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Older adults are threatened by the risk of muscle atrophy and excess accumulation of adipose tissue. The objective of this study was to determine whether an essential amino acid enriched meal replacement would reduce excess fat and foster skeletal muscle retention, potentially improving physical function in this cohort.Using a double blind, randomized controlled trial, we compared the influence of an experimental meal replacement enriched with essential amino acids (EMR) to a commercially available, widely used meal replacement (Optifast®) provided once/day (q.d.) for four weeks on body composition, skeletal muscle and physical function in obese older participants. Twenty-eight individuals completed either EMR (n = 13) or Optifast® (n = 15) supplementation protocols. Measurements of body composition, thigh skeletal muscle cross-sectional area (CSA), blood panels, intrahepatic lipid, and physical function were completed pre- and post-supplementation.Body fat mass, visceral fat mass and volume, and intrahepatic lipid were reduced with EMR but not with Optifast®. Thigh muscle CSA increased (Δ 2.4 ± 3.0 cmBeneficial alterations in fat and muscle support the use of EMR-based meal replacements in obese older adults.ISRCTN registry under Reference Number ISRCTN15814848.

A collaborative research model was developed and tested to enable regional healthcare systems to join multisite clinical trials emanating from the Clinical and Translational Science Award (CTSA) Trial Innovation Network (TIN) by the Institute of Translational Health Sciences at the University of Washington and the Northwest Participant and Clinical Interactions (NW PCI) Network. The NW PCI is a collaborative group of regional research programs located at medical centers, healthcare systems, and universities across Washington, Wyoming, Alaska, Montana, and Idaho. This article describes the purpose, development, barriers, and initial experience with feasibility assessment for TIN-supported studies in the NW PCI. The tools and processes of the NW PCI Network were adapted to enable network sites to assess studies for clinical relevance and feasibility. Seven of seventeen TIN-supported studies were reviewed for consideration; three of which resulted in successful completion of study documentation for site selection by NW PCI sites. The NW PCI/TIN model can be adapted by other CTSAs to increase involvement of regional research programs in national multisite clinical research studies. Barriers to expanding TIN-supported trials to regional networks include short timelines for study document submissions, insufficient site reimbursement rates, and non-feasible study designs.

We have previously demonstrated that the acute ingestion of essential amino acids may augment net protein balance in the elderly. Using a double blind, randomized controlled trial, our objective was to compare an experimental meal replacement enriched with essential amino acids (EMR) compared to a commercial meal replacement (Optifast®) provided once/day (q.d.) for four weeks on body composition and physical function in older, obese participants. Twenty-seven individuals (69±5 yrs; body mass index of 32±4 kg/m2) were randomly assigned to EMR (n=13) or Optifast® (n=15) supplementation. Measurements of body composition, skeletal muscle cross-sectional area (CSA), intrahepatic lipid and physical function were completed pre- and post-supplementation. Body mass, fat mass, and visceral fat mass were reduced with EMR but not altered with Optifast®. Thigh muscle CSA increased ( 4.1 ± 1.9 cm2, P = 0.03) with EMR but not Optifast®. There was a significant increase in the distance covered during the six-minute walk test with EMR ( 21±26 m) but no change in Optifast® ( 22±54 m). Improvements in body composition and physical function support the efficacious use of EMR-based meal replacements in the obese elderly.

Wild game consumption has been associated with health benefits but the acute influence on human protein metabolism remains unknown. We compared feeding-induced responses of equivalent amounts of free-range reindeer (FR) and commercial beef (CB) on protein kinetics using stable isotope methodology. Seven participants (age: 40 ± 14 years; body mass index: 24 ± 3 kg/m2) completed two randomised studies, ingesting 2 oz of FR or CB. L-[ring 2H5]phenylalanine & L-[ring 2H2]tyrosine were delivered via primed, continuous intravenous infusion. Blood samples were collected during the basal period and following consumption of FR or CB. Feeding-induced changes in whole-body protein synthesis (PS), protein breakdown (PB), and net protein balance (NB) were determined via plasma sample isotope enrichment analysis by gas chromatography-mass spectrometry; plasma essential amino acid (EAA) concentrations were determined by liquid chromatography-electrospray ionisation-mass spectrometry. Plasma post-prandial EAA concentrations were higher with FR compared to CB (P

Background: Physical activity is recommended to mitigate the incidence of obesity, but delivery of community wide initiatives is cumbersome. The challenges met by such programs are magnified when implementation transpires in the remote villages of Alaska. To overcome the difficulty of this challenge in the Arctic, the Skiku/AK Nordic cross-country skiing program was developed. The objective of this study was to evaluate whether access to Skiku/AK Nordic program would promote physical activity levels that met the daily recommendations for physical activity in Alaska Native children. Methods: Eight children (4 females and 4 males; 10±2 years/age) were recruited from Kaktovik, Alaska for participation in this study. Expert coaches and staff provided one week of cross-country ski instruction and access to ski equipment. Physical activity was monitored using ActiGraph GT3X+ accelerometers. Data collected from the devices was then downloaded and analyzed using ActiLife software. Results: The participants expended ~586 calories/day devoted to physical activity. Light and moderate physical activity was 68±38 minutes/day and 447±248 minutes/day, respectively. Conclusions: Delivery of the Skiku/AK Nordic program promoted favorable levels of physical activity in Alaska Native children. Further research is needed to assess the longitudinal and seasonal effectiveness of the Skiku/AK Nordic program.

We have previously reported negative energy balance and health benefits during an Alaska backcountry expeditionary hunting (ABEH) immersion in two males. The purpose of our present study was to increase the number of participants, include females, and evaluate macronutrient intake and serum lipids. Four men (age: 46 ± 6 year, BMI: 26 ± 1 kg/m2) and three women (age: 46 ± 11 year, BMI: 25 ± 3 kg/m2) were recruited. Doubly labeled water methodology and dietary recall were utilized to assess energy expenditure and energy intake, respectively. Data were collected during pre‐ and post‐ABEH visits. Body composition was measured using dual‐energy x‐ray absorptiometry and the cross‐sectional area of skeletal muscle in the upper leg (XT), and intrahepatic lipid (IHL) was determined using magnetic resonance imaging and/or spectroscopy (MRI/MRS). Blood parameters were measured by LabCorp. Paired T‐tests were used for statistical analysis. Data are reported as mean ± SD and considered significant at p, The majority of the scientific literature on exercise training has focused on standardized concepts. We assert that movement constancy of the hunter gatherer lifestyle may offer protection against metabolic abnormalities but has been largely understudied. In the context of unscripted negative energy balance, muscle preservation, and rapid improvements in metabolic biomarkers were demonstrated in both healthy females and males during an Alaskan backcountry hunting expedition.

Wild game consumption has been associated with health benefits, but the influence on protein metabolism remains unknown. We compared the feeding-induced response to 2 oz of free-range reindeer (FR) versus commercial beef (CB) using stable isotope methodology. Seven male and female participants (age: 38±12 years; body mass index: 24±3 kg/m2) completed two studies using a randomized, crossover design in which they ingested 2 oz of FR or CB. L-[ring 2H5]phenylalanine & L-[ring 2H2]tyrosine were delivered via primed, continuous intravenous infusion. Blood samples were collected during the basal period and following consumption of FR or CB. Feeding-induced changes in whole body protein synthesis (PS), protein breakdown (PB), and net protein balance (NB) were determined via analysis of plasma samples for phenyalanine and tyrosine enrichment by gas chromatography mass spectrometry; plasma essential amino acid concentrations were determined by liquid chromatography-electrospray ionization-mass spectrometry. Plasma post-prandial essential amino acid (EAA) concentrations were higher with the ingestion of FR compared to CB (P=0.02). The acute feeding-induced response in PS was not different in either trial, but PB was reduced with the ingestion of FR compared to CB (P

Introduction The Alaska Mountain Wilderness Ski Classic is a self-supported ultramarathon cross-country skiing event that traverses one of the mountain ranges of Alaska each winter. Unique aspects of this event challenge athletes with a significant amount of physical and mental stress while in the chronically cold conditions of the Arctic. Assessment of energy requirements or body composition has never been performed during this event. The objective of the study was to evaluate the influence of the 2016 Alaska Mountain Wilderness Ski Classic on caloric expenditure and body composition. Methods Caloric expenditure was estimated using GT3x+ Actigraph accelerometers and ActiLife software. Lean tissue mass, total fat mass, visceral fat mass, and bone mineral density were measured using a General Electric iDXA before and after the event. Data are presented as mean±SD. Differences were analyzed using paired t tests with significance at P Results Fifteen participants (age=32.7±6.6 years, body mass index=23.7±2.3 kg·m2) completed the study, 8 males and 7 females. Caloric expenditure was 6238±1390 kcal·day-1, and 37,163±8425 kcal for the entire event. Fat mass was reduced from pre-event (∆1.3±0.7 kg, P=0.00003). There was an increase in lean tissue mass (∆1.7±1.3 kg, P=0.0003) and relative skeletal muscle index (∆0.2±0.2 kg·m², P=0.001). There was no change in bone mineral density (∆0±0 g·cm3, P=0.4). Conclusions Despite the metabolic demands, fat mass was reduced and lean tissue mass was preserved. Future studies of this event should be directed toward assessment of the nutritional provisions utilized and the mechanisms responsible for the preservation of lean tissue mass.

The age-related concomitant loss of skeletal muscle and accumulation of excess adipose tissue have been commonly referred to as sarcopenic obesity. While weight loss may help mitigate the metabolic abnormalities linked to obesity, low fitness levels and muscle atrophy complicate the effectiveness of lifestyle interventions. Because of low levels of compliance, suboptimal economic efficiency, and low functional capacity, there has been no consensus on optimal therapy. This includes the use of high-protein diets that do not ensure muscle preservation during weight loss in this segment of the population. The primary objectives of this review are to discuss the relevance of sarcopenic obesity, examine the feasibility of weight loss in the elderly, and highlight new approaches to the problem.

IntroductionThe Institute of Translational Health Sciences (ITHS) promotes and supports translational research collaboration between clinicians, communities, and investigators across the five-state Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region. The ITHS has developed a collaborative regional clinical research network, the Northwest Participant & Clinical Interactions Network (NW PCI), involving 12 diverse clinical health systems and academic institutions.MethodsThis descriptive article details NW PCI’s development, infrastructure and governance, tools, characteristics, and initial outcomes.ResultsRegional NW PCI sites are conducting largely industry-sponsored studies; they are interested in including more grant-funded research. Regional NW PCI sites had over 1,240 open studies involving over 6700 patients in 2016. NW PCI trials are largely industry-sponsored; NW PCI sites are interested in including more grant-funded research. In its first three years, the NW PCI Coordinating Center facilitated regional sites’ participation in 34 new grant and contract applications across diverse topics.ConclusionThe NW PCI model supports the goals of the developing CTSA Trial Innovation Network by increasing access to cutting-edge research across the Northwestern U.S., by supporting investigators seeking diverse populations, including those with rare diseases, for their research studies, and by providing settings to test implementation and dissemination of effective interventions.

Purpose The Yukon Arctic Ultra is considered the longest and coldest ultraendurance event in the world. Cold exposure and exercise has been reported to influence circulating levels of myokines, adipokines, and hepatokines that may influence considerable alterations in the regulation of metabolism. The purpose of the study was to evaluate the influence of the Yukon Arctic Ultra (430-mile event) on potential activators of brown fat, metabolites, and body composition in healthy individuals. Methods Eight male and female participants (mean ± SEM: age, 44 ± 3 yr; body mass index, 23.4 ± 0.9) were recruited for participation. Blood samples were collected at pre-event, mid-event, and post-event checkpoints. Results The temperature during the event ranged from -45°C to -8°C. Because of these extremely challenging conditions, 50% of the participants withdrew from competition by the 300-mile mark, and those that surpassed 300 miles lost a significant (P = 0.002; P = 0.01) amount of body weight (76 ± 5 kg to 73 ± 4 kg) and fat mass (13 ± 1 kg to 12 ± 3 kg), respectively. With respect to serum irisin, there was a trend (P = 0.06) toward significance from pre-event (1033 ± 88 ng·mL), mid-event (1265 ± 23 ng·mL) to post-event (1289 ± 24 ng·mL). Serum meteorin-like and fibroblast growth factor-21 remained stable throughout the event. There were no changes in creatinine, acetoacetate, acetate, and valine. Serum lactate decreased (P = 0.04) during the event. Conclusions The influence of cold exposure and extreme physical exertion may promote substantial increases in serum irisin, and specific alterations in substrate metabolism that largely preserve skeletal muscle and physiological resilience.

Excess alcohol consumption is a top risk factor for death and disability. Fatty liver will likely develop and the risk of liver disease increases. We have previously demonstrated that an essential amino acid supplement (EAAS) improved protein synthesis and reduced intrahepatic lipid in the elderly. The purpose of this exploratory pilot study was to initiate the evaluation of EAAS on intrahepatic lipid (IHL), body composition, and blood lipids in individuals with mild to moderate alcohol use disorder (AUD). Following consent, determination of eligibility, and medical screening, 25 participants (18 males at 38 &plusmn, 15 years/age and 7 females at 34 &plusmn, 18 years/age) were enrolled and randomly assigned to one of two dosages: a low dose (LD: 8 g of EAAS twice/day (BID)) or high dose (HD: 13 g of EAAS BID). Five of the twenty-five enrolled participants dropped out of the intervention. Both groups consumed the supplement BID for 4 weeks. Pre- and post-EAAS administration, IHL was determined using magnetic resonance imaging/spectroscopy, body composition was analyzed using dual-energy X-ray absorptiometry, and blood parameters were measured by LabCorp. T-tests were used for statistical analysis and considered significant at p &lt, 0.05. While there was no significant change in IHL in the LD group, there was a significant 23% reduction in IHL in the HD group (p = 0.02). Fat mass, lean tissue mass, bone mineral content, and blood lipids were not altered. Post-EAAS phosphatidylethanol was elevated and remained unchanged in LD at 407 &plusmn, 141 ng/mL and HD at 429 &plusmn, 196 ng/mL, indicating chronic and excess alcohol consumption. The HD of the proprietary EAAS formulation consumed BID seemed to lower IHL in individuals with mild to moderate AUD. We suggest that further studies in a larger cohort be conducted to more completely address this important area of investigation.

Objective: The purpose of this study was to evaluate pre- and postseason measures of body composition, skeletal muscle, and blood parameters/liver lipid in wildland firefighters (WLFF) over the fire season. Methods: Alaskan WLFF (N = 27) crews were evaluated pre- and postwildfire season, which included 63 ± 10 operational days. Body composition, thigh muscle area, and liver lipid were quantified using dual-energy radiograph absorptiometry and magnetic resonance imaging, respectively. Blood metabolic and lipid panels were also collected and analyzed. Results: Total body, fat, and visceral fat mass increased from pre- to postseason (P

The purported healthy aspects of subsistence foods have led to the popularity of the Paleo diet. There has been very little focus, surprisingly, on health benefits derived from the nomadic nature of humans during the Paleolithic era. The purpose of our study was to examine total energy expenditure (TEE), total energy intake (TEI), body composition, blood lipids, and intrahepatic lipid in humans during a 12‐day Alaskan backcountry expeditionary hunting (ABEH) immersion. Four healthy men (age: 42 ± 3 year, BMI: 27 ± 1 kg/m2) were recruited for the study. TEE was measured using the doubly labeled water method and a food diary was utilized to assess TEI. Body composition was measured using dual energy X‐ray absorptiometry (DXA); cross‐sectional area of the thigh (XT) and intrahepatic lipid (IHL) were measured using molecular imaging. Blood samples were collected for the measurement of blood lipids. DXA, XT, IHL, and blood data were collected pre‐ and immediately post‐ABEH. Results were analyzed using paired t‐tests and considered significant at P

Summary Background & aims Older individuals are susceptible to the loss of muscle and accumulation of fat. To address this problem, we have compared protein kinetics following consumption of an essential amino acid (EAA)-enriched meal replacement (EMR) to consumption of a high-protein meal replacement beverage (Bariatric Advantage, BA) using stable isotope methodology. Methods Eight older (67 ± 2), obese (35 ± 2 kg/m2) female and male participants completed two studies using a randomized, crossover design in which they ingested each meal replacement. The isotopic tracers L-[2H5]phenylalanine & L-[2H2]tyrosine were delivered via primed, continuous intravenous infusion throughout a basal period and following consumption of EMR or BA. We determined changes in whole body protein synthesis (PS), protein breakdown (PB), and net protein balance (NB) from fasted states via analysis of plasma samples by LC-ESI-MS. Results PS was higher (P = 0.03) and PB was less (P = 0.005) with EMR in comparison to BA. As a result, NB was much greater (P = 0.00003) following the ingestion of EMR as compared to BA. Conclusions In comparison with BA, which has a higher amount of intact protein that any other meal replacement, EMR promoted a greater increment in NB. These data support the potential efficacy of EMR as a meal replacement for the preservation of lean tissue mass during weight loss in older, overweight individuals.

Objective: Cardiac cachexia is a condition associated with heart failure, particularly in the elderly, and is characterized by loss of muscle mass with or without the loss of fat mass. Approximately 15% of elderly heart failure patients will eventually develop cardiac cachexia; such a diagnosis is closely associated with high morbidity and increased mortality. While the mechanism(s) involved in the progression of cardiac cachexia is incompletely established, certain factors appear to be contributory. Dietary deficiencies, impaired bowel perfusion, and metabolic dysfunction all contribute to reduced muscle mass, increased muscle wasting, increased protein degradation, and reduced protein synthesis. Thus slowing or preventing the progression of cardiac cachexia relies heavily on dietary and exercise-based interventions in addition to standard heart failure treatments and medications. Methods: The aim of the present study was to test the feasibility of an at-home exercise and nutrition intervention program in a population of elderly with heart failure, in an effort to determine whether dietary protein supplementation and increased physical activity may slow the progression, or prevent the onset, of cardiac cachexia. Frail elderly patients over the age of 55 with symptoms of heart failure from UAMS were enrolled in one of two groups, intervention or control. To assess the effect of protein supplementation and exercise on the development of cardiac cachexia, data on various measures of muscle quality, cardiovascular health, mental status, and quality of life were collected and analyzed from the two groups at the beginning and end of the study period. Results: More than 50% of those who were initially enrolled actually completed the 6-month study. While both groups showed some improvement in their study measures, the protein and exercise group showed a greater tendency to improve than the control group by the end of the six months. Conclusion: These findings suggest that with a larger cohort, this intervention may show significant positive effects for elderly patients who are at risk of developing cardiac cachexia.

Variations in skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), carntine palmitoyltransferase-1 (CPT-1), perilipin protein 2 (PLIN2), and adipose tissue triglyceride lipase (ATGL), and comparative gene identification-58 (CGI-58) have been described as playing important roles in the metabolic regulation of lipid oxidation, and may influence intramyocellular lipid (IMCL) and muscle lipid droplet size (LDS). While acute changes in caloric balance and/or aerobic capacity may affect lipid metabolism, the influence of sustained weight loss derived from caloric restriction with weight loss (CWL) compared with exercise training with weight loss (EWL) on the abovementioned parameters has not been fully elucidated. Using a combination of metabolic feeding and/or supervised exercise training, we evaluated the influence of stabilized weight loss elicited by CWL compared with EWL without the confounding influence of acute alterations in caloric balance on molecular markers of mitochondrial metabolism and lipid droplet size in middle-aged overweight individuals with impaired glucose tolerance. There were no significant changes in PGC-1α, CPT-1, PLIN2, ATGL and, CGI-58 messenger RNA (mRNA) in CWL and EWL. While there were no changes in ATGL mRNA in CWL, there was a strong trend (P = 0.05) for the ΔATGL mRNA in EWL with stabilized weight loss. There were no significant changes in IMCL or LDS within skeletal muscle in CWL or EWL, respectively. In conclusion, under the conditions of chronic caloric balance following dietary or exercise-based interventions, mediators of mitochondrial function, IMCL and LDS, were largely unaffected. Future studies should focus on intervention-based changes in protein expression and/or phosphorylation and the relationship to physiological endpoints.

Older individuals are often forced to move to a long-term care facility (1), and this change in lifestyle status may lead to an increase in morbidity and mortality (2). These risks are compounded by a reduction in physical activity, which has been shown to precipitate the onset of insulin resistance and the degradation of skeletal muscle in younger individuals (3). Unfortunately, the deleterious influence of bed rest on metabolism has not been evaluated in older adults. Our study sought to examine potential changes in the regulation of glucose and fatty acid metabolism that might be affected by bed rest due to clinical events such as hospitalization, surgery, and hip fracture in the absence of any pre existing co morbidities. A recent review has promoted the assertion that physical inactivity may promote the concomitant development of insulin resistance, impairments in lipid trafficking, alterations in substrate utilization, and increased deposition of intracellular lipid (4). Moreover, the overall elevation in plasma free fatty acids (FFA) might stem from this “metabolic inflexibilty,” and have a chronic, detrimental influence on the worsening of hepatic and peripheral insulin resistance (5). For example, excess FFA promotes an increase in hepatic-derived very low–density lipoprotein (VLDL) (6) and the excessive deposition of hepatic lipid, highlighting the important role of the liver in the etiology of insulin resistance (7). Although bed rest studies in young individuals describe insulin resistance in presence of decreased lipolysis (8), the effects of bed rest on insulin resistance and FFA metabolism have not been evaluated in older individuals. Therefore, we hypothesized that short-term bed rest would result in the acute onset of hepatic and peripheral insulin resistance and would be potentiated by changes in FFA metabolism in this segment of the population. If short-term bed rest does promote these physiological perturbations, countermeasures must be developed to offset these detrimental clinical consequences. We utilized a continuous octreotide, basal glucagon replacement, and a multistage insulin infusion (MSI) designed to examine hepatic and peripheral insulin resistance prior to and immediately following 10 days of strict bed rest. The MSI was combined with the infusion of [6,6 2H2]glucose and [1-13C]palmitate and subsequent plasma analysis by gas chromatography/mass spectrometry to derive rates of endogenous glucose production (glucose R a) and free fatty acid rate of appearance (FFA R a), respectively.

Purpose of review The primary focus of this review is to characterize the physiological elements of sarcopenia. In addition, we will also describe the impact of bedrest on sarcopenia and how various countermeasures may be able to offset the deleterious clinical consequences of unanticipated bedrest or hospitalization. It is well known that the aging process presents many challenges to the maintenance of overall health. With the increasing rate of obesity and the potentially simultaneous development of sarcopenia, bedrest presents a difficult clinical challenge to the elderly individual. Recent findings The etiology of accelerated sarcopenia has been described as a syndrome. The characteristics of this syndrome include combined alterations in neuromuscular control and muscle protein synthesis that increase the risk of morbidity and mortality in the elderly population. Moreover, the acute onset of bedrest-induced insulin resistance may further complicate the nutritionally derived maintenance of muscle mass and physical function. Summary Even though many questions remain unresolved concerning the optimal clinical management of elderly individuals who undergo unanticipated bedrest, the supplementation of essential amino acids has shown promise as a therapeutic strategy to minimize the detrimental influence of hospitalization in the elderly. In turn, this nutritional adjunctive therapy may reduce the length of stay and the likelihood of repeated hospitalization.

Adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte and muscle triglyceride hydrolysis, and comparative gene identification-58 (CGI-58) is an essential cofactor. We studied the expression of ATGL and CGI-58 in human adipose and muscle and examined correlations with markers of muscle fatty acid oxidation. Nondiabetic volunteers were studied. Subjects with impaired glucose tolerance were treated with pioglitazone or metformin for 10 weeks. Subjects with normal glucose tolerance underwent a 12-week training program. We examined changes in ATGL and CGI-58 with obesity and insulin resistance, and effects of exercise and pioglitazone. Adipose triglyceride lipase messenger RNA (mRNA) expression showed no correlation with either body mass index or insulin sensitivity index in either adipose or muscle. However, adipose ATGL protein levels were inversely correlated with body mass index (r = -0.64, P < .02) and positively correlated with insulin sensitivity index (r = 0.67, P < .02). In muscle, ATGL mRNA demonstrated a strong positive relationship with carnitine palmitoyltransferase I mRNA (r = 0.82, P < .0001) and the adiponectin receptors AdipoR1 mRNA (r = 0.71, P < .0001) and AdipoR2 mRNA (r = 0.74, P < .0001). Muscle CGI-58 mRNA was inversely correlated with intramyocellular triglyceride in both type 1 (r = -0.35, P < .05) and type 2 (r = -0.40, P < .05) fibers. Exercise training resulted in increased muscle ATGL, and pioglitazone increased adipose ATGL by 31% (P < .05). Pioglitazone also increased ATGL in adipocytes. Adipose ATGL protein is decreased with insulin resistance and obesity; and muscle ATGL mRNA is associated with markers of fatty acid oxidation in muscle, as is CGI-58. The regulation of ATGL and CGI-58 has important implications for the control of lipotoxicity.

To examine the influence of moderate-intensity (50% of VO(2peak)) exercise training (MI) versus high-intensity (75% of VO(2peak)) exercise training (HI) on regional fat distribution and plasma adiponectin, we randomized 18 overweight (body mass index [BMI] = 30 +/- 1 kg/m(2)) elderly (71 +/- 1 years) to HI, MI, or a control group (CON). Subjects enrolled in HI or MI completed a 12-week exercise training protocol designed to expend 1000 kcal/week. Body composition testing was completed prior to and following the exercise training using dual energy X-ray absorptiometry and a computed tomography scan. Plasma adiponectin was measured using enzymelinked immunoassay (ELISA). VO(2peak) improved in HI and MI, whereas there was no change in VO(2peak) in CON. No significant change in body weight, BMI, and % fat occurred in MI, HI, or CON. Although there was a significant reduction in visceral fat with HI (-39 cm(2)), there was no change in the MI or CON groups. In addition, there was a significant increase in thigh muscle attenuation in the HI group. There were no changes in thigh muscle attenuation in the MI and CON groups. Also, there was no change in plasma adiponectin in the MI, HI, or CON groups. In summary, our direct comparison of exercise intensity without weight loss promotes the efficacy of HI in the reduction in visceral fat, even without changes in adiponectin.

Body fatness and its distribution are strongly and independently associated with peripheral insulin action. However, these associations are limited in their ability to predict the independent nature of hepatic and peripheral insulin resistance, especially in obese women. To define the relationships more precisely between regional fat distribution and adiponectin, and hepatic and peripheral insulin resistance, we studied 22 obese (43 +/- 0.1%) women who underwent a dual-energy X-ray absorptiometry scan and a computed tomography scan at the L4-L5 level. An octreotide (60 ng x kg(-1) x min(-1)), glucagon (0.65 ng x kg(-1) x min(-1)), and two-step insulin (0.25 mU x kg(-1) x min(-1) and 1.0 mU x kg(-1) x min(-1)) infusion was performed to quantify insulin-mediated suppression of hepatic glucose production (SGP) and insulin-stimulated glucose disposal (ISGD) in a simultaneous fashion. Hepatic glucose production (HGP) was measured using a primed, constant infusion of [6,6(2)H(2)] glucose. Mean plasma insulin increased from 5.6 +/- 0.1 microU/mL at baseline to 15.1 +/- 1.5 microU/mL in the first stage, and to 80.7 +/- 0.5 microU/mL in the second stage. Although there was no significant relationship between visceral adipose tissue (VAT) and basal HGP (r = 0.34, p = 0.117), there was a significant inverse correlation (r = -0.67, p = 0.003) between VAT and SGP. There was a significant correlation (r = 0.55, p = 0.008) between adiponectin and ISGD. In conclusion, these data support: (1) the inability of basal glucose metabolism to accurately reflect hepatic insulin resistance, (2) the deleterious role of VAT in the development of insulin resistance in the liver, and (3) provide additional support for the positive influence of adiponectin against peripheral insulin resistance in obese, postmenopausal women.

Common complications of type 2 diabetes (T2D) are eye, kidney and nerve diseases, as well as an increased risk for the development of cardiovascular disease and cancer. The overwhelming influence of these conditions contributes to a decreased quality of life and life span, as well as significant economic consequences. Although obesity once served as a surrogate marker for the risk of T2D, we know now that excess adipose tissue secretes inflammatory cytokines that left unchecked, accelerate the progression to insulin resistance and T2D. In addition, excess alcohol consumption may also increase the risk of T2D. From a therapeutic standpoint, lifestyle interventions such as dietary modification and/or exercise training have been shown to improve glucose homeostasis but may not normalize the disease process unless weight loss is achieved and increased physical activity patterns are established. Furthermore, utilization of natural products may serve as a significant adjunct in the fight against insulin resistance but further research is needed to ascertain their validity. Since it is clear that pharmaceutical therapy plays a significant role in the treatment of insulin resistance, this review will also discuss some of the newly developed pharmaceutical therapies that may work in conjunction with lifestyle interventions, and lessen the burden of behavioral change as the only strategy against the development of T2D.

COKER, R. H., N. P. HAYS, R. H. WILLIAMS, A. D. BROWN, S. A. FREELING, P. M. KORTEBEIN, D. H. SULLIVAN, R. D. STARLING, and W. J. EVANS. Exercise-Induced Changes in Insulin Action and Glycogen Metabolism in Elderly Adults. Med. Sci. Sports Exerc., Vol. 38, No. 3, pp. 433–438, 2006. Purpose: Although data suggest that physical activity is associated with decreased insulin resistance, recommendations for exercise training are not specific for age or level of obesity. Therefore, we examined the influence of moderate-intensity (50% of V u O2max) exercise training (MI) versus high-intensity (75% of V u O2max) exercise training (HI) on insulin-stimulated glucose disposal (ISGD) in elderly individuals. Methods: Following medical examinations, 21 overweight (body mass index = 29 T 1k gIm j2 ) elderly (74 T 1 yr) subjects were randomized to 1) HI, 2) MI, or a 3) nonexercising control group. Subjects enrolled in HI or MI completed a 12-wk exercise training regimen designed to expend 1000 kcalIwk j1 . ISGD was assessed using a hyperinsulinemic, euglycemic clamp pre- and postintervention. ISGD was corrected for hepatic glucose production (glucose Ra) using a constant rate infusion of [6,6- 2 H2]glucose and determined during the last 30 min of the clamp by subtracting glucose Ra from the exogenous glucose infusion rate. Nonoxidative glucose disposal was calculated using indirect calorimetry. Body composition testing was completed using dual energy x-ray absorptiometry. Results: ISGD increased by approximately 20% with HI ($ of 1.4 T 0.5 mgIkg j1 FFMImin j1 ). However, ISGD did not change ($ of j0.4 T 0.1 mgIkg j1 FFMImin j1 ) with MI and was not different ($ of j0.2 T 0.1 mgIkg j1 FFMImin j1 ) in the control group. Nonoxidative glucose disposal increased with HI ($ of 1.4 T 0.5 mgIkg j1 FFMImin j1 ), but there was no change in nonoxidative glucose disposal with MI or

Previous studies have demonstrated that aerobic exercise training and weight loss have independent effects on insulin-stimulated glucose disposal (ISGD). We hypothesized that ad libitum consumption of a high-carbohydrate diet would result in weight loss and improved ISGD, and that aerobic exercise training would facilitate greater improvements in ISGD compared with diet alone.Older participants (13 women, 9 men; age = 66 +/- 1 year) with impaired glucose tolerance were randomly assigned to an ad libitum diet alone (18% fat, 19% protein, 63% carbohydrate) or this diet plus aerobic exercise training (4 d/wk, 45 min/d, 80% VO(2peak)) for 12 weeks. ISGD, abdominal fat distribution, muscle glycogen, and glycogen synthase activity were assessed pre- and postintervention.Consumption of the diet resulted in significant weight loss and an improvement in ISGD. Consumption of the diet plus exercise training also resulted in weight loss and increased ISGD, but results were not significantly different from those in the diet-alone group. Mean abdominal visceral and subcutaneous adipose tissue cross-sectional areas were smaller postintervention compared to baseline with no difference between groups. Exercise training and consumption of the diet increased muscle glycogen content (344.7 +/- 21.3 to 616.7 +/- 34.4 micromol.g(-1)) and decreased glycogen synthase activity (0.21 +/- 0.02 to 0.13 +/- 0.01) compared to the diet alone.These results demonstrate that consumption of an ad libitum, high-carbohydrate diet alone or in combination with aerobic exercise training results in weight loss and improved insulin sensitivity. Furthermore, exercise combined with this diet appears to limit additional increases in insulin sensitivity due to muscle glycogen supercompensation with a concomitant adaptive response of glycogen synthase.

There is a general perception that increased physical activity will improve glucose homeostasis in all individuals. While this is an attractive concept, this conclusion may be overly simplistic and even misleading. The topic was reviewed extensively over 30 years ago and it was concluded that acute exercise enhances glucose uptake. However, in some cases the chronic influence of interventions utilizing exercise may have little effect on glucose metabolism. Moreover, insulin resistance often returns to near baseline levels within a couple of days following cessation of the exercise bout; leaving the overall effectiveness of the intervention in question. Since improving glucose homeostasis should be the focal endpoint of any intervention designed to mitigate the overwhelming degree of insulin resistance in individuals at risk for metabolic disease, it is essential to evaluate the key components of a successful approach.

These studies were conducted to determine the magnitude and mechanism of compensation for impaired glucagon and insulin responses to exercise. For this purpose, dogs underwent surgery >16 days before experiments, at which time flow probes were implanted and silastic catheters were inserted. During experiments, glucagon and insulin were fixed at basal levels during rest and exercise using a pancreatic clamp with glucose clamped (PC/GC; n = 5), a pancreatic clamp with glucose unclamped (PC; n = 7), or a pancreatic clamp with glucose unclamped + intraportal propranolol and phentolamine hepatic α- and β-adrenergic receptor blockade (PC/HAB; n = 6). Glucose production (Ra) was measured isotopically. Plasma glucose was constant in PC/GC, but fell from basal to exercise in PC and PC/HAB. Ra was unchanged with exercise in PC/GC, but was slightly increased during exercise in PC and PC/HAB. Despite minimal increases in epinephrine in PC/GC, epinephrine increased approximately sixfold in PC and PC/HAB during exercise. In summary, during moderate exercise, 1) the increase in Ra is absent in PC/GC; 2) only a moderate fall in arterial glucose occurs in PC, due to a compensatory increase in Ra; and 3) the increase in Ra is preserved in PC/HAB. In conclusion, stimulation of Ra by a mechanism independent of pancreatic hormones and hepatic adrenergic stimulation is a primary defense against overt hypoglycemia.

To test whether hepatic insulin action and the response to an insulin-induced decrement in blood glucose are enhanced in the immediate postexercise state as they are during exercise, dogs had sampling (artery, portal vein, and hepatic vein) catheters and flow probes (portal vein and hepatic artery) implanted 16 days before a study. After 150 min of moderate treadmill exercise or rest, dogs were studied during a 150-min hyperinsulinemic (1 mU · kg−1· min−1) euglycemic ( n = 5 exercised and n = 9 sedentary) or hypoglycemic (65 mg/dl; n = 8 exercised and n = 9 sedentary) clamp. Net hepatic glucose output (NHGO) and endogenous glucose appearance (Ra) and utilization (Rd) were assessed with arteriovenous and isotopic ([3-3H]glucose) methods. Results show that, immediately after prolonged, moderate exercise, in relation to sedentary controls: 1) the glucose infusion rate required to maintain euglycemia, but not hypoglycemia, was higher; 2) Rdwas greater under euglycemic, but not hypoglycemic conditions; 3) NHGO, but not Ra, was suppressed more by a hyperinsulinemic euglycemic clamp, suggesting that hepatic glucose uptake was increased; 4) a decrement in glucose completely reversed the enhanced suppression of NHGO by insulin that followed exercise; and 5) arterial glucagon and cortisol were transiently higher in the presence of a decrement in glucose. In summary, an increase in insulin action that was readily evident under euglycemic conditions after exercise was abolished by moderate hypoglycemia. The means by which the glucoregulatory system is able to overcome the increase in insulin action during moderate hypoglycemia is related not to an increase in Rabut to a reduction in insulin-stimulated Rd. The primary site of this reduction is the liver.

Several studies have highlighted the detrimental influence of bed rest on metabolism and muscle protein synthesis (1–4). Additional studies have demonstrated that chronic bed rest may result in the loss of postural muscles, leading to increased risk of falls and disability (5). Realizing the high incidence of anorexia in the geriatric population (6), our group has studied the influence of bed rest in the elderly under eucaloric conditions and still observed reductions in strength in healthy older individuals despite the lack of deficiencies in macronutrient intake or caloric balance (7). Walking speed has been confirmed as a clear predictor for adverse health-related events (8). In addition, the findings from Health Aging and Body Composition study demonstrated that age-related reductions in thigh and grip strength were closely correlated with increased mortality (9). These changes in lean mass were consistent in earlier reports, and changes in physical function were not evaluated in these studies. Recently, Drummond and coworkers (10) demonstrated significant bed rest-induced reductions in total lean mass that were linked to impairment in the response to amino acids. Even small reductions in physical activity in older adults have also resulted in changes altered muscle protein synthesis associated with reductions in insulin sensitivity (11). In addition, we recently demonstrated significant reductions in hepatic and peripheral insulin sensitivity with short-term bed rest in older adults (12). Therefore, bed rest might promote tissue lipid accumulation and aggravated insulin resistance in the elderly that has been linked to detrimental reductions in muscle mass and strength (13). Therefore, we hypothesized that short-term bed rest would promote reductions in muscle strength and physical function, and that these changes would be related to the reduction of lean mass. We also sought to examine the relationships between changes in lean mass and muscle strength and physical function.

Context Lysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been tested in the geriatric population. Objective: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low-dose lysine (2 grams), and oral glucose and high dose lysine (5 grams) lysine in 7 older (66 ± 1 years/age), overweight/obese (BMI = 28 ± 2 kg/m2) individuals. Methods We utilized a dual tracer technique (i.e., [6,6-2H2] glucose primed constant infusion and 1-[13C] glucose oral ingestion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios. Results Post-absorptive plasma glucose and insulin concentrations were not different between the three trials. Similarly, the response of glucose and insulin concentrations during the oral glucose tolerance tests (OGTT) was similar in the three trials. The results of the Matsuda index (ISI/M) were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogenous glucose rate of appearance (glucose Ra) for control, 2 g lysine and 5 g lysine (1.2 ± 0.1, 1.1 ± 0.1, 1.3 ± 0.1 mg•kg-1•min-1), respectively. With respect to peripheral insulin sensitivity, there were no significant differences in the glucose rate of disappearance (glucose Rd) for control, 2 g lysine and 5 g lysine (4.2 ± 0.1, 4.3 ± 0.2, and 4.5 ± 0.4 mg•kg-1•min-1), respectively. Conclusions Previous studies in younger participants have suggested that lysine may have a beneficial effect on glucose metabolism. However, acute lysine supplementation in the older population does not facilitate beneficial changes in glucose Ra or glucose Rd. Electronic supplementary material The online version of this article (doi:10.1186/1743-7075-11-49) contains supplementary material, which is available to authorized users.

Context: Lysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been evaluated in older individuals. Objective: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low-dose lysine (2 g), and oral glucose and high dose lysine (5 g) lysine in 7 older (66±1 years/age), overweight (BMI = 31±2 kg/m2) individuals. Methods: We utilized a dual tracer technique (ie., [1-13C] glucose oral ingestion and [6,6-2H2] glucose infusion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios. Results: Plasma glucose and insulin data were not different between the control, 2 g lysine and 5 g of lysine trials. The results of the Matsuda index were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogeno...

This study was aimed at assessing the role of carotid body function in neuroendocrine and glucoregulatory responses to exercise. The carotid bodies and associated nerves were removed (CBR, n = 6) or left intact (Sham, n = 6) in anesthetized dogs >16 days before experiments, and infusion and sampling catheters were implanted. Conscious dogs were studied at rest and during 150 min of exercise. Isotopic dilution was used to assess glucose production (Ra) and disappearance (Rd). Arterial glucagon was reduced in CBR compared with Sham at rest (29 ± 3 vs. 47 ± 3 pg/ml). During exercise, glucagon increased more in Sham than in CBR (47 ± 9 vs. 15 ± 2 pg/ml). Cortisol and epinephrine levels were similar in the two groups at rest and during exercise. Basal norepinephrine was similar in CBR and Sham. During exercise, norepinephrine increased by 432 ± 124 pg/ml in Sham, but by only 201 ± 28 pg/ml in CBR. Basal arterial plasma glucose was 108 ± 2 and 105 ± 2 mg/dl in CBR and Sham, respectively. Arterial glucose dropped by 10 ± 3 mg/dl at onset of exercise in CBR ( P < 0.01) but was unchanged in Sham (decrease of 3 ± 2 mg/dl, not significant). Basal glucose kinetics were equal in Sham and CBR. At onset of exercise, Raand Rdwere transiently uncoupled in CBR (i.e., Rd> Ra) but were closely matched in Sham. In steady-state exercise, Raand Rdwere closely matched in both groups. Insulin was equal in the basal period and decreased similarly during exercise. These studies suggest that input from the carotid bodies, or receptors anatomically close to them, 1) is important in control of basal glucagon and the exercise-induced increment in glucagon, 2) is involved in the sympathetic response to exercise, and 3) participates in the non-steady-state coupling of Rato Rd, but 4) is not essential to glucoregulation during sustained exercise.

To determine the importance of basal glucagon to the stimulation of net splanchnic glucose output (NSGO) during exercise, seven healthy males performed cycle exercise during a pancreatic islet cell clamp. In one group (BG), glucagon was replaced at basal levels and insulin was adjusted to achieve euglycemia. In another group (GD), only insulin was replaced at the identical rate used in BG, and basal glucagon was not replaced. Exogenous glucose infusion was necessary to maintain euglycemia during exercise in BG and during rest and exercise in GD. Arterial glucagon was at least twofold greater in BG than in GD throughout the pancreatic islet cell clamp. Although basal NSGO remained stable in BG (2.5 ± 0.5 mg · kg−1 · min−1), basal NSGO dropped by 70% in GD (0.7 ± 0.3 mg · kg−1 · min−1). NSGO was also greater in BG than in GD at 10 min of moderate exercise, most likely due to the residual effect of basal glucagon replacement. However, NSGO increased slightly and remained similar throughout the remainder of moderate and heavy exercise in BG and GD. Therefore, a mechanism independent of changes in pancreatic hormones and/or the level of glycemia contributes toward modest stimulation of NSGO during moderate and heavy exercise.

The carotid bodies are sensitive to glucose in vitro and can be stimulated to cause hyperglycemia in vivo. The aim of this study was to determine if the carotid bodies are involved in basal glucoregulation or the counterregulatory response to an insulin-induced decrement in arterial glucose in vivo. Dogs were surgically prepared >16 days before the experiment. The carotid bodies and their associated nerves were removed (carotid body resected [CBR]) or left intact (Sham), and infusion and sampling catheters were implanted. Removal of carotid bodies was verified by the absence of a ventilatory response to NaCN. Experiments were performed in 18-h fasted conscious dogs and consisted of a tracer ([3-3H]glucose) equilibration period (-120 to -40 min), a basal period (-40 to 0 min), and an insulin infusion (1 mU x kg(-1) x min(-1)) period (0-150 min) during which glucose was infused as needed to clamp at mildly hypoglycemic (65 mg/dl) or euglycemic (105 mg/dl) levels. Basal (8 microU/ml) and clamp (40 microU/ml) insulin levels were similar in both groups. Basal arterial glucagon was reduced in CBR compared with Sham (30 + 2 vs. 40 +/- 2 pg/ml) and remained reduced in CBR during hypoglycemia (peak levels of 36 +/- 3 vs. 52 +/- 7 pg/ml). Cortisol levels were not significantly different between the 2 groups in the basal state, but were reduced during the hypoglycemic clamp in CBR. Catecholamine levels were not significantly different between the 2 groups in the basal and hypoglycemic periods. The glucose infusion rate required to clamp glucose at 65 mg/dl was 2.5-fold greater in CBR compared with Sham (4.0 +/- 0.4 vs. 1.6 +/- 0.4 mg x kg(-1) x min(-1)). Basal endogenous glucose appearance (R(a)) was equal in CBR and Sham (2.5 +/- 0.1 vs. 2.5 +/- 0.2 mg x kg(-1) x min(-1)). During the hypoglycemic clamp, insulin suppressed R(a) in CBR but not Sham (1.1 +/- 0.2 vs. 2.5 +/- 0.2 mg x kg(-1) x min(-1) during the last 30 min of the clamp), reflecting impaired counterregulation. Glucose disappearance (R(d)) in the basal state was similar in CBR and Sham, whereas it was elevated in CBR during the hypoglycemic clamp (4.8 +/- 0.1 vs. 3.9 +/- 0.1 mg x kg(-1) x min(-1) during the last 30 min of the clamp). R(d) was also elevated in euglycemic clamp studies, indicating an effect of carotid body resection independent of hypoglycemia. There were no other measured systematic endocrine or metabolic effects of carotid body resection during euglycemic clamps. In conclusion, we found that the carotid bodies (or receptors anatomically close by) play an important role in the insulin-induced counterregulatory response to mild hypoglycemia.

The purpose of this study was to determine the role of direct hepatic adrenergic stimulation in the control of endogenous glucose production (Ra) during moderate exercise in poorly controlled alloxan-diabetic dogs. Chronically catheterized and instrumented (flow probes on hepatic artery and portal vein) dogs were made diabetic by administration of alloxan. Each study consisted of a 120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min recovery, and 30-min blockade test period. Either vehicle (control; n = 6) or α (phentolamine)- and β (propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create suprapharmacological levels at the liver. Isotopic ([3-3H]glucose, [U-14C]alanine) and arteriovenous difference methods were used to assess hepatic function. Arterial plasma glucose was similar in controls (345 ± 24 mg/dl) and HAB (336 ± 23 mg/dl) and was unchanged by exercise. Basal arterial insulin was 5 ± 1 mU/ml in controls and 4 ± 1 mU/ml in HAB and fell by ∼50% during exercise in both groups. Basal arterial glucagon was similar in controls (56 ± 10 pg/ml) and HAB (55 ± 7 pg/ml) and rose similarly, by ∼1.4-fold, with exercise in both groups. Despite greater arterial Epi and NE levels in HAB compared with controls during the basal and exercise periods, exercise-induced increases in catecholamines from basal were similar in both groups. Gluconeogenic conversion from alanine and lactate and the intrahepatic efficiency of this process were increased by twofold during exercise in both groups. Rarose similarly by 2.9 ± 0.7 and 2.7 ± 1.0 mg ⋅ kg−1⋅ min−1at time = 150 min during exercise in controls and HAB. During the blockade test period, arterial plasma glucose and Rarose to 454 ± 43 mg/dl and 11.3 mg ⋅ kg−1⋅ min−1in controls, respectively, but were essentially unchanged in HAB. The attenuated response to the blockade test in HAB substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results demonstrate that direct hepatic adrenergic stimulation does not play a role in the stimulation of Raduring exercise in poorly controlled diabetes.

Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. Experimental protocol: exercise (−180 to −30 min), transition (−30 to −20 min), basal period (−20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and −10 ± 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg ⋅ kg−1⋅ min−1, negative = uptake) was 4.2 ± 0.3 (basal period) and −1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and −3.2 ± 0.4, respectively ( P < 0.005 vs. Pe). Total glucose infusion (mg ⋅ kg−1⋅ min−1) was 11 ± 1 in Po and 8 ± 1 in Pe ( P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. Conclusions: the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.