Norepinephrine transporter availability in brown fat is reduced in obesity: a human PET study with [11C] MRB.

The energy-dissipating properties of brown adipose tissue (BAT) have been proposed as therapeutic targets for obesity and diabetes. Little is known about basal BAT activity. Capitalizing on the dense sympathetic innervation of BAT, we have previously shown that BAT can be detected in humans under resting room temperature (RT) conditions by using (S,S)-11C-O-methylreboxetine (MRB), a selective ligand for the norepinephrine transporter (NET). In this study, we determine whether MRB labeling of human BAT is altered by obesity. Fifteen healthy, nondiabetic Caucasian women (nine lean, age 25.6 ± 1.7, BMI 21.8 ± 1.3 kg/m2; six obese age 30.8 ± 8.8 BMI 37.9 ± 6.6 kg/m2) underwent PET-CT imaging of the neck/supraclavicular region using 11C-MRB under RT conditions. The distribution volume ratio (DVR) for 11C-MRB was estimated via multilinear reference tissue model 2 (MRTM2) referenced to the occipital cortex. Two women (one lean and one with obesity) had no detectable BAT. Of the women with detectable BAT, women with obesity had lower 11C-MRB DVR (0.80 ± 0.12 BAT DVR) compared to lean (1.15 ± 0.19 BAT DVR) (p = 0.004). Our findings are consistent with reports that NET is decreased in obesity and suggest that the sympathetic innervation of BAT is altered in obesity.

Noradrenergic Activity in the Human Brain: A Mechanism Supporting the Defense Against Hypoglycemia.

Context: Hypoglycemia, one of the major factors limiting optimal glycemic control in insulin-treated patients with diabetes, elicits a brain response to restore normoglycemia by activating counterregulation. Animal data indicate that local release of norepinephrine (NE) in the hypothalamus is important for triggering hypoglycemia-induced counterregulatory (CR) hormonal responses. Objective: To examine the potential role of brain noradrenergic (NA) activation in humans during hypoglycemia. Design: A hyperinsulinemic-hypoglycemic clamp was performed in conjunction with positron emission tomographic imaging. Participants: Nine lean healthy volunteers were studied during the hyperinsulinemic-hypoglycemic clamp. Design: Participants received intravenous injections of (S,S)-[11C]O-methylreboxetine ([11C]MRB), a highly selective NE transporter (NET) ligand, at baseline and during hypoglycemia. Results: Hypoglycemia increased plasma epinephrine, glucagon, cortisol, and growth hormone and decreased [11C]MRB binding potential (BPND) by 24% ± 12% in the raphe nucleus (P < 0.01). In contrast, changes in [11C]MRB BPND in the hypothalamus positively correlated with increments in epinephrine and glucagon levels and negatively correlated with glucose infusion rate (all P < 0.05). Furthermore, in rat hypothalamus studies, hypoglycemia induced NET translocation from the cytosol to the plasma membrane. Conclusions: Insulin-induced hypoglycemia initiated a complex brain NA response in humans. Raphe nuclei, a region involved in regulating autonomic output, motor activity, and hunger, had increased NA activity, whereas the hypothalamus showed a NET-binding pattern that was associated with the individual's CR response magnitude. These findings suggest that NA output most likely is important for modulating brain responses to hypoglycemia in humans.

Serum vitamin D levels and risk of prevalent tuberculosis, incident tuberculosis and tuberculin skin test conversion among prisoners.

Poor vitamin D status has been associated with tuberculosis (TB); whether poor status is cause or consequence of disease is uncertain. We conducted a case-control study and two nested case-control studies to determine whether vitamin D levels were associated with active TB, tuberculin skin test (TST) conversion, and risk of progression to the active TB in prisoners in Brazil. In multivariable conditional logistic regression, subnormal vitamin D levels (OR, 3.77; 95% CI, 1.04-13.64) were more likely in prisoners with active TB. In contrast, vitamin D was not found to be a risk factor for either TST conversion (OR, 2.49; 95% CI, 0.64-9.66) or progression to active disease (OR, 0.59; 95% CI, 0.13-2.62). Black race (OR, 11.52; 95% CI, 2.01-63.36), less than 4 years of schooling (OR, 2.70; 95% CI, 0.90-8.16), cigarette smoking (OR, 0.23; 95% CI, 0.06-0.79) were identified as risk factors for TST conversion. Risk of progression to active TB was found to be associated with cigarette smoking (OR, 7.42; 95% CI, 1.23-44.70). Our findings in the prison population show that poor vitamin D status is more common in individuals with active TB, but is not a risk factor for acquisition of latent TB or progression to active TB.

The Impact of Ventilation and Early Diagnosis on Tuberculosis Transmission in Brazilian Prisons.

Prisoners have among the highest incidence of tuberculosis (TB) globally. However, the contribution of the prison environment on transmission is not well understood and structural characteristics have received little attention as effective epidemiological interventions in TB control. We evaluated architectural characteristics and estimated ventilation rates in 141 cells in three prisons in central west Brazil using steady-state exhaled carbon dioxide (CO2) levels. We used a modified Wells-Riley equation to estimate the probability of infection for inmates sharing a cell with an infectious case and projected the impact of interventions, including early diagnosis and improved ventilation. Overall, prison cells were densely populated (mean 2.1 m(2) per occupant) and poorly ventilated, with only three cells meeting World Health Organization (WHO) standards for per-person ventilation (60 L/s) applied in infection control settings. In the absence of interventions, projected mean risk of infection was 78.0% during a 6-month period. Decreasing time-to-diagnosis by 25% reduced transmission risk by 8.3%. Improving ventilation to WHO standards decreased transmission by 38.2%, whereas optimizing cross-ventilation reduced transmission by 64.4%. Prison environments promote high infection risk over short-time intervals. In this context, enhanced diagnostics have a limited impact on reducing transmission. Improving natural ventilation may be required to effectively control TB in prisons.

Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand.

INTRODUCTION: Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS: Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7kg/m(2); 5 F: age 25.4±2.1, BMI 22.1±1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS: As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS: Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.

A pilot study: the importance of inter-individual differences in inorganic arsenic metabolism for birth weight outcome.

Inorganic arsenic (iAs) exposure is detrimental to birth outcome. We lack information regarding the potential for iAs metabolism to affect fetal growth. Our pilot study evaluated postpartum Romanian women with known birth weight outcome for differences in iAs metabolism. Subjects were chronically exposed to low-to-moderate drinking water iAs. We analyzed well water, arsenic metabolites in urine, and toenail arsenic. Urine iAs and metabolites, toenail iAs, and secondary methylation efficiency increased as an effect of exposure (p<0.001). Urine iAs and metabolites showed a significant interaction effect between exposure and birth weight. Moderately exposed women with low compared to normal birth weight outcome had greater metabolite excretion (p<0.03); 67% with low compared to 10% with normal birth weight outcome presented urine iAs >9 µg/L (p=0.019). Metabolic partitioning of iAs toward excretion may impair fetal growth. Prospective studies on iAs excretion before and during pregnancy may provide a biomarker for poor fetal growth risk.

Glucose utilization rates regulate intake levels of artificial sweeteners.

It is well established that animals including humans attribute greater reinforcing value to glucose-containing sugars compared to their non-caloric counterparts, generally termed 'artificial sweeteners'. However, much remains to be determined regarding the physiological signals and brain systems mediating the attribution of greater reinforcing value to sweet solutions that contain glucose. Here we show that disruption of glucose utilization in mice produces an enduring inhibitory effect on artificial sweetener intake, an effect that did not depend on sweetness perception or aversion. Indeed, such an effect was not observed in mice presented with a less palatable, yet caloric, glucose solution. Consistently, hungry mice shifted their preferences away from artificial sweeteners and in favour of glucose after experiencing glucose in a hungry state. Glucose intake was found to produce significantly greater levels of dopamine efflux compared to artificial sweetener in dorsal striatum, whereas disrupting glucose oxidation suppressed dorsal striatum dopamine efflux. Conversely, inhibiting striatal dopamine receptor signalling during glucose intake in sweet-naïve animals resulted in reduced, artificial sweetener-like intake of glucose during subsequent gluco-deprivation. Our results demonstrate that glucose oxidation controls intake levels of sweet tastants by modulating extracellular dopamine levels in dorsal striatum, and suggest that glucose utilization is one critical physiological signal involved in the control of goal-directed sweetener intake.

Blood pressure hyperreactivity: an early cardiovascular risk in normotensive men exposed to low-to-moderate inorganic arsenic in drinking water.

BACKGROUND: Essential hypertension is associated with chronic exposure to high levels of inorganic arsenic in drinking water. However, early signs of risk for developing hypertension remain unclear in people exposed to chronic low-to-moderate inorganic arsenic. OBJECTIVE: We evaluated cardiovascular stress reactivity and recovery in healthy, normotensive, middle-aged men living in an arsenic-endemic region of Romania. METHODS: Unexposed (n = 16) and exposed (n = 19) participants were sampled from communities based on WHO limits for inorganic arsenic in drinking water (<10 µg/l). Water sources and urine samples were collected and analyzed for inorganic arsenic and its metabolites. Functional evaluation of blood pressure included clinical, anticipatory, cold pressor test, and recovery measurements. Blood pressure hyperreactivity was defined as a combined stress-induced change in SBP (> 20 mmHg) and DBP (>15 mmHg). RESULTS: Drinking water inorganic arsenic averaged 40.2 ± 30.4 and 1.0 ± 0.2 µg/l for the exposed and unexposed groups, respectively (P < 0.001). Compared to the unexposed group, the exposed group expressed a greater probability of blood pressure hyperreactivity to both anticipatory stress (47.4 vs. 12.5%; P = 0.035) and cold stress (73.7 vs. 37.5%; P = 0.044). Moreover, the exposed group exhibited attenuated blood pressure recovery from stress and a greater probability of persistent hypertensive responses (47.4 vs. 12.5%; P = 0.035). CONCLUSIONS: Inorganic arsenic exposure increased stress-induced blood pressure hyperreactivity and poor blood pressure recovery, including persistent hypertensive responses in otherwise healthy, clinically normotensive men. Drinking water containing even low-to-moderate inorganic arsenic may act as a sympathetic nervous system trigger for hypertension risk.

Response to acute psychophysical stress and 24-hour glycemic control in healthy older people.

We examined the relation between stress reactivity and 24 h glycemic control in 17 inactive, healthy older people (≥60 years) under both a novel psychophysical stress and a seated control condition. Plasma cortisol was measured over the course of the stress and recovery periods. Glycemic control was determined over the subsequent 3 h from an oral glucose tolerance test (OGTT) and over 24 h via continuous glucose monitoring (CGM). We observed significant (P < 0.05) elevations in perceived stress, cardiovascular activity, and peak cortisol response at 30 min (10.6 ± 3.1 versus 8.6 ± 2.6 µg·dL(-1), resp.) during the stress compared with the control condition; however, 3 h OGTT glucose and insulin responses were similar between conditions. The CGM data suggested a 30-40 min postchallenge delay in peak glucose response and attenuated glucose clearance over the 6 h following the stress condition, but these alterations were not statistically significant. Healthy older people may demonstrate minimal disruption in metabolic resiliency following everyday psychological stress.

The gut-brain dopamine axis: a regulatory system for caloric intake.

Post-ingestive factors are known to strongly modulate feeding behavior by providing feedback signals to the central nervous system on the current physiological state of the organism. Of particular interest is the identification of the physiological pathways that permit the brain to sense post-ingestive signals. We will review recent evidence supporting the concept that direct stimulation of the gastrointestinal tract with nutrients induces release of the catecholamine neurotransmitter dopamine. In addition, changes in dopamine efflux produced by direct stimulation of the gastrointestinal tract were found to reflect the caloric load of the infusates, suggesting that dopamine signaling may function as a central caloric sensor that mediates adjustments in intake according to the caloric density of a meal. Consistent with the above, blockade of dopamine signaling disrupts flavor-nutrient associations and impairs the regulatory capacity to maintain constant caloric intake during intra-gastric feeding. Future research must determine the exact pathways linking gut nutrient administration to dopamine efflux. Current evidence points to parallel contributions by pre- and post-absorptive pathways, indicating that dopamine systems constitute a site of convergence through which distinct physiological signals can exert control over ingestive behaviors.

Regulation of fat intake in the absence of flavour signalling.

Animals, including humans, can achieve precise regulation of caloric intake by adjusting consumption in response to covert changes in energy density. It remains unknown, however, whether the presence of flavour cues are required for the ability to maintain constant caloric intake. Also unknown are the brain circuits that may function as the central calorie monitors that control adaptive adjustments in energy intake. Here we show that mice trained to lick a dry spout in order to receive intra-gastric infusions of a fat emulsion maintained constant hourly caloric intake by adjusting the number of dry licks in response to changes in caloric density. Animals also increased dry licking according to hunger levels, and developed conditioned preferences for dry sippers associated with high calorie infusions. Importantly, striatal dopamine levels were closely associated with the amount of calories ingested, rather than with the number of dry licks produced. Dopamine levels in dorsal and ventral striatum also reflected caloric density in mice passively receiving intra-gastric infusions of fat emulsions. Consistent with the above, systemic administration of the dopamine receptor blocker haloperidol markedly increased the production of dry licks needed to obtain high-calorie infusions, as if the caloric density of the infusions had been diluted. Conversely, haloperidol markedly decreased the production of dry licks needed to obtain low-calorie infusions. Taken together, our results support the proposition that brain dopamine circuits function as one central sensor of calorie ingestion, since (1) extracellular striatal dopamine levels fluctuate in proportion to the caloric density of nutrients infused in the gut; and (2) inhibiting dopamine receptor signalling disrupts the animals' ability to maintain constant caloric intake across experimental sessions.

Effects of ad libitum ingestion of monosodium glutamate on weight gain in C57BL6/J mice.

Although the umami compound monosodium glutamate (MSG) is a widely used flavor enhancer, controversy still persists regarding the effects of MSG intake on body weight. It has been claimed, in particular, that chronic MSG intake may result in excessive body weight gain and obesity. In this study we assessed the effects of chronic (16 weeks) ad libitum MSG on body weight and metabolism of C57BL6/J mice. Adult male mice were divided in four experimental groups and fed with either a low-fat (LF) or high-fat (HF) diet and with either two bottles of plain water or one bottle containing 1% MSG and another one containing water according to a factorial design. Mice were monitored weekly for body weight and food/fluid intake for 15 weeks. At the end of the experiments, the circulating levels of leptin, insulin, total protein, total cholesterol, triglyceride, blood urea nitrogen, and non-esterified fatty acids were also analyzed. Our results show that MSG intake did not influence body weight in either LF or HF groups. Interestingly, although animals overall displayed strong preferences for MSG against water, preferences were relatively higher in LF compared to HF group. Consistent with the body weight data, while significant differences in leptin, insulin, total cholesterol, and non-esterified fatty acids were found between HF and LF groups, such an effect was not influenced by MSG intake. Finally, indirect calorimetry measurements revealed similar energy expenditure levels between animals being presented water only and MSG only. In summary, our data does not support the notion that ad libitum MSG intake should trigger the development of obesity or other metabolic abnormalities.

Nutrient selection in the absence of taste receptor signaling.

When allowed to choose between different macronutrients, most animals display a strong attraction toward carbohydrates compared with proteins. It remains uncertain, however, whether this food selection pattern depends primarily on the sensory properties intrinsic to each nutrient or, alternatively, metabolic signals can act independently of the hedonic value of sweetness to stimulate elevated sugar intake. Here we show that Trpm5(-/-) mice, which lack the cellular mechanisms required for sweet and several forms of l-amino acid taste transduction, develop a robust preference for d-glucose compared with isocaloric l-serine independently of the perception of sweetness. Moreover, a close relationship was found between glucose oxidation and taste-independent nutrient intake levels, with animals increasing intake as a function of glucose oxidation rates. Furthermore, microdialysis measurements revealed nutrient-specific dopaminergic responses in accumbens and dorsal striatum during intragastric infusions of glucose or serine. Specifically, intragastric infusions of glucose induced significantly higher levels of dopamine release compared with isocaloric serine in both ventral and dorsal striatum. Intragastric stimulation of dopamine release seemed to depend on glucose utilization, because administration of an anti-metabolic glucose analog resulted in lower dopamine levels in striatum, an effect that was reversed by intravenous glucose infusions. Together, our findings suggest that carbohydrate-specific preferences can develop independently of taste quality or caloric load, an effect associated with the ability of a given nutrient to regulate glucose metabolism and stimulate brain dopamine centers.

Specific relation between abdominal obesity and early-phase hyperglycemia is modulated by hepatic insulin resistance in healthy older women.

OBJECTIVE: To describe the impact of abdominal obesity and hepatic insulin resistance on phase-specific glycemic responses in older women. RESEARCH DESIGN AND METHODS: We studied 23 healthy older women (60-88 years old). Abdominal obesity was defined by an abdominal circumference > or =95 cm. Plasma glucose and insulin were measured in response to a 3-h oral glucose tolerance test. Insulin suppression of hepatic glucose production was determined using in vivo clamp techniques. RESULTS: Despite identical prevailing insulin concentrations, glucose excursions 30 min postchallenge (but not later) were greater in women with abdominal obesity than in those without (162 +/- 19 vs. 132 +/- 16 mg/dl; P < 0.01). There was a strong correlation between hepatic glucose production suppression under low-dose insulin infusion and early-phase glucose excursions from the oral glucose tolerance test (r = -0.83; P < 0.001) in women with abdominal obesity, but not in women without (r = 0.44; P < 0.11). CONCLUSIONS: Abdominal obesity relates specifically to early-phase hyperglycemia via hepatic insulin resistance, even in healthy older women.

Simple exercise recovery index for sympathetic overactivity is linked to insulin resistance.

UNLABELLED: Exercise HR recovery (HRR) has proven an effective clinical means to assess parasympathetic dysfunction linked to all-cause mortality, but an analogous functional assessment for sympathetic dysfunction has not been developed. PURPOSE: We investigated whether exercise recovery provides additional cardiorespiratory information, beyond the initial HRR period, to index sympathetic overactivity associated with insulin resistance. METHODS: Young people (N = 20) with diverse percent body fat (9%-52%) were studied using fasting, oral glucose tolerance test (OGTT), and high-carbohydrate meal measurements. Participants also completed a graded fitness test (oxygen consumption peak test on cycle ergometer) after which HR and oxygen consumption (V x O2) measurements were continued for 3 min into recovery. The first, rapid phase of exercise recovery was used as the clinical measurement for parasympathetic control (HRR = HR2 min - HRmax). The second, initial plateau phase of exercise recovery was used to calculate a novel functional index for sympathetic overactivity (the plateau value for the ratio of HR normalized for V x O2 (HR/V x O2 plat)). RESULTS: As expected, parasympathetic function (HRR) was within the normal range in these young people (-58 +/- 2 bpm). The index for sympathetic overactivity varied over a wide range from 9 to 34 bpm/(mL x kg x min(-1)), with obese adolescents having values in the highest 25th percentile. We found that this simple index was correlated to both the OGTT-derived whole-body insulin sensitivity index (r = -0.74, P < 0.001) and Homeostasis Assessment Model for Insulin Resistance (r = 0.76, P < 0.001), independent of percent body fat and parasympathetic function. Meal-induced thermogenesis was also associated with HR/V x O2 plat (r = -0.64, P < 0.01) but not with HRR. CONCLUSION: In young individuals, recovery from intense exercise may provide a simple means to quantify both parasympathetic and sympathetic function. The exercise recovery index for sympathetic overactivity was linked to insulin resistance.

Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance.

OBJECTIVE: Although metformin (MET) is an insulin sensitizer currently used as an adjunct to the treatment of some of the complications of childhood obesity besides type 2 diabetes mellitus, few studies have comprehensively examined its metabolic and clinical effects in obese children with normal glucose tolerance (NGT). METHODS: We therefore conducted a 4-month double-blind clinical trial in 28 obese [mean body mass index (BMI): 40.3 +/- 5.7 kg/m(2)], insulin-resistant [homeostasis model assessment - insulin resistance: 7.6 +/- 2.8 and whole body insulin sensitivity index (WBISI): 1.5 +/- 0.7] adolescents (age 15.0 +/- 1.3 yr) randomized to MET (n = 15, dose 1500 mg daily) or placebo (n = 13). RESULTS: The treatment with MET was well tolerated. MET treatment was associated with a decreased BMI (p = 0.02) as well as with a reduction in subcutaneous fat (p = 0.03), particularly the deep subcutaneous fat (p = 0.04) as assessed by magnetic resonance imaging. Postintervention, the MET group had a 35% improvement in insulin sensitivity (WBISI) compared with the placebo group (p = 0.008). However, significance was lost with adjustments for differences in baseline insulin sensitivity (p = 0.09). While there was no change in inflammatory cytokines or lipid parameters, cardiovascular function as assessed by heart rate recovery after exercise improved with MET and worsened in placebo (p = 0.03). CONCLUSION: Short-term use of MET is well tolerated by obese children with NGT and has a beneficial effect on BMI and autonomic control of the heart as well as a trend toward improved insulin sensitivity. Thus, long-term treatment with MET may provide a means to ameliorate the cardio-metabolic consequences of adolescent obesity.

Abdominal obesity in older women: potential role for disrupted fatty acid reesterification in insulin resistance.

CONTEXT: Excess abdominal adiposity is a primary factor for insulin resistance in older age. OBJECTIVES: Our objectives were to examine the role of abdominal obesity on adipose tissue, hepatic, and peripheral insulin resistance in aging, and to examine impaired free fatty acid metabolism as a mechanism in these relations. DESIGN: This was a cross-sectional study. SETTING: The study was performed at a General Clinical Research Center. PARTICIPANTS: Healthy, inactive older (>60 yr) women (n = 25) who were not on hormone replacement therapy or glucose-lowering medication were included in the study. Women with abdominal circumference values above the median (>97.5 cm) were considered abdominally obese. MAIN OUTCOME MEASURES: Whole-body peripheral glucose utilization, adipose tissue lipolysis, and hepatic glucose production were measured using in vivo techniques according to a priori hypotheses. RESULTS: In the simple analysis, glucose utilization at the 40 mU insulin dose (6.3 +/- 2.8 vs. 9.1 +/- 3.4; P < 0.05), the index of the insulin resistance of basal hepatic glucose production (23.6 +/- 13.0 vs. 15.1 +/- 6.0; P < 0.05), and insulin-stimulated suppression of lipolysis (35 vs. 54%; P < 0.05) were significantly different between women with and without abdominal obesity, respectively. Using the glycerol appearance rate to free fatty acid ratio as an index of fatty acid reesterification revealed markedly blunted reesterification in the women with abdominal adiposity under all conditions: basal (0.95 +/- 0.29 vs. 1.35 +/- 0.47; P < 0.02); low- (2.58 +/- 2.76 vs. 6.95 +/- 5.56; P < 0.02); and high-dose (4.46 +/- 3.70 vs. 12.22 +/- 7.13; P < 0.01) hyperinsulinemia. Importantly, fatty acid reesterification was significantly (P < 0.01) associated with abdominal circumference and hepatic and peripheral insulin resistance, regardless of total body fat. CONCLUSION: These findings support the premise of dysregulated fatty acid reesterification with abdominal obesity as a pathophysiological link to perturbed glucose metabolism across multiple tissues in aging.

Progressive improvement in glucose tolerance following lower-intensity resistance versus moderate-intensity aerobic training in older women.

BACKGROUND: Few studies have compared long-term moderate-intensity aerobic versus light-resistance training on serial improvements in glucose tolerance in older people. METHODS: Healthy, inactive older (74 +/- 5 [SD] years) women (N = 20) were randomized into either a high-volume, moderate-intensity aerobic (ATM, n = 12) or a lower-intensity resistance training (RTL, n = 8) group. Both groups exercised under supervision 4 times per week for 45- to 60-min sessions over 9 months. Measurements of plasma glucose, insulin, and free fatty acid (FFA) responses to an oral glucose tolerance test (OGTT) were performed at baseline and at 3, 6, and 9 months 48 hours after the last exercise session. RESULTS: We observed significant improvements in 2-hour glucose concentrations at 3, 6, and 9 months among women in the RTL(152 +/- 42 vs 134 +/- 33 vs 134 +/- 24 vs 130 +/- 27 mg x dL-1; P < .05), but not the ATM(151 +/- 25 vs 156 +/- 37 vs 152 +/- 40 vs 155 +/- 39 mg x dL-1) group. These improvements were accompanied by an 18% (P < .07) decrease in basal FFA concentrations in the RTLgroup, whereas basal and 30-min FFA concentrations increased (P < .05) after training in the ATMgroup. CONCLUSIONS: These findings suggest that the net physiological benefits of exercise might have been blunted in the ATMgroup, owing to higher circulating levels of FFA, which might have temporarily interfered with insulin action.

Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat.

BACKGROUND: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. METHODS: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. FINDINGS: Elevated ALT (> 35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18-35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. INTERPRETATION: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.

Exercise and improved insulin sensitivity in older women: evidence of the enduring benefits of higher intensity training.

Few studies have compared the relative benefits of moderate- vs. higher intensity exercise training on improving insulin sensitivity in older people while holding exercise volume constant. Healthy older (73 +/- 10 yr) women (N = 25) who were inactive, but not obese, were randomized into one of three training programs (9-mo duration): 1) high-intensity [80% peak aerobic capacity (V(O2)peak); T(H)] aerobic training; 2) moderate-intensity (65% V(O2)peak; T(M)) aerobic training; or 3) low-intensity (stretching) placebo control (50% V(O2)peak); C(TB)). Importantly, exercise volume (300 kcal/session) was held constant for subjects in both the T(H) and the T(M) groups. V(O2)peak was determined by using a graded exercise challenge on a treadmill. Total body fat and lean mass were determined with dual-energy X-ray absorptiometry. The rate of insulin-stimulated glucose utilization as well as the suppression of lipolysis were determined approximately 72 h after the final exercise bout by using a two-step euglycemic-hyperinsulinemic clamp. We observed improved glucose utilization at the higher insulin dose with training, but these improvements were statistically significant only in the T(H) (21%; P = 0.02) compared with the T(M) (16%; P = 0.17) and C(TB) (8%; P = 0.37) groups and were observed without changes in either body composition or V(O2)peak. Likewise in the T(H) group, we detected a significant improvement in insulin-stimulated suppression (%) of adipose tissue lipolysis at the low-insulin dose (38-55%, P < 0.05). Our findings suggest that long-term higher intensity exercise training provides more enduring benefits to insulin action compared with moderate- or low-intensity exercise, likely due to greater transient effects.