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Hypertension is characterized by systemic microvascular endothelial dysfunction, in part due to a functional absence of hydrogen sulfide (H2S)-mediated endothelium-dependent dilation. Treatment with a sulfhydryl-donating ACE inhibitor (SH-ACE inhibitor) improves endothelial function in preclinical models of hypertension. To date, no studies have directly assessed the effects of SH-ACE-inhibitor treatment on H2S-dependent vasodilation in humans with hypertension. We hypothesized that SH-ACE-inhibitor treatment would improve H2S-mediated endothelium-dependent vasodilation. Ten adults with hypertension [1 woman and 9 men; 56 ± 9 yr; systolic blood pressure (SBP): 141 ± 8.5 mmHg; diastolic blood pressure (DBP): 90.3 ± 6 mmHg] were treated (16 wk) with the SH-ACE-inhibitor captopril. Red blood cell flux (laser-Doppler flowmetry) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh; 10-10 to 10-1 M) alone (control) and in combination with an inhibitor of enzymatic H2S production [10-3 M aminooxyacetate (AOAA)] preintervention and postintervention. Cutaneous vascular conductance (CVC; flux/mmHg) was calculated and normalized to the site-specific maximal CVC (0.028M sodium nitroprusside and local heat to 43°C). Area under the curve was calculated using the trapezoid method. The 16- wk SH-ACE-inhibitor treatment resulted in a reduction of blood pressure (systolic BP: 129 ± 10 mmHg; diastolic BP: 81 ± 9 mmHg, both P < 0.05). Preintervention, inhibition of H2S production had no effect on ACh-induced vasodilation (316 ± 40 control vs. 322 ± 35 AU AOAA; P = 0.82). Captopril treatment improved ACh-induced vasodilation (316 ± 40 pre vs. 399 ± 55AU post; P = 0.04) and increased the H2S-dependent component of ACh-induced vasodilation (pre: -6.6 ± 65.1 vs. post: 90.2 ± 148.3 AU, P = 0.04). These data suggest that SH-ACE-inhibitor antihypertensive treatment improves cutaneous microvascular endothelium-dependent vasodilation in adults with hypertension, in part via H2S-dependent mechanisms. [ABSTRACT FROM AUTHOR]

This study investigated the effects of different multiple low doses of streptozotocin (STZ), namely 35 and 55 mg/kg, on the onset and progression of diabetes in mice. Both doses are commonly used in research, and although both induced a loss of beta cell mass, they had distinct effects on whole glucose tolerance, beta cell function, and gene transcription. Mice treated with 55 mg/kg became rapidly glucose intolerant, whereas those treated with 35 mg/kg had a slower onset and remained glucose tolerant for up to a week before becoming equally glucose intolerant as the 55 mg/kg group. Beta cell mass loss was similar between the two groups, but the 35 mg/kg-treated mice had improved glucose-stimulated insulin secretion in gold-standard hyperglycemic clamp studies. Transcriptomic analysis revealed that the 55 mg/kg dose caused disruptions in nearly five times as many genes as the 35 mg/kg dose in isolated pancreatic islets. Pathways that were downregulated in both doses were more downregulated in the 55 mg/kg-treated mice, whereas pathways that were upregulated in both doses were more upregulated in the 35 mg/kg-treated mice. Moreover, we observed a differential downregulation in the 55 mg/kg-treated islets of beta cell characteristic pathways, such as exocytosis or hormone secretion. On the other hand, apoptosis was differentially upregulated in 35 mg/kgtreated islets, suggesting different transcriptional mechanisms in the onset of STZ-induced damage in the islets. This study demonstrates that the two STZ doses induce distinctly mechanistic progressions for the loss of functional beta cell mass. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 lg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ±0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only (R² = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ±0.9 vs. 9.6 ± 1.7%, P < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes. [ABSTRACT FROM AUTHOR]

Interrupting prolonged sitting with intermittent exercise enhances postprandial glycemic control but has unknown effects on sensitizing skeletal muscle to dietary amino acids. We hypothesized that brief walking or body weight squats would enhance the utilization of dietary phenylalanine for myofibrillar protein synthesis (MyoPS) during prolonged sitting. Participants (1 males and 5 females; ~23 yr; ~25.1 kg/m²; ~1,300 steps/day) completed three 1.5-h trials consisting of prolonged sitting (SIT) or sitting with intermittent (every 30 min) walking (WALK) or body weight squatting (SQUAT). Two mixed-macronutrient meals (~55:30:15% carbohydrate: fat:protein), enriched with L-[ring-²H5]phenylalanine or L-[ring-13C6]phenylalanine, were provided to mimic breakfast and lunch. Tracer incorporation into myofibrillar protein was determined from the vastus lateralis with MyoPS estimated using plasma enrichment as precursor surrogate. Phosphorylation of candidate anabolic signaling proteins was determined by immunoblot-ting. There was no difference between conditions (P ≥ 0.78) in the time course or area under the curve for plasma phenylalanine enrichment. MyoPS was greater (P < 0.05, weighted planned comparison) in SQUAT (0.103±0.030%/h) and WALK (0.118±0.031%/h) compared with SIT (0.080±0.032%/h). When compared with SIT, there were moderate-to-large effect sizes, respectively, for SQUAT [effect size (ES) = 0.15; 95% CI -0.10-1.55] and WALK (ES = 1.10; 95% CI 0.20-1.91). Fold change in rpS6Ser240/244 phosphorylation was greater in SQUAT compared with SIT (1.6 ±2.1 vs. 1.6 ± 0.45-fold, P < 0.05) with no difference (P ≥ 0.21) in any other targets measured (4E-BP1Thr31/46, eEF2Thr56, mTORSer2448, ERK1/2Thr202/Tyr204). Interrupting prolonged sitting with short "activity snacks" improves the utilization of dietary amino acids for MyoPS. The long-term impact of this practical lifestyle modification for muscle mass or quality should be investigated. NEW & NOTEWORTHY Prolonged sitting can impair postprandial glycemia, lipidemia, and insulin sensitivity regardless of previous health status. We demonstrate that interrupting prolonged sitting with brief periods of activity, such as body weight squats or short bouts of walking, improves the efficiency of dietary amino acid utilizations for muscle contractile protein synthesis. This further emphasizes the importance of minimizing sedentary time to improve the postprandial metabolism of all macronutrients. [ABSTRACT FROM AUTHOR]

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFα) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in nonlactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 extracellular signal-regulated kinase (ERK1/2) following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21-resistant state. [ABSTRACT FROM AUTHOR]

Although the patterns of response within the sympathoadrenal medullary (SAM) system and hypothalamo-pituitary adrenal (HPA) axis are interesting and important in their own accord, the overall response to acute psychological stress involves reactivity of both pathways. We tested the hypothesis that consideration of the integrated response of these pathways may reveal dysregulation of the stress systems, which is not evident when considering either system alone. Age-matched lean and overweight/obese men were subjected to a Trier Social Stress Test and reactivity of the SAM system (salivary a-amylase, systolic blood pressure, diastolic blood pressure, and heart rate) and the HPA axis (salivary cortisol) were measured. Relative reactivity of SAM system and HPA axis was calculated as the ratio between the measures from each pathway. Although analysis of reactivity of individual stress pathways showed no evidence of dysfunction in overweight/obese compared with lean men, analysis of HPA/SAM reactivity revealed significantly lower cortisol over systolic blood pressure (CoSBP) and cortisol over diastolic blood pressure (CoDBP) reactivity in overweight/obese compared with lean men. Other measures of HPA/SAM reactivity and all measures of SAM/HPA reactivity were unaltered in overweight/obese compared with lean men. These findings suggest that the cortisol response per unit of blood pressure response is blunted in men with elevated adiposity. Furthermore, these findings support a notion of a coordinated overall approach to activation of the stress pathways with the degree of activation in one pathway being related to the degree of activation in the other. [ABSTRACT FROM AUTHOR]

Exercise is a treatment in rheumatoid arthritis, but participation in moderate-to-vigorous exercise is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. We compared the acute effects of active breaks in sitting with those of moderate-to-vigorous exercise on cardiometabolic risk markers in patients with rheumatoid arthritis. In a crossover fashion, 15 women with rheumatoid arthritis underwent three 8-h experimental conditions: prolonged sitting (SIT), 30-min bout of moderate-to-vigorous exercise followed by prolonged sitting (EX), and 3-min bouts of light-intensity walking every 30 min of sitting (BR). Postprandial glucose, insulin, c-peptide, triglycerides, cytokines, lipid classes/subclasses (lipidomics), and blood pressure responses were assessed. Muscle biopsies were collected following each session to assess targeted proteins/genes. Glucose [-28% in area under the curve (AUC), P = 0.036], insulin (-28% in AUC, P = 0.016), and c-peptide (-27% in AUC, P = 0.006) postprandial responses were attenuated in BR versus SIT, whereas only c-peptide was lower in EX versus SIT (-20% in AUC, P = 0.002). IL-1b decreased during BR, but increased during EX and SIT (P = 0.027 and P = 0.085, respectively). IL-1ra was increased during EX versus BR (P = 0.002). TNF-α concentrations decreased during BR versus EX (P = 0.022). EX, but not BR, reduced systolic blood pressure (P = 0.013). Lipidomic analysis showed that 7 of 36 lipid classes/subclasses were significantly different between conditions, with greater changes being observed in EX. No differences were observed for protein/gene expression. Brief active breaks in sitting can offset markers of cardiometabolic disturbance, which may be particularly useful for patients who may find it difficult to adhere to exercise. [ABSTRACT FROM AUTHOR]

The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole body insulin resistance or a normal adjustment to potentially increased hepatic insulin action is unknown. We examined the effects of 36- versus 12-h fasting on insulin secretion and whole body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action were studied using stable isotopes, whereas whole body insulin action and insulin secretion were studied using an intravenous glucose tolerance test (IVGTT) and minimal modeling. Insulin, glucose, and lipid profiles were subsequently measured during a refeeding meal test. Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action, contrasting an increase in whole body insulin resistance. Accordingly, prolonged fasting was associated with opposite-directed effects on hepatic versus whole body insulin secretion disposition indices. Thirtysix- hour fasting compared with 12-h fasting was associated with increased serum insulin levels during the refeeding meal test. In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ-specific insulin action into account may lead to erroneous conclusions. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the mechanisms known to regulate glucose homeostasis in human skeletal muscle of healthy and prediabetic subjects exercising in normobaric hypoxia. Seventeen healthy (H; 28.8 ± 2.4 yr; maximal oxygen consumption (... O2max): 45.1 ± 1.8 mL·kg-1·min-1) and 15 prediabetic (P; 44.6 ± 3.9 yr; ... O2max: 30.8 ± 2.5 mL·kg-1·min-1) men were randomly assigned to two groups performing an acute exercise bout (heart rate corresponding to 55% ... O2max) either in normoxic (NE) or in hypoxic (HE; fraction of inspired oxygen FIO2 14.0%) conditions. An oral glucose tolerance test (OGTT) was performed in a basal state and after an acute exercise bout. Muscle biopsies from m. vastus lateralis were taken before and after exercise. Venous blood samples were taken at regular intervals before, during, and after exercise. The two groups exercising in hypoxia had a larger area under the curve of blood glucose levels during the OGTT after exercise compared with baseline (H: þ11%; P: þ4%). Compared with pre-exercise, an increase in p-TBC1D1 Ser237 and in p-AMPK Thr172 was observed postexercise in P NE (+95%; +55%, respectively) and H HE (+91%; +43%, respectively). An increase in p-ACC Ser212 was measured after exercise in all groups (H NE: +228%; P NE: +252%; H HE: +252%; P HE: +208%). Our results show that an acute bout of exercise in hypoxia reduces glucose tolerance in healthy and prediabetic subjects. At a molecular level, some adaptations regulating glucose transport in muscle were found in all groups without associations with glucose tolerance after exercise. The results suggest that hypoxia negatively affects glucose tolerance postexercise through unidentified mechanisms. [ABSTRACT FROM AUTHOR]

Cardiorespiratory fitness (CRF) is positively associated with insulin sensitivity, whereas excessive levels of visceral adipose tissue (AT) and liver fat (LF) are both associated with insulin resistance and impaired plasma glucose-insulin homeostasis. To what extent levels of visceral AT and LF content contribute to the relationship between CRF and indices of plasma glucose-insulin homeostasis is uncertain. Our objective was to explore the interactions among CRF, visceral AT, and LF with glucose tolerance/insulin levels in asymptomatic and apparently healthy individuals. CRF was measured in 135 women and 177 men with a maximal treadmill graded exercise test. Indices of plasma glucose-insulin homeostasis were derived from a 3-h oral glucose tolerance test (OGTT) performed in the morning after a 12-h fast. Visceral AT levels and LF content were measured using magnetic resonance imaging and spectroscopy. For any given CRF level, women presented significantly lower visceral AT and LF than men as well as lower homeostasis model assessment of insulin resistance (HOMA-IR) and plasma glucose-insulin levels during the OGTT compared with men. In both sexes, there were significant negative correlations between CRF and HOMA-IR as well as glucose and insulin levels measured during the OGTT. Both glucose and insulin levels during the OGTT correlated positively with visceral AT and LF. In women and men, being in the top CRF tertile was associated with low levels of visceral AT and LF. Multivariable linear regression analyses suggested that visceral AT and LF were plausible mediators of the association between CRF and indices of plasma glucose-insulin homeostasis. [ABSTRACT FROM AUTHOR]

Consumption of a single, sugar-sweetened beverage (SSB) impairs vascular endothelial function. Regular aerobic exercise improves endothelium-dependent vasodilation; however, it is unknown whether these beneficial effects persist with frequent SSB consumption. Therefore, the purpose of this study was twofold; we studied the effects of repetitive SSB consumption (75 g d-glucose, 3 times/day) for 1 wk (Glu, n = 13, 23 ± 4 yr, 23.5 ± 3.4 kg/m²) on endothelium-dependent vasodilation (FMD). Then, in a separate cohort, we investigated whether 45 min of moderate-intensity aerobic exercise on five separate days offset the hypothesized decrease in FMD during the Glu protocol (Glu+Ex, n = 11, 21 ± 3 yr, 23.8 ± 2.4 kg/m²). Baseline, fasting [glucose] (P = 0.15), [insulin] (P = 0.25), %FMD (P = 0.48), absolute FMD (P = 0.66), and shear rate area under the curve (SRAUC; P = 0.82) were similar between groups. Following the interventions, fasting [glucose] (Glu: 94 ± 6 to 92 ± 6 mg/dL, Glu+Ex: 89 ± 8 to 87 ± 6 mg/dL, P = 0.74) and [insulin] (Glu: 11.3 ± 6.2 to 11.8 ± 8.9 μU/mL, Glu+Ex: 8.7 ± 2.9 to 9.4 ± 3.2 μU/mL, P = 0.89) were unchanged. %FMD was reduced in Glu (6.1 ± 2.2 to 5.1 ± 1.3%) and increased in Glu+Ex (6.6 ± 2.2 to 7.8 ± 2.4%, P < 0.05 for both). SRAUC increased similarly in both Glu [17,715 ± 8,275 to 22,922 ± 4,808 arbitrary units (A.U.)] and Glu+Ex (18,216 ± 4,516 to 21,666 ± 5,392 A.U., main effect of time P < 0.05). When %FMD was adjusted for SRAUC, attenuation was observed in Glu (0.41 ± 0.18 to 0.23 ± 0.08%/s × 103, P < 0.05) but not Glu+Ex (0.38 ± 0.14 to 0.38 ± 0.13%/s × 103, P = 0.88). Despite unchanged fasting [glucose] and [insulin], repeated consumption of SSBs impaired conduit artery vascular endothelial function. Additionally, subjects who engaged in regular moderate-intensity aerobic exercise did not demonstrate the same SSB-induced endothelial dysfunction. Collectively, these data suggest aerobic exercise may offset the deleterious effects of repetitive SSB consumption. [ABSTRACT FROM AUTHOR]

High-intensity exercise inhibits appetite, in part, via alterations in the peripheral concentrations of the appetite-regulating hormones acylated ghrelin, active glucagon-like peptide-1 (GLP-1), and active peptide tyrosine-tyrosine (PYY). Given lactate may mediate these effects, we used sodium bicarbonate (NaHCO3) supplementation in a double-blind, placebo-controlled, crossover design to investigate lactate’s purported role in exercise-induced appetite suppression. Eleven males completed two identical high-intensity interval training sessions (10 × 1 min cycling bouts at ~90% heart rate maximum interspersed with 1-min recovery), where they ingested either NaHCO3 (BICARB) or sodium chloride (NaCl) as a placebo (PLACEBO) preexercise. Blood lactate, acylated ghrelin, GLP-1, and PYY concentrations, as well as overall appetite were assessed preexercise and 0, 30, 60, and 90 min postexercise. Blood lactate was greater immediately (P < 0.001) and 30 min postexercise (P = 0.049) in the BICARB session with an increased (P = 0.009) area under the curve (AUC). The BICARB session had lower acylated ghrelin at 60 (P = 0.014) and 90 min postexercise (P = 0.016), with a decreased AUC (P = 0.039). The BICARB session had increased PYY (P = 0.034) with an increased AUC (P = 0.031). The BICARB session also tended (P = 0.060) to have increased GLP-1 at 30 (P = 0.003) and 60 min postexercise (P < 0.001), with an increased AUC (P = 0.030). The BICARB session tended (P = 0.059) to reduce overall appetite, although there was no difference in AUC (P = 0.149). These findings support a potential role for lactate in the high-intensity exercise-induced appetite-suppression. NEW & NOTEWORTHY We used sodium bicarbonate to increase lactate accumulation or sodium chloride as a placebo. Our findings further implicate lactate as a mediator of exercise-induced appetite suppression, given exercise-induced increases in lactate during the sodium bicarbonate session altered peripheral concentrations of appetite-regulating hormones, culminating in a reduction of appetite. This supports a lactate-dependent mechanism of appetite suppression following high-intensity exercise and highlights the potential of using lactate as a means of inducing a caloric deficit. [ABSTRACT FROM AUTHOR]

The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female cycling and pregnant rats. In the nonpregnant state, female Sprague-Dawley rats offered a 3-wk free-choice high-fat, high-sucrose diet had greater energy intake, adiposity, serum leptin, and triglyceride concentrations compared with rats fed with standard chow and developed glucose intolerance. In addition, choice-diet-fed rats had larger cardiac ventricular weights, smaller kidney and pancreas weights, and higher blood pressure than chow-fed rats, but they did not exhibit resistance artery endothelial dysfunction. When the free-choice diet continued throughout pregnancy, rats remained hyperphagic, hyperleptinemic, and obese. Choice pregnant rats exhibited uterine artery endothelial dysfunction and had smaller fetuses compared with chow pregnant rats. Pregnancy normalized mean arterial blood pressure and pancreas weights in choice rats. These studies are the first to provide a comprehensive evaluation of free-choice high-fat, high-sucrose diet on metabolic and cardiovascular functions in female rats, extending the previous studies in males to female cycling and pregnant rodents. Free-choice diet may provide a new model of preconceptual maternal obesity to study the role of increased energy intake, individual food components, and preexisting maternal obesity on maternal and offspring physiological responses during pregnancy and after birth. [ABSTRACT FROM AUTHOR]

A prospective, randomized, controlled study was designed to determine relative aerobic and anaerobic (lactic and alactic) contributions at supramaximal exercise intensities using two different methods. Thoroughbred racehorses (n = 5) performed a maximal rate of oxygen consumption ( V̇o2max) test and three supramaximal treadmill runs (105, 115, and 125% V̇o2max). Blood lactate concentration (BL) was measured at rest, every 15 s during runs, and 2, 5, 10, 20, 30, 40, 50, and 60 min postexercise. In method 1, oxygen demand was calculated for each supramaximal intensity based on the V̇o2maxtest, and relative aerobic and anaerobic contributions were calculated from measured V̇o2 and the accumulated oxygen deficit. In method 2, aerobic contribution was calculated using the trapezoidal method to determine V̇o2 during exercise. A monoexponential model was fitted to the postexercise V̇o2 curve. Alactic contribution was calculated using the coefficients of this model. Lactate anaerobic contribution was calculated by multiplying the peak to resting change in BL by 3. Linear mixed-effects models were used to examine the effects of exercise intensity and method (as fixed effects) on measured outcomes (P ≤ 0.05). Relative aerobic and anaerobic contributions were not different between methods (P = 0.20). Horses’ mean contributions were 81.4, 77.6, and 72.5% (aerobic), and 18.5, 22.3, and 27.4% (anaerobic) at 105, 115, and 125% V̇o2max, respectively. Individual alactic anaerobic energy was not different between supramaximal exercise intensities (P = 0.43) and was negligible, contributing a mean of 0.11% of the total energy. Relative energy contributions can be calculated using measured V̇o2 and BL in situations where the exercise intensity is unknown. Understanding relative metabolic demands could help develop tailored training programs. NEW & NOTEWORTHY Relative energy contributions of horses can be calculated using measured V̇o2 and BL in situations where the exercise intensity is unknown. Horses’ mean contributions were 81.4, 77.6, and 72.5% (aerobic), and 18.5, 22.3, and 27.4% (anaerobic) at 105, 115, and 125% of V̇o2max, respectively. Individual alactic capacity was unaltered between supramaximal exercise intensities and accounted for a mean contribution of 0.11% of energy use. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction and Type 2 diabetes are associated with perturbed circadian rhythms. However, exercise appears to ameliorate circadian disturbances, as it can phase-shift or reset the internal clock system. Evidence is emerging that exercise at a distinct time of day can correct misalignments of the circadian clock and influence energy metabolism. This suggests that timing of exercise training can be important for the prevention and management of metabolic dysfunction. In this study, obese, high-fat diet-fed mice were subjected to voluntary wheel running (VWR) at two different periods of the day to determine the effects of time-of-day-restricted VWR on basal and insulin-stimulated glucose disposal. VWR in the late dark phase reduced body weight gain compared with VWR in the beginning of the dark phase. Conversely, time-of-day-restricted VWR did not influence insulin action and glucose disposal, since skeletal muscle and adipose tissue glucose uptake and insulin signaling remained unaffected. Protein abundance of the core clock proteins, brain-muscle arnt-like 1 (BMAL1), and circadian locomotor output control kaput (CLOCK), were increased in skeletal muscle after VWR, independent of whether mice had access to running wheels in the early or late dark phase. Collectively, we provide evidence that VWR in the late dark phase ameliorates diet-induced obesity without altering insulin action or glucose homeostasis. [ABSTRACT FROM AUTHOR]

Exercise performed in the fasted state acutely increases fatty acid availability and utilization. Furthermore, activation of energy-sensing pathways and fatty acid metabolic genes can be augmented by fasting and fasted exercise. However, whether a similar effect occurs at higher exercise intensities remains poorly understood. This study aimed to assess the effect of fed and fasted exercise upon postexercise signaling and mRNA responses during moderate- to high-intensity steady-state exercise. Eight male participants [age: 25 (SD 2) yr, Vo2peak: 47.9 (SD 3.8) ml·kg-1·min-1] performed 1 h of cycling at 70% Wmax in the fasted (FAST) state or 2 h following ingestion of a carbohydrate-rich mixed-macronutrient breakfast (FED). Muscle biopsies were collected pre-, immediately, and 3 h postexercise from the medial vastus lateralis, while venous blood samples were collected throughout the trial. Plasma, nonesterified fatty acid, and glycerol concentrations were elevated during FAST compared with FED, although substrate utilization during exercise was similar. AMPKThr172 phosphorylation was ~2.5-fold elevated postexercise in both trials and was significantly augmented by ~30% during FAST. CREBSer133 phosphorylation was elevated approximately twofold during FAST, although CREBSer133 phosphorylation acutely decreased by ~50% immediately postexercise. mRNA expression of PDK4 was approximately three- to fourfold augmented by exercise and approximately twofold elevated throughout FAST, while expression of PPARGC1A mRNA was similarly activated (~10-fold) by exercise in both FED and FAST. In summary, performing moderate- to high-intensity steady-state exercise in the fasted state increases systemic lipid availability, elevates phosphorylation of AMPKThr172 and CREBSer133, and augments PDK4 mRNA expression without corresponding increases in whole body fat oxidation and the mRNA expression of PPARGC1A. [ABSTRACT FROM AUTHOR]

Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (-5%, P < 0.05), whereas both LC+Ex (-16%, P < 0.001) and LC (-12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: -32%, LC: -45%, and LC+Ex: -44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (-76%, P = 0.035) and a tendency for a reduction in LC (-70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (-27%, P = 0.001) and LC+Ex (-35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking. [ABSTRACT FROM AUTHOR]

Regular exercise-induced acute inflammatory responses are suggested to improve the inflammatory profile and insulin sensitivity. As body temperature elevations partly mediate this response, passive heating might be a viable tool to improve the inflammatory profile. This study investigated the acute and chronic effects of hot water immersion on inflammatory and metabolic markers. Ten sedentary, overweight men [body mass index (BMI): 31.0 ± 4.2 kg/m2, mean ± SD] were immersed in water set at 39°C for 1 h (HWI) or rested for 1 h at ambient temperature (AMB). Venous blood was obtained before the session, immediately postsession, and 2 h postsession for assessment of monocyte intracellular heat shock protein-72 (iHsp72) and plasma concentrations of extracellular Hsp72 (eHsp72), interleukin-6 (IL-6), fasting glucose, insulin, and nitrite. Thereafter, participants underwent a 2-wk intervention period, consisting of 10 hot water immersion sessions (INT). Eight BMI-matched participants (BMI: 30.0 ± 2.5 kg/m2) were included as control (CON). Plasma IL-6 and nitrite concentrations were higher immediately following HWI compared with AMB (IL-6 P < 0.001, HWI: 1.37 ± 0.94 to 2.51 ± 1.49 pg/ml; nitrite P = 0.04, HWI: 271 ± 52 to 391 ± 72 nM), whereas iHsp72 expression was unchanged (P = 0.57). In contrast to resting iHsp72 expression (P = 0.59), fasting glucose (P = 0.04; INT: 4.44 ± 0.93 to 3.98 ± 0.98 mmol/l), insulin (P = 0.04; INT: 68.1 ± 44.6 to 55.0 ± 29.9 pmol/l), and eHsp72 (P = 0.03; INT: 17 ± 41% reduction) concentrations were lowered after INT compared with CON. HWI induced an acute inflammatory response and increased nitric oxide bioavailability. The reductions in fasting glucose and insulin concentrations following the chronic intervention suggest that hot water immersion may serve as a tool to improve glucose metabolism. NEW & NOTEWORTHY A single hot water immersion (HWI) session induces an acute increase in plasma interleukin-6 and nitrite concentrations but does not acutely elevate heat shock protein-72 expression in monocytes [intracellular Hsp72 (iHsp72)]. A chronic HWI intervention reduces fasting glucose and insulin concentrations in the absence of changes in resting iHsp72. Therefore, HWI shows potential as a strategy to combat chronic low-grade inflammation and improve glucose metabolism in individuals without the physical capacity to do so using exercise. [ABSTRACT FROM AUTHOR]

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) (n = 12) or Western diet (WD) (n = 24) for 5 mo, after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) (n = 12/group) for 2 mo. Seven months of WD caused gut dysbiosis, increased arterial stiffness (SD 412.0 ± 6.0 vs. WD 458.3 ± 9.0 cm/s, P < 0.05) and endothelial dysfunction (28% decrease in max dilation, P < 0.05), and reduced l-NAME-inhibited dilation. Vascular dysfunction was accompanied by significant increases in circulating LPS-binding protein (LBP) (SD 5.26 ± 0.23 vs. WD 11 ± 0.86 µg/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 ± 0.25 vs. WD 7.09 ± 1.07 pg/ml, P < 0.05); aortic expression of phosphorylated nuclear factor-κB (p-NF-κB) (P < 0.05); and perivascular adipose expression of NADPH oxidase subunit p67phox (P < 0.05). Impairments in vascular function correlated with reductions in Bifidobacterium spp. Antibiotic treatment successfully abrogated the gut microbiota and reversed WD-induced arterial stiffness and endothelial dysfunction. These improvements were accompanied by significant reductions in LBP, IL-6, p-NF-κB, and advanced glycation end products (AGEs), and were independent from changes in body weight and glucose tolerance. These results indicate that gut dysbiosis contributes to the development of WD-induced vascular dysfunction, and identify the gut microbiota as a novel therapeutic target for obesity-related vascular abnormalities. [ABSTRACT FROM AUTHOR]

Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D (n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD (P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/μl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte- platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D. [ABSTRACT FROM AUTHOR]

High-intensity exercise suppresses appetite partly through changes in peripheral appetite-regulating hormones. Lactate and IL-6 mediate the release of these hormones in animal/cell models and may provide a mechanistic link between exercise intensity and appetite regulation. The current study examined changes in appetite-regulating hormones, lactate, and IL-6 after different intensities of running. Eight males completed four experimental sessions: 1) moderate-intensity continuous training (MICT; 65% V̇o2max); 2) vigorous-intensity continuous training (VICT; 85% V̇o2max); 3) sprint interval training (SIT; repeated "all-out" sprints); and 4) Control (CTRL; no exercise). Acylated ghrelin, active glucagon-like peptide-1 (GLP-1), total peptide YY (PYY), lactate, IL-6, and appetite perceptions were measured pre-, immediately postexercise, 30 min postexercise, and 90 min postexercise. Energy intake was recorded over 3 days. VICT and SIT suppressed ghrelin (P < 0.001), although SIT elicited a greater (P = 0.016 vs. MICT) and more prolonged (P < 0.001 vs. all sessions) response. GLP-1 increased immediately after MICT (P < 0.001) and 30 min after VICT (P < 0.001) and SIT (P < 0.002), while VICT elicited a greater postexercise increase in PYY vs. MICT (P = 0.027). Postexercise changes in blood lactate and IL-6 correlated with the area under the curve values for ghrelin (r = -0.60, P < 0.001) and GLP-1 (r = 0.42, P = 0.017), respectively. Appetite was suppressed after exercise (P < 0.001), although more so after VICT (P < 0.027) and SIT (P < 0.001) vs. MICT, and energy intake was reduced on the day after VICT (P < 0.017 vs. MICT and CTRL) and SIT (P = 0.049 vs. MICT). These findings support an intensity-dependent paradigm for appetite regulation following exercise and highlight the potential involvement of lactate and IL-6.NEW & NOTEWORTHY This study examines the involvement of two potential mechanisms (lactate and IL-6) that may explain the intensity-dependent effects of acute exercise on appetite-related parameters. Our findings support a clear intensity-dependent paradigm for appetite regulation following exercise, as highlighted by the change in acylated ghrelin and the suppression of appetite and energy intake after vigorous exercise (continuous and intermittent). Further, our findings extend previous work in animal/cell models by providing evidence for the potential role of lactate and IL-6 in mediating changes in appetite-related parameters following exercise in humans. [ABSTRACT FROM AUTHOR]

Feeding profoundly affects metabolic responses to exercise in various tissues, but the effect of feeding status on human adipose tissue responses to exercise has never been studied. Ten healthy overweight men aged 26 5 yr (mean SD) with a waist circumference of 105 10 cm walked at 60% of maximum oxygen uptake under either fasted or fed conditions in a randomized, counterbalanced design. Feeding comprised 648 115 kcal 2 h before exercise. Blood samples were collected at regular intervals to examine changes in metabolic parameters and adipokine concentrations. Adipose tissue samples were obtained at baseline and 1 h after exercise to examine changes in adipose tissue mRNA expression and secretion of selected adipokines ex vivo. Adipose tissue mRNA expression of pyruvate dehydrogenase kinase isozyme 4 (PDK4), adipose triglyceride lipase, hormone-sensitive lipase (HSL), fatty acid translocase/CD36, glucose transporter type 4 (GLUT4), and insulin receptor substrate 2 (IRS2) in response to exercise were lower in fed compared with fasted conditions (all P 0.05). Postexercise adipose IRS2 protein was affected by feeding (P 0.05), but Akt2, AMPK, IRS1, GLUT4, PDK4, and HSL protein levels were not different. Feeding status did not impact serum and ex vivo adipose secretion of IL-6, leptin, or adiponectin in response to exercise. This is the first study to show that feeding before acute exercise affects postexercise adipose tissue gene expression, and we propose that feeding is likely to blunt long-term adipose tissue adaptation to regular exercise. [ABSTRACT FROM AUTHOR]

Our objective was to examine the respective contributions of changes in visceral adiposity, subcutaneous adiposity, liver fat, and cardiorespiratory fitness (CRF) to the improvements in cardiometabolic risk markers in response to a 3-yr healthy eating/physical activity lifestyle intervention. Ninety-four out of 144 viscerally obese healthy men completed a 3-yr lifestyle intervention. Body weight, body composition, and fat distribution were assessed by anthropometry and DEXA/computed tomography. CRF, adipokines, lipoprotein/lipid profile, and 75 g of oral glucose tolerance were assessed. CRF and visceral and subcutaneous adiposity significantly improved over the 3-yr intervention, with a nadir in year 1 and a partial regain in year 3. Liver fat (estimated by insulin hepatic extraction) stabilized from year 1 to year 3, whereas HOMA-IR, ISI-Matsuda index, and adiponectin continued to improve. Multivariate analysis revealed that both visceral adiposity and estimated liver fat reductions contributed to the improved ISI-Matsuda index observed over 3 yr (r2 = 0.28, P < 0.001). Three-year changes in fat mass and CRF were independently associated with changes in visceral fat (adjusted r2 = 0.40, P < 0.001), whereas only changes in CRF were associated with changes in estimated liver fat (adjusted r2 = 0.18, P < 0.001). A long-term (3 yr) healthy eating/physical activity intervention in men improves several cardiometabolic risk markers over the long term (3 yr) despite a partial body weight regain observed between year 1 and year 3. The improvement in CRF contributes to visceral and estimated liver fat losses over the long term, which in turn explain the benefits of the lifestyle intervention on cardiometabolic risk profile. [ABSTRACT FROM AUTHOR]

Adaptation of neural responses to repeated muscle stretching likely represents implicit learning to minimize muscle resistance to perturbations. To test this hypothesis, the forearm was placed on a horizontal manipulandum. Elbow flexors or extensors compensated an external load and were stretched by 20° or 70° rotations. Participants were instructed not to intervene by intentionally modifying the muscle resistance elicited by stretching. In addition to phasic stretch reflexes (SRs), muscle stretching was associated with inhibitory periods (IPs) in the ongoing muscle activity starting at minimal latencies of ∼35 ms. The SR amplitude decreased dramatically across 5-12 trials and was not restored after a resting period of 3-5 min, despite the increase in stretch amplitude from 20° to 70°, but IPs remained present. When SRs were suppressed, stretching of originally nonstretched, antagonist muscles initiated after the rest period showed immediate SR suppression while IPs remained present in the first and subsequent trials. Adaptation to muscle stretching thus includes features characteristic of implicit learning such as memory consolidation and generalization. Adaptation may be achieved by central shifts in the threshold positions at which muscles begin to be activated. Shifts are thought to be prepared in advance and triggered with stretch onset. Threshold position resetting provides a comprehensive explanation of the results in the broader context of the control of posture, movement, and motor learning in the healthy and damaged nervous system. [ABSTRACT FROM AUTHOR]

PlanHab is a planetary habitat simulation study. The atmosphere within future space habitats is anticipated to have reduced PO2, but information is scarce as to how physiological systems may respond to combined exposure to moderate hypoxia and reduced gravity. This study investigated, using a randomized-crossover design, how insulin sensitivity, glucose tolerance, and circulating lipids were affected by 16 days of horizontal bed rest in normobaric normoxia [NBR: FIO2 = 0.209; PIO2 = 133.1 (0.3) mmHg], horizontal bed rest in normobaric hypoxia [HBR: FIO2 = 0.141 (0.004); PIO2 = 90.0 (0.4) mmHg], and confinement in normobaric hypoxia combined with daily moderate intensity exercise (HAMB). A mixed-meal tolerance test, with arterialized-venous blood sampling, was performed in 11 healthy, nonobese men (25-45 yr) before (V1) and on the morning of day 17 of each intervention (V2). Postprandial glucose and c-peptide response were increased at V2 of both bed rest interventions (P < 0.05 in each case), with c-peptide: insulin ratio higher at V2 in HAMB and HBR, both in the fed and fasted state (P < 0.005 in each case). Fasting total cholesterol was reduced at V2 in HAMB [-0.47 (0.36) mmol/l; P < 0.005] and HBR [-0.55 (0.41) mmol/l; P < 0.005]. Fasting HDL was lower at V2 in all interventions, with the reduction observed in HBR [-0.30 (0.21) mmol/l] greater than that measured in HAMB [-0.13 (0.14) mmol/l; P < 0.005] and NBR [-0.17 (0.15) mmol/l; P < 0.05]. Hypoxia did not alter the adverse effects of bed rest on insulin sensitivity and glucose tolerance but appeared to increase insulin clearance. The negative effect of bed rest on HDL was compounded in hypoxia, which may have implications for long-term health of those living in future space habitats. [ABSTRACT FROM AUTHOR]

GSK-1614235 and KGA-2727 are potent, selective inhibitors of the SGLT1 sodium-dependent glucose transporter. Nonclinical (KGA-2727) and clinical (GSK-1614235) trials assessed translation of SGLT1 inhibitor effects from rats to normal human physiology. In rats, KGA-2727 (0.1 mg/kg) or vehicle was given before oral administration of 3-O-methyl-α-D-glucopyranose (3-O-methylglucose, 3-OMG) containing 3-[³H]OMG tracer. Tracer absorption and distribution were assessed from plasma, urine, and fecal samples. SGLT1 inhibition reduced urine 3-OMG recovery and increased fecal excretion. SGLT1 inhibitor effects on plasma glucose, insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were also measured during a standard meal. Incremental glucose, insulin, and GIP concentrations were decreased, indicating downregulation of β-cell and K cell secretion. Minimal effects were observed in the secretion of the L cell product, GLP-1. With the use of a three-way, crossover design, 12 healthy human subjects received placebo or 20 mg GSK-1614235 immediately before or after a meal. Five minutes into the meal, 3-OMG was ingested. Postmeal dosing had little impact, yet premeal dosing delayed and reduced 3-OMG absorption, with an AUC0-10 of 231 ± 31 vs. 446 ± 31 μg·h-1·ml-1, for placebo. Recovery of tracer in urine was 1.2 ± 0.7 g for premeal dosing and 2.2 ± 0.1 g for placebo. Incremental concentrations of insulin, C-peptide, and GIP were reduced for 2 h with premeal GSK-1614235. Total GLP-1 concentrations were significantly increased, and a trend for increased peptide YY (PYY) was noted. SGLT1 inhibitors block intestinal glucose absorption and reduce GIP secretion in rats and humans, suggesting SGLT1 glucose transport is critical for GIP release. Conversely, GLP-1 and PYY secretion are enhanced by SGLT1 inhibition in humans. [ABSTRACT FROM AUTHOR]

Disturbances in fat oxidation have been associated with an increased risk of obesity and metabolic disorders such as insulin resistance. There is large inter-subject variability in the capacity to oxidize fat when a person is physically active, although the significance of this for metabolic health is unclear. We investigated whether the maximal capacity to oxidize fat during exercise is related to 24-h fat oxidation and insulin sensitivity. Maximal fat oxidation (MFO; indirect calorimetry during incremental exercise) and insulin sensitivity (Quantitative Insulin Sensitivity Check Index) were measured in 53 young, healthy men (age 24 ± 7 yr, ...O2max 52 ± 6 ml ⋅ kg-1 ⋅ min-1). Fat oxidation over 24 h (24-h FO; indirect calorimetry) was assessed in 16 young, healthy men (age 26 ± 8 yr, ...O2max 52 ± 6 ml ⋅ kg-1 ⋅ min-1) during a 36-h stay in a whole-room respiration chamber. MFO (g/min) was positively correlated with 24-h FO (g/day) (R = 0.65, P = 0.003; R = 0.46, P = 0.041 when controlled for ...2max [l/min]), 24-h percent energy from FO (R = 0.58, P = 0.009), and insulin sensitivity (R = 0.33, P = 0.007). MFO (g/min) was negatively correlated with 24-h fat balance (g/day) (R = 0.51, P = 0.021) but not significantly correlated with 24-h respiratory quotient (R = 0.29, P = 0.142). Although additional investigations are needed, our data showing positive associations between MFO and 24-h FO, and between MFO and insulin sensitivity in healthy young men suggests that a high capacity to oxidize fat while one is physically active could be advantageous for the maintenance of metabolic health. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP-1R (Glp1r-/-). Exenatide (30 nmol·kg-1·day-1) was infused subcutaneously for 12 wk in Glp1r-/- and wild-type (Glp1r+/+) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r-/- mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r+/+ mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC0-2h, ALT, and HLC in Glp1r+/+ mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r-/- versus Glp1r+/+ mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel "GLP-1" receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r+/+ versus Glp1r-/- mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides. [ABSTRACT FROM AUTHOR]

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; nn 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol·kg-11·min-11 was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo- Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the variability of subcutaneous abdominal adipose tissue (AT) dynamics in obese subjects with a wide range of insulin sensitivity (IS) and the correlation between these two metabolic measures. Ten obese (BMI 30-40 kg/m2) nondiabetic subjects with (n = 6) and without (n = 4) the metabolic syndrome were studied following a 12-wk ²H2O labeling period. Subcutaneous abdominal AT biopsies were collected. Deuterium incorporation into triglyceride (TG)-glycerol and TG-palmitate were measured by gas chromatography-mass spectrometry for the calculation of fractional TG synthesis (fTG) and fractional de novo lipogenesis (fDNL). Muscle IS and insulin-mediated nonesterified fatty acid (NEFA) suppression (a measure for adipose IS) indexes were derived from the oral glucose tolerance test (OGTT). The ability of subcutaneous abdominal AT to synthesize lipids varied significantly in obese subjects (fTG range 7-28%, fDNL range 1.1-4.6%) with significantly lower values (35% reduction) for both parameters in obese with the metabolic syndrome fTG correlated positively with muscle IS (r = 0.64, P = 0.04) and inversely with NEFA suppression during the OGTT (r=-0.69, P = 0.03). These results demonstrate a large variability in subcutaneous abdominal AT lipid turnover in obesity. Moreover, a reduced capacity for subcutaneous abdominal AT fat storage is associated with muscle and adipose tissue insulin resistance as well as with the metabolic syndrome, thus identifying a form of obesity at heightened risk for type 2 diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Prenatal and early postnatal nutritional status may predispose offspring to impaired glucose tolerance and changes in insulin sensitivity in adult life. The long-term consequences of changes in maternal dietary fatty acid composition were determined in rats. From day 1 until day 12 of pregnancy, rats were given isocaloric diets containing 9% nonvitamin fat based on soybean, olive, fish (FO), linseed, or palm oil. Thereafter, they were maintained on the standard diet; offspring were studied at different ages. Body weight at 4, 8, and 12 mo and lumbar adipose tissue and liver weights at 12 mo did not differ between females on the different diets, whereas in males the corresponding values were all lower in the offspring from the FO group compared with the other dietary groups. Plasma glucose concentrations (both basal and after an oral glucose load) did not change with sex or dietary group, but plasma insulin concentrations were lower in females than in males and, in males, were lowest in the FO group. Similar relations were found with both the homeostasis model assessment of insulin resistance and insulin sensitivity index. In conclusion, the intake of more n-3 fatty acids (FO diet) during early pregnancy reduced both fat accretion and age-related decline in insulin sensitivity in male offspring but not in females. It is proposed that the lower adiposity caused by the increased n-3 fatty acids during the intrauterine life was responsible of the lower insulin resistance in male offspring. [ABSTRACT FROM AUTHOR]

We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-13C]glucose tracer was added to the meal, and a [6,6-2H2]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ± 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P ⩽ 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity. [ABSTRACT FROM AUTHOR]

Model-based studies of responses of auditory nerve fibers to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe spiking activity while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of individual auditory nerve fibers that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semianalytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data of response to high and low pulse rate stimulation. We find that the model, although constructed to fit data from single and paired pulse experiments, can accurately predict responses to unmodulated and modulated pulse train stimuli. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds. [ABSTRACT FROM AUTHOR]

Rats offered chow, lard, and 30% sucrose solution (choice) rapidly become obese. We tested metabolic disturbances in rats offered choice, chow+lard, or chow+30% sucrose solution [chow+liquid sucrose (LS)] and compared them with rats fed a composite 60% kcal fat, 7% sucrose diet [high-fat diet (HFD)], or a 10% kcal fat, 35% sucrose diet [low-fat diet (LFD)]. Choice rats had the highest energy intake, but HFD rats gained the most weight. After 23 days carcass fat was the same for choice, HFD, chow+lard, and chow+LS groups. Glucose clearance was the same for all groups during an intraperitoneal glucose tolerance test (GTT) on day 12, but fasting insulin was increased in choice, LFD fed, and chow+LS rats. By contrast, only choice and chow+LS rats were resistant to an intraperitoneal injection of 2 mg leptin/kg on day 17. In experiment 2 choice rats were insulin insensitive during an intraperitoneal GTT, but this was corrected in an oral GTT due to GLP-1 release. UCP-1 protein was increased in brown fat and inguinal white fat in choice rats, and this was associated with a significant increase in energy expenditure of choice rats during the dark period whether expenditure was expressed on a per animal or a metabolic body size basis. The increase in expenditure obviously was not great enough to prevent development of obesity. Further studies are required to determine the mechanistic basis of the rapid onset of leptin resistance in choice rats and how consumption of sucrose solution drives this process. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is commonly observed in women with a previous diagnosis of gestational diabetes mellitus (GDM). Whether arterial stiffness is also related to pregnancy and/or postpartum glucose intolerance has not been determined. We examined the influence of GDM during pregnancy and hyperglycemia in the postpartum period on arterial function. Thirty postpartum women were stratified into one of three groups: 1) normoglycemic pregnancy, normoglycemic postpartum (NORM), 2) GDM during pregnancy, normoglycemic postpartum (GDM-N); and 3) GDM during pregnancy, hyperglycemic postpartum (GDM-H). Ten never-pregnant controls were also recruited (Control). All measures were made at 2 mo postpartum or in the early follicular phase in Control women. Arterial stiffness was assessed by pulse wave velocity (PWV) and brachial and carotid artery distensibility. Endothelial function was determined by flowmediated dilation (FMD). PWV was not different between the four groups. Distensibility of the brachial and carotid arteries was lower in GDM-N women (brachial: 1.1 × 10-3 mmHg-1 ± 3.6 × 10-4; carotid: 2.0 × 10-3 ± 3.3 × 10-4) and GDM-H (brachial: 1.4 × 10-3 mmHg-1 ± 4.1 × 10-4; carotid: 1.8 × 10-3 mmHg-1 ± 5.0 × 10-4) compared with NORM women (brachial: 3.4 × 10-3 mmHg-1 ± 7.0 × 10-4; carotid: 3.9 × 10-3 ± 7.4 × 10-4). However, only brachial artery distensibility returned to Control levels by 2 mo postpartum in the NORM women. FMD was lower in previously GDM women (GDM-N: 4.1% ± 2.3; GDM-H: 4.4% ± 0.9) compared with NORM women (10.8% ± 1.3; P < 0.01). These findings suggest that the vascular function of women in the early postpartum period is influenced by GDM during pregnancy and the persistence of clinical and/or subclinical hyperglycemia after delivery. [ABSTRACT FROM AUTHOR]

We used the rat whisker touch as a model system to investigate the correlation between the response function of cortical neurons and the behavior of rats in a sensory detection versus discrimination task. The rat whisker–barrel system is structurally well characterized and represents one of the main channels through which rodents collect information about the environment. In experiment 1, we recorded neuronal activity (n = 235) in the whisker area of the rat somatosensory cortex in anesthetized rats while applying vibrotactile stimuli of varying amplitudes to the whiskers. Neurons showed a characteristic sigmoidal input–output function, with an accelerating nonlinearity at low stimulus amplitudes and a compressive nonlinearity at high stimulus amplitudes. We further quantified the performance of individual neurons for stimulus detection and for discrimination across different stimulus pairs with identical amplitude differences. For near-threshold stimuli, the neuronal discrimination performance surpassed the detection performance despite the fact that detection and discrimination represented identical amplitude differences. This is consistent with the accelerating nonlinearity observed at low stimulus intensities. In the second stage of the experiment, four rats were trained to select the higher-amplitude stimulus between two vibrations applied to their whiskers. Similar to neuronal results, the rats' performance was better for the discrimination task compared with the detection task. The behavioral performance followed the same trend as that of the population of individual neurons. Both behavioral and neuronal data are consistent with the "pedestal effect" previously reported in human psychophysics. [ABSTRACT FROM AUTHOR]

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP- 1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg-1·day-1) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1β, IL-2, IL-6, MCP- I, IFNγ, and TNFα) and pancre- atitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or Iipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide up- regulated Reg3b but not 116, Cc12, Nfkbl, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents. [ABSTRACT FROM AUTHOR]

The transition from wakefulness to sleep is associated with a pronounced decline in diuresis, a necessary physiological process that allows uninterrupted sleep. The aim of this study was to assess the effect of acute sleep deprivation (SD) on urine output and renal water, sodium, and solute handling in healthy young volunteers. Twenty young adults (10 male) were recruited for two 24-h studies under standardized dietary conditions. During one of the two admissions, subjects were deprived of sleep. Urine output, electrolyte excretions, and osmolar excretions were calculated. Activated renin, angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide were measured in plasma, whereas prostaglandin E2 and melatonin were measured in urine. SD markedly increased the diuresis and led to excess renal sodium excretion. The effect was more pronounced in men who shared significantly higher diuresis levels during SD compared with women. Renal water handling and arginine vasopressin levels remained unaltered during SD, but the circadian rhythm of the hormones of the renin-angiotensin-aldosterone system was significantly affected. Urinary melatonin and prostaglandin E2 excretion levels were comparable between SD and baseline night. Hemodynamic changes were characterized by the attenuation of nocturnal blood pressure dipping and an increase in creatinine clearance. Acute deprivation of sleep induces natriuresis and osmotic diuresis, leading to excess nocturnal urine production, especially in men. Hemodynamic changes during SD may, through renal and hormonal processes, be responsible for these observations. Sleep architecture disturbances should be considered in clinical settings with nocturnal polyuria such as enuresis in children and nocturia in adults. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by hyperglycemia, a deficit in β-cells, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify β-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether β-cell formation is derived exclusively from β-cell replication, or whether other sources of β-cells (OSB) are present, and 2) to what extent, if any, there is attempted β-cell regeneration in the HIP rat and if this is through β-cell replication or OSB. We conclude that formation and maintenance of adult β-cells depends largely (-80%) on formation of β-cells independent from β-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted β-cell regeneration that substantially slows loss of β-cell mass. [ABSTRACT FROM AUTHOR]

Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [11C]acetate and [11C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+ 70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation. [ABSTRACT FROM AUTHOR]

Diabetes constitutes an increasingly prevalent disease, dramatically associated with an enhanced mortality risk in the developed world. A high prevalence of diabetes has recently been described at Réunion Island, a French department located in the Indian Ocean. At the University of La Réunion, a laboratory course involving students was designed to teach them blood glucose measurements and to examine the influence of food intake on their glycemic response. Using glucose meters, test strips, lancet devices, and sterile lancets, students determined their basal and postprandial glycemia. After plotting the variation over time of their glycemia, students calculated their glycemic response to a meal as the area under the curve. First, students observed that their glycemia had increased rapidly after food intake to values of <1.4 g/l and then decreased to normal values, proving the existence of a physiological regulatory system for glycemia. Using impedance balances, students then determined their body mass index and fat mass percentages. Positive and significant correlations were established between students' fat mass percentages and the glycemic response to the meal. A higher postprandial response was indeed noticed for students having higher fat percentages. Therefore, this laboratory allows students to observe the regulation of glycemia. It also alerts them to the correlation between higher body fat content and a higher glycemic response, which can be related to diabetic disorders. This laboratory constitutes an active illustration of their plenary lesson in endocrinology and particularly for the session dealing with glucose regulation. [ABSTRACT FROM AUTHOR]

The Wnt family of secreted glycoproteins had previously been shown to regulate diverse processes during early development. Wnt signaling also plays a key role in the homeostasis of adult tissues maintaining stem cell pluripotency and determining differentiating cell fate. The age-related decrease in Wnt signaling may contribute to increased muscle adiposity and diminished bone strength. In the current study, we investigated the long-term metabolic consequences of the upregulated Wnt/β-catenin signaling in skeletal muscles of adult diet-induced obese (DIO) rats. To this end, we generated a recombinant adeno-associated virus (rAAV) vector encoding murine Wnt10b cDNA. The long-term expression of rAAV1-Wnt10b was tested after intramuscular injection in the female DIO rat. Animals fed high-fat diet and treated with rAAV1-Wnt10b showed a sustained reduction in body weight compared with controls, and expression of Wnt10b was accompanied by a reduction in hyperinsulinemia and triglyceride plasma levels as well as improved glucose homeostasis. Nuclear magnetic resonance methods revealed that ectopic expression of Wnt10b resulted in a decrease in both global and muscular fat deposits in DIO rats. The long-range effect of locally expressed Wnt10b was also manifested through the increased bone mineral density. The detailed analysis of molecular markers revealed fibroblast growth factor-4 and vascular endothelial growth factor as possible mediators of the systemic effect of Wnt10b transgene expression. Our data demonstrate that altering Wnt/β-catenin signaling in the skeletal muscle of an adult animal invokes moderate responses with favorable metabolic profile, bringing the notion of alternative therapeutic modality in the treatment of obesity, diabetes, and osteoporosis. [ABSTRACT FROM AUTHOR]

The effects of macronutrients on gastric volume changes, emptying, and gastrointestinal symptoms are incompletely understood. Three liquid meals of 500 ml (fat emulsion, 375 kcal; protein solution, 375 kcal; glucose solution, 400 kcal) were infused into the stomach of 12 healthy volunteers on three occasions. Studies were performed in seated body position using an open-configuration magnetic resonance imaging (MRI) system. MRI imaging sequences, assessing stomach and meal volumes, were performed prior to and at times t = 0, 3, 6, 9, 12, 15, 25, 35, 45, 60, 75, and 90 mm after meal administration. Areas under the curve for the early emptying phase (0-15 and 0-45 mm) were calculated, and characteristics of the volume curves were analyzed by a gastric emptying model. Gastrointestinal symptoms were assessed by a self-report scale. Initial (r = 0 mm) and early postprandial gastric volumes were highest for glucose because of lower initial emptying. However, in the early emptying phase the characteristics of the volume curves for stomach and meal were uniform for all macronutrients. Perceptions of fullness and satiety were linearly associated with postprandial gastric volumes, but not with macronutrient composition. Isovolumic macronutrient meals modulate gastric volume response by initial meal emptying patterns. Macronutrient specific accommodation responses, as shown in barostat studies, are not reflected as gastric volume responses under noninvasive conditions. [ABSTRACT FROM AUTHOR]

Acute caffeine (Caf) ingestion impairs glucose tolerance in able-bodied humans during an oral glucose tolerance test (OGTT). The mechanism responsible for this effect remains unclear, however, it is suggested to be due to the accompanying increase in epinephrine concentration. We examined whether or not Caf would elicit a glucose intolerance in persons with tetraplegia (TP) who do not exhibit an increased epinephrine response following Caf ingestion. All TP [n = 14; 9 incomplete (Inc) lesion, 5 complete (Corn) lesion] completed two OGTT 1 h after consuming either gelatin (PI) or Caf capsules (dose = 4 mg/kg). Blood samples were collected at baseline (time = 0 min), 1 h after capsule ingestion (time = 60 min), and every 30 rain during the OGTT (time = 90–180 rain). Glucose, insulin, proinsulin, and C-peptide responses were similar (P > 0.05) between treatments, demonstrating no effect of Caf on glucose tolerance. This lack of a Caf effect may be due to the low epinephrine concentration that remained unchanged (P > 0.05) throughout all experiments. Interestingly, the Corn exhibited a 50% higher glucose response (P ≤ 0.05) and a 46% (P > 0.05) lower insulin response (vs. Inc), suggesting a more pronounced glucose intolerance within this subgroup. Furthermore, nine TP (5 Com, 4 Inc) had glucose levels of ≥ 7.8 mM at the end of the OGTT (time = 180 min), classifying them as glucose intolerant. In summary, acute Caf ingestion does not increase epinephrine concentration or impair glucose tolerance in TP. [ABSTRACT FROM AUTHOR]

The transition from day to night is associated with a pronounced decline in diuresis with reductions in the amount of excreted water, electrolytes, and other end products of our metabolism. Failure to do so leads to a large urine output at night, a condition known as nocturnal polyuria, encountered in a large proportion of children with nocturnal enuresis. The aim of this study was to clarify the mechanisms responsible for the nocturnal polyuria seen in enuretics with inadequate response to desmopressin (dDAVP). Forty-six enuretics (7-14 yr of age) and fifteen age-matched controls were admitted for a 24-h protocol with standardized fluid and sodium intake, comprising urine collections, blood sampling, and blood pressure monitoring. We included patients with severe enuresis (5 ± 1 wet nights/wk) showing <50% reduction in wet nights on dDAVP. We characterized the patients on the basis of their nocturnal urine production. The children with nocturnal polyuria excreted larger amounts of sodium and urea at night than nonpolyurics and controls. Solute-free water reabsorption as well as urinary arginine vasopressin and aquaporin-2 excretion were normal in polyurics, and no differences were found in atrial natriuretic peptide, angiotensin II, aldosterone, and renin levels. Urinary prostaglandin E2 (PGE2) excretion was significantly higher in polyurics. The nocturnal polyunia in children with dDAVP-resistant nocturnal enuresis seems to be the result of augmented sodium and urea excretion. The high urinary PGE2 levels found in these children point toward a role for increased prostaglandin synthesis in the pathogenesis of enuresis-related polyunia. [ABSTRACT FROM AUTHOR]

Multiple studies demonstrate that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with the opioid agonist morphine attenuates the development of analgesic tolerance. Sex differences in the effects of noncompetitive, but not competitive NMDA receptor antagonists on acute morphine analgesia, have been reported in mice, yet the role of sex in modulation of morphine tolerance by NMDA receptor antagonists has yet to be addressed. Therefore, we tested whether there is a sex difference in the effect of NMDA receptor antagonists on the development of morphine analgesic tolerance in C57BL/6J mice. Acutely, at a dose required to affect morphine tolerance in male mice, the noncompetitive NMDA receptor antagonist dizocilpine (MK-801) prolonged morphine analgesia similarly in both sexes in the hot plate and tail withdrawal assays. In the hot plate assay, coadministration of MK-801 or the competitive antagonist 3-(2-carboxpiperazin-4-yl)propyl-1-phosphanoic acid (CPP) with morphine attenuated the development of tolerance in male mice, while having no effect in females. Like normal and sham females, ovariectomized mice were similarly insensitive to the attenuation of morphine tolerance by MK-801 in the hot plate assay. Surprisingly, in the tail withdrawal assay, MK-801 facilitated the development of morphine-induced hyperalgesia and tolerance in males but not females. The results demonstrate that male mice are more sensitive to modulation of nociception and morphine analgesia after repeated coadministration of NMDA receptor antagonists. Furthermore, the underlying mechanisms are likely to be different from those mediating the sex difference in the modulation of acute morphine analgesia that has previously been reported. [ABSTRACT FROM AUTHOR]

Our aim was to measure whole body energy expenditure alter a mixed liquid meal, with and without simultaneous propranolol infusion, in patients with cirrhosis. We also wanted to investigate the effect of propranolol on substrate fluxes and oxygen uptake in the tissues drained by the hepatic vein and azygos vein in the postprandial period in these patients. Whole-body oxygen uptake, hepatic blood flow, hepatic venous pressure gradient and net-hepatic fluxes of oxygen, lactate, glucose, glycerol, and free fatty acids (FFA) were measured in 12 patients with alcoholic cirrhosis before and for 2 h after ingestion of a mixed liquid meal (700 kcal). Half of the patients (n = 6) were randomized to a treatment group receiving intravenous infusion of propranolol in combination with the meal. The meal-induced energy expenditure was significantly lower in patients given propranolol [15.0 ± 18.9 vs. 67.0 ± 26.1 kJ/120 min (means ± SD), P < 0.01]. Meal-induced whole body oxygen uptake was lower in patients receiving propranolol (19.2 ± 38 vs. 135.7 ± 61 mmol/120 min, P < 0.01), and the meal-induced increase in splanchnic oxygen uptake was nonexistent when propranolol was administered in combination (-13.2 ± 34.8 vs. 110.4 ± 34.8 mmol/120 min, P = 0.04). Postprandially, the propranolol group had a tendency toward a reduced splanchnic glucose output, and the FFA uptake was significantly reduced. Propranolol reduces meal-induced whole body oxygen uptake and energy expenditure as well as splanchnic oxygen uptake. The splanchnic reduction in oxygen consumption can explain almost the entire reduction in whole body oxygen consumption. [ABSTRACT FROM AUTHOR]

Adrenal androgen production is reduced in association with disease severity in HIV-infected women. This response may be maladaptive in terms of maintenance of lean body mass, functional status, and immune function. The aim of this study was to assess whether the use of an adrenal enzyme inhibitor of 11β-hydroxylase might increase androgen production in this population. We conducted a randomized, double-blind, placebo-controlled study of metyrapone (500 mg po qid) or placebo for 2 wk in 10 HIV-infected women with AIDS wasting [weight <90% ideal body weight (IBW) or weight loss >10%] and reduced androgen levels. Basal and ACTH-stimulated androgen, mineralocorticoid, and glucocorticoid levels were measured at baseline and after 14 days of treatment. Subjects were similar in age (40.9 ± 0.9 yr), weight (91.7 ± 3.5% IBW) and hormone concentrations at study entry. Total testosterone (84 ± 54 vs. -0.4 ± 2 ng/dl, P = 0.024), free testosterone (6.5 ± 2.8 vs. 0.1 ± 0.1 pg/ml, P = 0.024), DHEA (5.0 ± 3.2 vs. -0.6 ± 0.5 μg/l, P = 0.024), and 11-deoxycortisol (2,145 ± 820 vs. -14 ± 22 ng/dl, P = 0.024) levels increased in response to metyrapone compared with placebo treatment. In response to ACTH, significant increases in the DHEA/cortisol ratio (174 ± 48 vs. 3 ± 3, P = 0.008) were seen in the metyrapone group compared with placebo. Blood pressure and electrolytes did not change, and signs of adrenal insufficiency were not apparent. These data demonstrate that inhibition of 11β-hydroxylase with metyrapone increases adrenal androgen secretion in HIV-infected women. Further studies are needed to assess the physiological effects of this strategy to increase anabolic hormone levels in severe stress, including detailed testing to rule out the potential risk of concomitant adrenal insufficiency. [ABSTRACT FROM AUTHOR]