Portal vein and systemic adiponectin concentrations are closely linked with hepatic glucose and lipoprotein kinetics in extremely obese subjects

Low systemic plasma adiponectin concentrations are associated with abnormalities in hepatic glucose and lipoprotein metabolism in obese people. However, the relationship between the delivery of adiponectin to the liver via the portal vein and hepatic glucose and lipoprotein metabolism is not known. We examined the relationship between hepatic substrate metabolism (glucose rate of appearance into plasma and hepatic very low-density lipoprotein [VLDL]-triglyceride [TG] and VLDL-apolipoprotein B-100 [apoB-100] secretion rates, determined by using stable isotope-labeled tracer techniques) and portal vein adiponectin concentration, in 8 insulin-resistant, extremely obese subjects (body mass index, 65 ± 7 kg/m²). Portal vein adiponectin concentration was inversely associated with basal glucose rate of appearance (r = −0.820, P = .013) and VLDL-TG (r = −0.823, P = .012) and VLDL-apoB-100 (r = −0.787, P = .020) secretion rates. Very similar correlations were obtained for radial artery adiponectin as a result of a mirroring relationship between portal and arterial adiponectin concentrations (r = 0.899, P = .002) and the absence of significant arteriovenous concentration differences (P = .570). Insulin resistance, assessed with the homeostasis model assessment score, was also strongly associated with hepatic glucose and lipid metabolic parameters, as well as with adiponectin concentrations in the portal vein and radial artery. These results suggest that adiponectin delivery to the liver, whether via the portal or the systemic circulation, may be an important regulator of basal hepatic glucose, VLDL-TG, and VLDL-apoB-100 production rates in obese people, possibly through direct effects on the liver or changes in hepatic insulin sensitivity. However, portal vein adiponectin does not appear to be superior to arterial adiponectin as a marker of hepatic metabolic dysregulation. Additional studies are needed to elucidate the mechanism(s) responsible for the strong association we observed between adiponectin and hepatic substrate metabolism.     

Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas

Primary aldosteronism (PA) and, in particular, its two commonest subtypes (i.e. idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA)) have been recognized as the most common cause of secondary hypertension. While 'conservative' medical treatment with aldosterone receptor antagonists is the therapeutic approach of choice in controlling blood pressure in patients with PA due to IHA, the more invasive (laparoscopic) adrenalectomy seems to be the most suitable therapy for patients with APA. In this review, we focus on the medical approach for the management of APA in cases where surgical excision of the adrenal is not possible.     

Effect of Roux-en-Y Gastric Bypass and Laparoscopic Adjustable Gastric Banding on Branched-Chain Amino Acid Metabolism

It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, possibly by decreased signaling through the mammalian target of rapamycin (mTOR). We evaluated plasma BCAAs and their C3 and C5 acylcarnitine metabolites, muscle mTOR phosphorylation, and insulin sensitivity (insulin-stimulated glucose R_d) in obese subjects before and after ∼20% weight loss induced by RYGB (n = 10, BMI 45.6 ± 6.7 kg/m²) or laparoscopic adjustable gastric banding (LAGB) (n = 10, BMI 46.5 ± 8.8 kg/m²). Weight loss increased insulin-stimulated glucose R_d by ∼55%, decreased total plasma BCAA and C3 and C5 acylcarnitine concentrations by 20–35%, and did not alter mTOR phosphorylation; no differences were detected between surgical groups (all P values for interaction >0.05). Insulin-stimulated glucose R_d correlated negatively with plasma BCAAs and with C3 and C5 acylcarnitine concentrations (r values −0.56 to −0.75, P < 0.05). These data demonstrate that weight loss induced by either LAGB or RYGB causes the same decline in circulating BCAAs and their C3 and C5 acylcarnitine metabolites. Plasma BCAA concentration is negatively associated with skeletal muscle insulin sensitivity, but the mechanism(s) responsible for this relationship is not known.Insulin resistance is a common metabolic complication of obesity (1,2) and an important risk factor for developing type 2 diabetes and the metabolic syndrome (3). Several mechanisms are purported to be responsible for obesity-induced insulin resistance, including abnormalities in fatty acid metabolism (4), systemic and adipose tissue inflammation (5), alterations in intracellular lipid metabolites (6), mitochondrial dysfunction (7), and endoplasmic reticulum stress (8). Recently, it has been proposed that an increase in circulating branched-chain amino acids (BCAAs), valine, leucine, and isoleucine, and their acylcarnitine metabolites, C3 and C5, is also involved in the pathogenesis of insulin resistance (9–11). Moreover, the plasma concentrations of these metabolites are prognostic for the development of type 2 diabetes (12) and for the improvement in insulin sensitivity in response to therapeutic interventions (13). The potential mechanism(s) responsible for the relationship between BCAA metabolism and insulin action is not clear. Studies conducted in rodent models and cultured rat myocytes found that increased exposure of skeletal muscle cells to BCAA impairs insulin action in concert with activation of the mammalian target of rapamycin (mTOR), which causes serine phosphorylation of insulin receptor substrate-1 and disrupts insulin signaling (9,14–16). In addition, amino acid infusion in human subjects activates the mTOR pathway and impairs skeletal muscle insulin action (17–19), whereas treatment with rapamycin, an mTOR inhibitor, increases skeletal muscle insulin sensitivity (17). Weight loss induced by bariatric surgery improves insulin sensitivity (20). However, the importance of BCAA metabolism in mediating the weight loss–induced improvement in insulin sensitivity after bariatric surgery is not clear. Data obtained from two centers found that both ∼10 and ∼22% weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery caused a greater decrease in BCAA concentrations than matched weight loss induced by calorie restriction alone, which led to the hypothesis that alterations in BCAA metabolism contribute to a weight loss–independent improvement in insulin sensitivity after altering gastrointestinal tract anatomy by RYGB (21).The purpose of the current study was to evaluate the hypothesis that weight loss induced by RYGB surgery causes greater alterations in BCAA metabolism and a greater reduction in skeletal muscle mTOR activation than matched weight loss induced by laparoscopic adjustable gastric banding (LAGB). Accordingly, plasma BCAA and C3 and C5 acylcarnitine concentrations, skeletal muscle mTOR phosphorylation, and skeletal muscle insulin sensitivity were assessed in obese subjects before and after ∼20% weight loss induced by RYGB or LAGB.     

Lifestyle factors affecting heel ultrasound in Greek females across different life stages

The use of quantitative ultrasound (QUS) of the bone is rapidly gaining in popularity, and QUS is widely used worldwide for the assessment of skeletal status. Although much has been learned about the influence of various factors on ultrasonic parameters in various populations, similar information at the local level is not available. This study was carried out to examine the effects of anthropometric, dietary, physical activity, reproductive, and other lifestyle factors on QUS parameters in healthy Greek women, including children (n=217), adults (n=235), and elderly (n=369) subjects. Calcaneal QUS measurements were performed with the SAHARA device, which measures broadband ultrasound attenuation (BUA) and speed of sound (SOS) through the os calcis; a composite parameter, the quantitative ultrasound index (QUI), and an estimate of heel bone mineral density (eBMD) were also derived. All QUS indices were higher in adult women than in girls or elderly women (P<0.05). The latter had a similar BUA to girls, but lower SOS, QUI, and eBMD (P<0.05). Most QUS parameters correlated positively with height, weight, body mass index (BMI), hip circumference, organized physical activity, and activity promoting bone mass, but negatively with the time devoted to sedentary activities and absolute carbohydrate intake (P<0.05). Age of menarche and years since menopause were negatively associated with QUS in the adult and elderly women, respectively (P<0.05). The latter relationship, however, was due to the confounding effect of advancing age. Overweight and obese females had significantly higher BUA and eBMD than normal-weight subjects (P<0.05), but similar SOS and QUI; this held true for all age groups. Likewise, in all ages, individuals spending more than 2 h/week on organized activities had significantly higher QUS indices than those spending less time on exercise (P<0.05). Further, postmenarchial girls had significantly higher age-adjusted BUA, SOS, QUI, and eBMD than premenarchial ones (P<0.05). Similarly, all QUS parameters were significantly higher in adult women with an early onset of menarche (<14 years old) than in those with a late onset (P<0.05), but no effects of menarche were detected among the elderly. No significant effects of calcium intake (which was generally adequate), smoking or alcohol drinking (which were generally low) on QUS indices were observed, in either age group. Available independent variables could explain approximately 16%–24% of the total variance in BUA, SOS, QUI and eBMD. The most important positive predictors of QUS were adulthood, time devoted to organized activities, and weight or BMI, while age and carbohydrate intake per se contributed negatively. In conclusion, age, body size, physical activity, and some aspects of reproductive history and diet appear to variably affect calcaneal QUS indices among otherwise healthy Greek women at different life stages.     

The type and intensity of exercise have independent and additive effects on bone mineral density

Previous research on the effects of running and swimming on areal bone mineral density (aBMD) is inconclusive. This study examined the putative roles of the type and intensity of exercise in this respect, by measuring aBMD (adjusted for age, weight, and height) of the total body and of various subregions in 52 males aged 17 - 30 yr (21 runners, 16 swimmers, 15 controls). The athletes were competing at either long-distance ("endurance", n = 17) or short-distance ("sprint", n = 20) events. Compared with controls, runners had significantly higher leg aBMD (+ 6.7 %, p < 0.05), while swimmers had significantly lower leg and total body aBMD (- 9.8 % and - 7.0 %, respectively, p < 0.05). Endurance athletes had significantly lower total body aBMD than controls (- 4.9 %, p < 0.05). Sprint athletes did not differ significantly from controls at any site, but they had significantly higher aBMD than endurance athletes throughout the skeleton (p < 0.05). Compared with controls, endurance swimmers had significantly lower aBMD at the legs and total body (- 14.8 % and - 10.4 %, respectively, p < 0.05), while sprint runners had significantly higher values for the legs, trunk, and total body (+ 8.0 %, + 10.0 %, and + 6.3 %, respectively, p < 0.05). Sprint swimmers and endurance runners did not differ from controls at any site or the total body. These results suggest that the type and intensity of exercise have independent and additive effects on bone density.     

Free fatty acid kinetics in the late phase of postexercise recovery: importance of resting fatty acid metabolism and exercise-induced energy deficit

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope–labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 ± 7 years; body mass index, 25 ± 4 kg/m²) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P ≤ .008) and net energy expenditure of exercise (P ≤ .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.     

Stable isotope tracer dilution for quantifying very low-density lipoprotein-triacylglycerol kinetics in man

BACKGROUND & AIM: A number of approaches have been employed in the past to measure very low-density lipoprotein (VLDL) triacylglycerol (TG) kinetics in humans in vivo, varying in the selection of tracer and mode of administration. All, however, make use of labeled TG precursors and more or less complicated mathematical models to derive the kinetic parameters of interest. The aim of the present study was to develop a conceptually straightforward method, based on the traditional tracer infusion technique, for quantifying VLDL-TG production rates in man using stable isotopes. METHOD: Our approach involves ingestion of [U-13C3]glycerol to endogenously label the glycerol in VLDL-TG, plasmapheresis, isolation of the newly 13C-labeled VLDL from plasma, and administration within the next 2-3 days via a primed constant autologous reinfusion. This procedure produces enough tracer for a priming dose plus 2-3 h of infusion. In the physiological conditions examined (basal and hyperglycemic states, fat- and carbohydrate-rich diets), with almost 3-fold ranging VLDL-TG pool sizes, a steady state in plasma VLDL-TG glycerol tracer-to-tracee ratio was readily achieved within 2 h. Consequently, calculations are made according to the isotope dilution principle, thus avoiding assumptions implicit in more complicated models. CONCLUSION: The stable isotope VLDL-TG tracer dilution method offers an alternative and reliable tool for the determination of endogenous VLDL-TG kinetics in man under a variety of metabolic states.