24.0; 17.9-29.8 compared with 16.1; 14.3-18.5 μmol · kg FFM-1 · h-1), and nonoxidative disposal (204; 190-247 compared with 138; 129-140 μmol · kg FFM-1 · h-1) (P <0.017 for all). After surgery, the morbidly obese had a marked improvement in IR (3.54; 3.06-6.08; P=0.008) and significant reductions in BCAA concentrations (113; 95-157 μmol/L) and leucine oxidation (9.37; 6.85-15.2 μmol · kg FFM-1 · h-1) (P=0.017 for both). Further, leucine flux in this group correlated significantly with IR (r=0.78, P <0.001). BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.

Arginine kinetics are altered in a pilot sample of adolescents and young adults with Barth syndrome

Barth syndrome (BTHS) is a rare, X-linked cardiomyopathy that is characterized by abnormalities in glucose and lipid metabolism, with less known regarding amino acid metabolism. This pilot study characterized whole-body arginine kinetics and found lower arginine rate of appearance into plasma (0.69 ± 0.09 vs. 0.88 ± 0.06 μmol/kgFFM/min, p < 0.01) and arginine non-oxidative disposal rate (0.64 ± 0.11 vs. 0.80 ± 0.03 μmol/kgFFM/min, p < 0.02) in adolescents and young adults with BTHS compared to Controls. This study provides a foundation for more in-depth studies on how arginine and potentially other amino acid abnormalities contribute to the pathology and clinical manifestations of BTHS.

Effects of threonine supplementation on whole-body protein synthesis and plasma metabolites in growing and mature horses

Current equine threonine requirement estimates do not account for probable use of threonine to maintain gut health and mucin synthesis. The objective of this study was to determine if threonine supplementation (+Thr) would increase whole-body protein synthesis (WBPS) in weanling colts (Study 1) and adult mares (Study 2). Both studies used a crossover design, where each of six animals was studied twice while receiving the isonitrogenous diets. The basal diets contained lower threonine levels (Basal) than the threonine (+Thr) supplemented diets. Threonine intakes in mg/kg BW/day were as follows: 79 (Basal) and 162 (+Thr) for Study 1 and 58 (Basal) and 119 (+Thr) for Study 2, in comparison to the NRC estimated requirements of 81 and 33 mg/kg BW/day for weanling and mature horses, respectively.Following 5 days of adaptation, blood samples were taken before and 90 min after the morning concentrate meal. The next day, whole-body phenylalanine kinetics were determined using a 2 h primed, constant infusion of [13C]sodium bicarbonate followed by a 4 h primed, constant infusion of [1-13C]phenylalanine. Most plasma amino acid (AA) concentrations were elevated post-feeding (P < 0.01). Lysine and valine plasma concentrations were lower (P < 0.10), while methionine, threonine, and glycine plasma concentrations were greater (P < 0.10) 90 min post concentrate meal feeding with +Thr in both studies. Phenylalanine flux, intake, oxidation and non-oxidative disposal were similar between treatments (P > 0.05). These findings suggest that supplementation of a single AA can affect the metabolism of several AAs and threonine was not a limiting AA in these diets.

Whole-body phenylalanine kinetics and skeletal muscle protein signaling in horses with pituitary pars intermedia dysfunction.

To compare whole-body phenylalanine kinetics and the abundance of factors in signaling pathways associated with skeletal muscle protein synthesis and protein breakdown between horses with pituitary pars intermedia dysfunction (PPID) and age-matched control horses without PPID. 12 aged horses (6 horses with PPID and 6 control horses; mean age, 25.0 and 25.7 years, respectively). Plasma glucose, insulin, and amino acids concentrations were determined before and 90 minutes after feeding. Gluteal muscle biopsy samples were obtained from horses 90 minutes after feeding, and the abundance and activation of factors involved in signaling pathways of muscle protein synthesis and breakdown were determined. The next day, horses received a priming dose and 2 hours of a constant rate infusion of (13)C sodium bicarbonate followed by a priming dose and 4 hours of a constant rate infusion of 1-(13)C phenylalanine IV; whole-body protein synthesis was determined. Plasma glucose and insulin concentrations were higher after feeding than they were before feeding for both groups of horses; however, no significant postprandial increase in plasma amino acids concentrations was detected for either group. Phenylalanine flux, oxidation, release from protein breakdown, and nonoxidative disposal were not significantly different between groups. No significant effect of PPID status was detected on the abundance or activation of positive or negative regulators of protein synthesis or positive regulators of protein breakdown. Results of this study suggested that whole-body phenylalanine kinetics and the postprandial activation of signaling pathways that regulate protein synthesis and breakdown in muscles were not affected by PPID status alone in aged horses.

Integrated analysis of chronic lipotoxicity on muscle metabolism and stress and its reversal by antioxidants.

Apart from elevated glucose, triglyceride and cholesterol, elevated levels of serum free-fatty acid (FFA) are observed in diabetic patients. Increased FFA load can cause multiple dysregulation which are collectively known as lipotoxicity. Impacts of FFA induced lipotoxicity were evaluated on various cellular responses of metabolism and stress in skeletal muscle myotubes. Under lipotoxicity, oxidative capacity of C2C12 myotubes was reduced and decreased levels ATP and NAD were observed. Lipotoxicity augmented non-oxidative disposal of metabolites in terms of lactate release, IMTG and ceramide synthesis. Concomitantly, insulin resistance was also observed. These impacts were in conjunction with increased cellular stress, inflammation, proteolysis and apoptosis. Quenching of lipotoxicity mediated oxidative stress by antioxidant reverted its deleterious impacts and restored insulin stimulated glucose uptake. In conclusion, the in vitro lipotoxicity makes a system which resembles in vivo pathology of muscle as seen in diabetic patients and represents an integrated perspective of lipotoxicity on various parameters of metabolism and stress.

Isoleucine requirement of pregnant sows1

The objective of this study was to determine the Ile requirement in early (d 39 to 61) and late (d 89 to 109) pregnancy using the indicator AA oxidation method. The same 7 Large White × Landrace sows in their fourth parity were used in early and late pregnancy. Each sow received 6 diets based on corn, corn starch, and sugar in both early and late pregnancy at constant feed allowances (2.5 kg/d). Diets provided Ile at 20, 40, 60, 80, 100, and 120% of the Ile requirement (6.2 g/d based on the 1998 NRC) in early and 60, 80, 100, 140, 160, and 180% in late pregnancy. After determination of (13)C background in expired CO2 and plasma free Phe for 1.5 h when confined in respiration chambers, sows were fed the tracer, L[1-(13)C]Phe, a rate of 2.0 mg/(kg BW·h) over 4 h divided into eight 30-min meals. Expired CO2 and plasma free Phe were analyzed for (13)C enrichment above background. Requirements were determined as the breakpoint in 2-phase nonlinear models. Sow BW was 246.5 kg in early and 271.6 kg in late pregnancy. Daily gain of the 6 sows was similar in early (344 g/d) and late pregnancy (543 g/d). During pregnancy, sow maternal gain was 19.1 ± 4.4 kg and litters of 17.7 ± 0.8 piglets weighed 22.6 ± 0.9 kg at birth. The Ile requirement was 3.6 ± 1.2 g/d (P = 0.001) in early pregnancy with a Phe retention (-0.59 g/d) and energy retention (-0.31 MJ/d) that were not different from 0. This indicates that the fourth parity sows had requirements close to maintenance in early pregnancy. The Ile requirement in late pregnancy was 9.7 ± 1.9 g/d (P = 0.001) when sows retained 3.30 g/d of Phe and -1.45 MJ/d of energy. The greater Ile requirement in late pregnancy was probably caused by the increased conceptus growth after d 70 of pregnancy. Phenylalanine flux, oxidation, and nonoxidative disposal increased (P < 0.1) from early to late pregnancy, but body protein breakdown did not. Phenylalanine oxidation, nonoxidative disposal, and retention increased (P < 0.01) with increasing Ile intake in early pregnancy but were not affected by Ile intake in late pregnancy. Body protein breakdown did not respond to Ile intake in early or late pregnancy. Although energy retention was similar in early and late pregnancy, the respiratory quotient decreased (P = 0.047) from early (1.05) to late pregnancy (0.98), indicating lipid mobilization in late pregnancy when Ile was at or above the requirement. The results of this study show that the Ile requirement of sows increases from early to late pregnancy.

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Dietary Pulse Consumption and Arterial Damage in Type 2 Diabetes

s / Can J Diabetes 36 (2012) S2eS22 S10 tissues insulin resistance and inflammation. In the present study, we investigated the effect of 4-phenylbutyrate (4-PBA), a chemical chaperon that prevents ER stress, on the regulation of tissues’ nonesterified fatty acids metabolism and diet-induced insulin resistance. Research Design and Methods: Control (chow fed) vs. diabetic (high-fat/high-fructose fed + small dose streptozotocin-treated e HFHFS) male Wistar rats were treated with 4-PBA (1g/kg/day) by oral gavage for 6 weeks. At the end of the treatment period, [8, 9-3H]-palmitate was infused during an euglycemic ehyperinsulinemic clamp followed by an i.v. bolus of [1-14C]-2bromopalmitate at steady-state to determine oxidative and non-oxidative nonesterified fatty acid (NEFA) metabolism in tissues. Results: HFHFS-fed rats displayed insulin resistance with high levels of fasting glucose and insulin. Increased NEFA fractional uptake by the gastrocnemius and reduced myocardial NEFA nonoxidative disposal was observed. Animals treated with 4-PBA displayed greater plasmatic NEFA rate of appearance and clearance. 4-PBA normalized gastrocnemius fractional uptake and increased NEFA oxidation and fractional uptake by the liver. SCAT of treated rats are characterized larger SC adipocytes with greater fractional and net NEFA uptake. In vitro, 4-PBA inhibits differentiation of adipocytes precursors but stimulates fatty acids uptake by mature adipocytes. Conclusions: Redistribution of NEFA fluxes by 4-PBA treatment does not restore insulin sensitivity in a nutritional model of T2D but reduced fasting glucose.

Gender differences in VLDL1 and VLDL2 triglyceride kinetics and fatty acid kinetics in obese postmenopausal women and obese men.

High plasma triglycerides (TG) have been shown to be independent and better predictors of cardiovascular disease than low-density lipoprotein (LDL) cholesterol in women. This may be due to gender differences in very-low-density lipoprotein 1 (VLDL(1))- and VLDL(2)-TG and fatty acid kinetics. Our objective was to investigate whether there are differences in VLDL(1)- and VLDL(2)-TG and fatty acid kinetics in obese men and postmenopausal women, a high risk group for cardiovascular disease. Stable isotopes techniques were used to measure fasting palmitate rate of appearance, metabolic clearance rate, oxidation rate, and nonoxidative disposal rate, VLDL(1)-TG and VLDL(2)-TG fractional catabolic rate (FCR) and production rate (PR). Whole-body fat distribution was measured by magnetic resonance imaging. Participants included 10 postmenopausal obese women and eight obese men matched for age, body mass index, and fasting plasma TG. The women had lower visceral fat and higher sc fat than the men (P < 0.001 and P < 0.002). Palmitate rate of appearance, metabolic clearance rate, nonoxidative disposal rate, and oxidation rate corrected for resting energy expenditure were greater in the women than the men (all P < 0.03). VLDL(2)-TG PR corrected for fat-free mass was higher in the women (P < 0.001). VLDL(2)-TG and VLDL(2)-cholesterol pools were higher in the women (P < 0.001 and P < 0.008). VLDL(1)-TG FCR and PR and VLDL(2)-TG FCR were not different between genders. Fatty acid and VLDL(2)-TG flux is higher in postmenopausal obese women than in obese men matched for fasting plasma TG levels.

High-carbohydrate/low-protein–induced hyperinsulinemia does not improve protein balance in children after cardiac surgery

ObjectiveIn pediatric cardiac surgery, fluid-restricted low-protein (LoProt) diets account for cumulative protein deficits with increased morbidity. In this setting, we aimed to inhibit proteolysis by a high-carbohydrate (HiCarb)-intake–induced hyperinsulinemia and improve protein balance. MethodsThe effect of a HiCarb/LoProt (glucose 10 mg · kg−1 · min−1/protein 0.7 g · kg−1 · d−1) versus a normal-carbohydrate (NormCarb)/LoProt (glucose 7.5 mg · kg−1 · min−1/protein 0.3 g · kg−1 · d−1) enteral diet on whole-body protein breakdown and balance was compared in a prospective, randomized, single-blinded trial in 24 children after cardiac surgery. On the second postoperative day, plasma insulin and amino acid concentrations, protein breakdown (endogenous rate of appearance of valine), protein synthesis (non-oxidative disposal of valine), protein balance, and the rate of appearance of urea were measured by using an isotopic infusion of [1-13C]valine and [15N2]urea. ResultsThe HiCarb/LoProt diet led to a serum insulin concentration that was three times higher than the NormCarb/LoProt diet (596 pmol/L, 80–1833, and 198 pmol/L, 76–1292, respectively, P = 0.02), without differences in plasma glucose concentrations. There were no differences in plasma amino acid concentrations, non-oxidative disposal of valine, and endogenous rate of appearance of valine between the groups, with a negative valine balance in the two groups (−0.65 μmol · kg−1 · min−1, −1.91 to 0.01, and −0.58 μmol · kg−1 · min−1, −2.32 to −0.07, respectively, P = 0.71). The serum cortisol concentration in the HiCarb/LoProt group was lower compared with the NormCarb/LoProt group (204 nmol/L, 50–544, and 532 nmol/L, 108–930, respectively, P = 0.02). ConclusionIn children with fluid restriction after cardiac surgery, a HiCarb/LoProt diet compared with a NormCarb/LoProt diet stimulates insulin secretion but does not inhibit proteolysis further and therefore cannot be advocated for this purpose.

A Protein–Leucine Supplement Increases Branched-Chain Amino Acid and Nitrogen Turnover But Not Performance

This study aimed to determine the effect of postexercise protein-leucine coingestion with CHO-lipid on subsequent high-intensity endurance performance and to investigate candidate mechanisms using stable isotope methods and metabolomics. In this double-blind, randomized, crossover study, 12 male cyclists ingested a leucine/protein/CHO/fat supplement (LEUPRO 7.5/20/89/22 g · h(-1), respectively) or isocaloric CHO/fat control (119/22 g · h(-1)) 1-3 h after exercise during a 6-d training block (intense intervals, recovery, repeated-sprint performance rides). Daily protein intake was clamped at 1.9 g · kg(-1) · d(-1) (LEUPRO) and 1.5 g · kg(-1) · d(-1) (control). Stable isotope infusions (1-(13)C-leucine and 6,6-(2)H2-glucose), mass spectrometry-based metabolomics, and nitrogen balance methods were used to determine the effects of LEUPRO on whole-body branched-chain amino acid (BCAA) and glucose metabolism and protein turnover. After exercise, LEUPRO increased BCAA levels in plasma (2.6-fold; 90% confidence limits = ×/÷ 1.1) and urine (2.8-fold; ×/÷ 1.2) and increased products of BCAA metabolism plasma acylcarnitine C5 (3.0-fold; ×/÷ 0.9) and urinary leucine (3.6-fold; ×/÷ 1.3) and β-aminoisobutyrate (3.4-fold; ×/÷ 1.4), indicating that ingesting ~10 g leucine per hour during recovery exceeds the capacity to metabolize BCAA. Furthermore, LEUPRO increased leucine oxidation (5.6-fold; ×/÷ 1.1) and nonoxidative disposal (4.8-fold; ×/÷ 1.1) and left leucine balance positive relative to control. With the exception of day 1 (LEUPRO = 17 ± 20 mg N · kg(-1), control = -90 ± 44 mg N · kg(-1)), subsequent (days 2-5) nitrogen balance was positive for both conditions (LEUPRO = 130 ± 110 mg N · kg(-1), control = 111 ± 86 mg N · kg(-1)). Compared with control feeding, LEUPRO lowered the serum creatine kinase concentration by 21%-25% (90% confidence limits = ± 14%), but the effect on sprint power was trivial (day 4 = 0.4% ± 1.0%, day 6 = -0.3% ± 1.0%). Postexercise protein-leucine supplementation saturates BCAA metabolism and attenuates tissue damage, but effects on subsequent intense endurance performance may be inconsequential under conditions of positive daily nitrogen balance.

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss. We studied 25 morbidly obese patients (BMI 51.7 ± 1.5 kg/m(2) [mean ± SEM]), 13 with non-insulin-treated type 2 diabetes (HbA(1c) 7.1 ± 0.5% [54 ± 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean (n = 8, BMI 23.0 ± 0.5 kg/m(2)) and obese (n = 14) volunteers who were BMI-matched (36.0 ± 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[(2)H(2)]glucose, lipolysis (rate of appearance of [(2)H(5)]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution). At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 ± 1.1 kg/m(2)), all diabetic patients were off glucose-lowering treatment and mean HbA(1c) was 5.4 ± 0.14% (36 ± 2 mmol/mol) (p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls. In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.

Resting energy expenditure and protein turnover are increased in patients with severe chronic obstructive pulmonary disease

The mechanisms leading to weight loss in patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Changes in protein metabolism and systemic inflammation may contribute to increased resting energy expenditure (REE) in COPD, leading to an energy imbalance and loss of fat and fat-free mass. The objective of this study was to determine first whether REE was increased in patients with COPD and, second, whether this was associated with increased protein turnover and/or systemic inflammation. Resting energy expenditure was determined using indirect calorimetry in 14 stable outpatients with severe COPD (7 with low and 7 with preserved body mass indices) and 7 healthy controls. Endogenous leucine flux, leucine oxidation, and nonoxidative disposal, indices of whole-body protein breakdown, catabolism, and synthesis, were measured using intravenous infusions of (13)C-bicarbonate and 1-(13)C-leucine. Total body water, from which fat-free mass and fat mass were calculated, was determined using an intravenous bolus of deuterated water. Plasma markers of systemic inflammation were also measured. As a group, subjects with COPD had increased REE adjusted for fat-free mass (P < .001) and faster rates of endogenous leucine flux (P = .006) and nonoxidative leucine disposal (P = .002) compared with controls. There was a significant correlation between REE and both endogenous leucine flux (P = .02) and nonoxidative leucine disposal (P = .008). Plasma concentrations of the inflammatory markers C-reactive protein and interleukin-6 were not different between COPD subjects and controls. Increased rates of protein turnover are associated with increased REE and loss of fat-free mass in COPD.

Comparison of leucine and dispensable amino acid kinetics between Indian women with low or normal body mass indexes during pregnancy

Evidence suggests that in women with a normal to high body mass index (BMI; in kg/m(2)), the extra amino acids needed during pregnancy are met through reduced oxidation. It is not known whether a woman with a low BMI can make this adaptation successfully. The objective was to measure and compare leucine kinetic parameters and alanine-nitrogen, glutamine amide-nitrogen, and glycine and cysteine fluxes in Indian women with a low and normal BMI in early and midpregnancy. Fasted- and fed-state kinetics were measured by infusing 1-[(13)C]leucine, [(2)H(2)]cysteine, [(2)H(2)]glycine, [5-(15)N]glutamine, and [(15)N]alanine in groups of 10 women with a low BMI (<18.5) and 10 women with a normal BMI (18.5-25) in the first and second trimesters of pregnancy. Leucine, glutamine, glycine, and cysteine fluxes were faster in women with a low BMI in both trimesters, but there was no difference in alanine flux between groups. This difference was explained in the first trimester by a higher proportion of fat-free mass in low-BMI women. Leucine oxidation and percentage of dietary leucine oxidized were higher in low-BMI women in both trimesters, but nonoxidative disposal was not different between groups. Although they use dietary protein less efficiently, low-BMI women maintain net protein synthesis at the same rate as do normal-BMI women and produce similar quantities of labile nitrogen for the de novo synthesis of other dispensable amino acids such as glycine and cysteine. The extra amino acids required for increased maternal protein synthesis during pregnancy are provided by an overall decrease in amino acid catabolism in women with normal or low BMI.

Ontogeny of methionine utilization and splanchnic uptake in critically ill children

To determine the rates of methionine splanchnic uptake and utilization in critically ill pediatric patients we used two kinetic models: the plasma methionine enrichment and the "intracellular" homocysteine enrichment. Twenty four patients, eight infants, eight children, and eight adolescents, were studied. They received simultaneous, primed, constant, intravenous infusions of l-[(2)H(3)]methylmethionine and enteral l-[1-(13)C]methionine. The ratio of [(13)C]homocysteine to [(13)C]methionine enrichment was 1.0 ± 0.15, 0.80 ± 0.20, and 0.66 ± 0.10, respectively, for the infants, children, and adolescents, and it was different between the infants and adolescents (P < 0.01). Methionine splanchnic uptake was 63, 45, and 36%, respectively, in the infants, children, and adolescents, and it was higher (P < 0.01) in the infants compared with the adolescents. The infants utilized 73% of methionine flux for nonoxidative disposal, while 27% was used for transulfuration (P < 0.001). Conversely, in the adolescents, 40% was utilized for nonoxidative disposal, while 60% was used for transulfuration. There is ontogeny on the rates of methionine splanchnic uptake and on the fate of methionine utilization in critically ill children, with greater methionine utilization for synthesis of proteins and methionine-derived compounds (P < 0.01) and decreased transulfuration rates in the infants (P < 0.01), while the opposite was observed in the adolescents. The plasma model underestimated methionine kinetics in children and adolescents but not in the infants, suggesting lesser dilution and greater compartmentation of methionine metabolism in the infant population. All patients were in negative methionine balance, indicating that the current enteral nutritional support is inadequate in these patients.

WHOLE-BODY CO2 PRODUCTION AS AN INDEX OF THE METABOLIC RESPONSE TO SEPSIS

Whole-body carbon dioxide (CO2) production (RaCO2) is an index of substrate oxidation and energy expenditure; therefore, it may provide information about the metabolic response to sepsis. Using stable isotope techniques, we determined RaCO2 and its relationship to protein and glucose metabolism in medical patients with sepsis and septic shock. Whole-body CO2 production, an index of basal metabolic rate, was measured in 13 patients with sepsis or septic shock and 7 healthy controls using an i.v. infusion of 13C-sodium bicarbonate. Endogenous leucine flux, leucine oxidation, and nonoxidative disposal, indices of whole-body protein breakdown, catabolism, and synthesis, were measured with an infusion of 1-13C-leucine, and glucose production and clearance were measured with an infusion of 2H2-glucose. There was no difference in mean RaCO2 between the patients and controls, but the patients had a wider range of values. The four patients with the lowest RaCO2 died. Protein breakdown and synthesis and glucose production were significantly faster in patients than in controls (P < 0.05). Whole-body CO2 production was positively correlated with protein breakdown (P = 0.001), protein synthesis (P < 0.01), and glucose clearance (P = 0.01). Patients with low metabolic rates (mean-2 SDs of controls) had slower protein breakdown and decreased glucose clearance compared with patients with high metabolic rates (mean + 2 SDs of controls). Septic patients were both hypometabolic and hypermetabolic. The correlation between RaCO2 and protein breakdown and synthesis as well as glucose clearance suggests that RaCO2 can provide information about substrate metabolism in septic patients. Because hypometabolism was associated with mortality and changes in protein and glucose metabolism in septic patients, it may be a useful clinical indicator of an inadequate metabolic response.

Glucose flux is elevated in men, but not women, during the post‐exercise recovery period

We tested whether glucose rate of appearance (Ra), disappearance (Rd), and metabolic clearance rate (MCR) would remain elevated following exercise. 10 men and 8 women received a primed‐continuous infusion of [6,6‐2H2]glucose tracer to measure glucose kinetics under 3 different conditions: 1) before, during and 3 h after 90 min of exercise at 45% VO2peak (E45), 2) before, during, and 3 h after 60 min of exercise at 65% VO2peak (E65), and 3) in a time‐matched sedentary control trial (C). Glucose Ra, Rd, MCR, and carbohydrate oxidation (CHOox) declined in C from the pre‐exercise time points to those corresponding to post‐exercise recovery in both men and women (P &lt; 0.05). In men and women, Ra, Rd, and MCR increased above C during exercise and were higher in E65 than E45 (p &lt; 0.05). Average Ra, Rd, and MCR remained elevated above C over 3 h of post‐exercise recovery in men following exercise in E45 and E65 (P &lt; 0.05). In contrast, average Ra and Rd did not remain significantly elevated during post‐exercise recovery in women, although MCR did remain significantly elevated in E65 in women during post‐exercise recovery (P &lt; 0.05). During post‐exercise recovery, CHOox was lower than in C in both sexes (P &lt; 0.05). Depressed CHOox with elevated glucose disposal (men) or maintained glucose disposal (women), characterizes post‐exercise recovery as a time of CHO mobilization and partitioning toward non‐oxidative disposal. NIH grant AR 42906.

Effect of timing of energy and carbohydrate replacement on post-exercise insulin action

The nutritional environment surrounding an exercise bout modulates post-exercise insulin action. The purpose of this study was to determine how timing energy and carbohydrate replacement proximate to an exercise bout influences exercise-enhanced insulin action. To create an appropriate baseline, sensitivity to insulin was reduced in 9 healthy young men (n=6) and women (n=3) by 2 days of energy surplus and detraining. Then, insulin action (glucose uptake per unit plasma insulin) was assessed by stable isotope dilution during a continuous glucose infusion 12 h after a standardized meal under 4 conditions. In 3 conditions, the meal replaced the energy and carbohydrate expended during an exercise bout (62.9+/-2.8 min cycle ergometry at 65% VO2 peak followed by ten 30 s sprints). The meal was given before (Pre), immediately after (ImmPost), or 3 h after exercise (Delay). The 4th condition was a no-exercise control (Control). Data were analyzed using linear mixed-effects models with planned contrasts. Relative to Control, insulin action increased by 22% in Pre (p=0.05), 44% in ImmPost (p<0.01), and 19% in Delay (p=0.09). Non-oxidative disposal was higher, and oxidative disposal was lower in ImmPost relative to Control and Pre (p<0.05). Hepatic glucose production was suppressed by the infusion to a greater extent in Pre and Delay (76.9%+/-8.8% and 81.2%+/-4.7%) compared with ImmPost (64.7%+/-10.0%). A bout of exercise enhances insulin action even when expended energy and carbohydrate are replaced. Further, timing of energy and carbohydrate consumption subtly modulates the effectiveness of exercise to enhance insulin action.