Insulin suppression of fatty acid skeletal muscle enzyme activity in postmenopausal women, and improvements in metabolic flexibility and lipoprotein lipase with aerobic exercise and weight loss.

BACKGROUND: Obesity and insulin resistance are characterized by metabolic inflexibility, a condition described as an inability to switch from fat oxidation during fasting to carbohydrate oxidation during hyperinsulinemia. The purpose of this study was to examine predictors of metabolic flexibility in 103 obese (37-59% fat), sedentary (VO2max: 19.4 ± 0.5 ml/kg/min), postmenopausal (45-76 years) women, and changes in metabolic flexibility with exercise and weight loss interventions. METHODS: Insulin sensitivity (M) and metabolic flexibility via an 80 mU/m2/min hyperinsulinemic-euglycemic clamp, VO2max, and body composition were measured. Metabolic flexibility was measured after 6-months aerobic training + weight loss (AEX + WL: n = 43) or weight loss (WL: n = 31). Basal and insulin-stimulated vastus lateralis skeletal muscle samples were available from a subset of these women (n = 45). RESULTS: Metabolic flexibility correlated inversely with glucose120 min of OGTT, fasting insulin, and the percent change (insulin-basal) in lipoprotein lipase (LPL) activity and positively with M, but not with VO2max, total body fat, visceral fat, or subcutaneous abdominal fat. Skeletal muscle acyl-CoA synthase and citrate synthase activities decreased during hyperinsulinemia. Metabolic flexibility increased after AEX + WL but not WL, and the percent change in metabolic flexibility was inversely related to the percent change in insulin's effect on LPL activity. CONCLUSION: Metabolic flexibility is related to insulin sensitivity and insulin's action on LPL. Furthermore, metabolic flexibility and insulin suppression of skeletal muscle LPL activity increase with AEX + WL in overweight and obese, sedentary older women.

Promotion of Successful Weight Management in Overweight and Obese Veterans (POWER-VET): Trial Design and Methods.

BACKGROUND: Almost 75% of US adults are overweight or obese. Though intentional weight loss of as little as 3% improves physical functioning and reduces cardiometabolic risk, most adults are unsuccessful at long-term weight maintenance. Our hypothesis is that intermittent fasting (IF: short periods of intense energy restriction) will reduce weight regain. IF may combat obesity due to its effects on nutrient-sensing signaling pathways and circadian rhythm. The objective of this randomized clinical trial is to test the effectiveness of an intensive body weight management program with and without IF. METHODS: In the Promotion of Successful Weight Management in Overweight and Obese Veterans (POWER-VET) trial (NCT04131647), 154 middle-aged and older adults (50-75 years) who are overweight and obese (BMI: 25-40 kg/m2) and seen at either a Baltimore, MD or San Antonio, TX Veterans Affairs Medical Center will be enrolled. Participants will undergo 12 weeks of weight loss (including a low-calorie heart healthy (HH) diet and exercise). Following weight loss, participants will be randomly assigned to one of two 24-week weight maintenance (WM) interventions: WM alone (continuation of HH diet and exercise) or WM + IF. The primary aim is to determine the effect of WM + IF compared to WM alone on body weight maintenance after intentional weight loss. DISCUSSION: Determining effective, translatable strategies that minimize weight regain following successful weight loss holds public health relevance. This POWER-VET trial introduces an innovative practice of IF to prevent weight regain after clinically significant weight reduction and could provide evidence-based recommendations to promote this type of intervention in middle aged and older adults.

Sex differences in insulin regulation of skeletal muscle glycogen synthase and changes during weight loss and exercise in adults.

OBJECTIVE: The authors sought to understand sex differences in muscle metabolism in 73 older men and women. METHODS: Body composition, VO2max, and insulin sensitivity (M) by 3-hour hyperinsulinemic-euglycemic clamp with vastus lateralis muscle biopsies were measured. RESULTS: Women had lower body weight, VO2max, and fat-free mass than men. Men had lower M, lower change (insulin minus basal) in muscle glycogen synthase (GS) activity, and lower change in AKT protein expression than women. M was associated with the change (insulin-basal) in GS activity and the change in AKT protein expression. Sex differences (n = 60) were tested with 6-month weight loss or 3×/week aerobic exercise training. The postintervention minus preintervention change (insulin-basal) (∆∆) in GS activity (fractional, independent, total) was higher in men than women in the weight loss group and ∆∆ in GS fractional activity was higher in women than men in the aerobic exercise group. In all participants, ∆∆ in GS fractional and independent activities was related to ∆∆ in AKT expression and glycogen content. CONCLUSIONS: Sex differences in insulin sensitivity may be explained at the cellular muscle level, and to improve skeletal muscle insulin action in older adults, it may be necessary to recommend different behavioral strategies depending on the individual's sex.

Toxoplasma gondii IgG Serointensity Is Positively Associated With Frailty.

BACKGROUND: Persistent inflammation related to aging ("inflammaging") is exacerbated by chronic infections and contributes to frailty in older adults. We hypothesized associations between Toxoplasma gondii (T. gondii), a common parasite causing an oligosymptomatic unremitting infection, and frailty, and secondarily between T. gondii and previously reported markers of immune activation in frailty. METHODS: We analyzed available demographic, social, and clinical data in Spanish and Portuguese older adults [N = 601; age: mean (SD) 77.3 (8.0); 61% women]. Plasma T. gondii immunoglobulin G (IgG) serointensity was measured with an enzyme-linked immunosorbent assay. The Fried criteria were used to define frailty status. Validated translations of Mini-Mental State Examination, Geriatric Depression Scale, and the Charlson Comorbidity Index were used to evaluate confounders. Previously analyzed biomarkers that were significantly associated with frailty in both prior reports and the current study, and also related to T. gondii serointensity, were further accounted for in multivariable logistic models with frailty as outcome. RESULTS: In T. gondii-seropositives, there was a significant positive association between T. gondii IgG serointensity and frailty, accounting for age (p = .0002), and resisting adjustment for multiple successive confounders. Among biomarkers linked with frailty, kynurenine/tryptophan and soluble tumor necrosis factor receptor II were positively associated with T. gondii serointensity in seropositives (p < .05). Associations with other biomarkers were not significant. CONCLUSIONS: This first reported association between T. gondii and frailty is limited by a cross-sectional design and warrants replication. While certain biomarkers of inflammaging were associated with both T. gondii IgG serointensity and frailty, they did not fully mediate the T. gondii-frailty association.

The Role of Companion Dogs in the VA Maryland Health Care System Whole Health(y) GeroFit Program.

GeroFit is a gym-based exercise program that promotes health and wellness among older sedentary veterans. The aims of the current study were to determine whether providing a companion dog as an alternative to gym-based exercise would similarly affect whole health outcomes. A total of 15 (n = 15) veterans (62 ± 11 years of age; 13 of 15 >54 years of age) underwent physical function testing, completed global and whole health questionnaires, and wore an accelerometer for 7 days before (baseline) and 3 months after a dog came into their home. The participants completed the Pet Attachment Scale (PAS), Dog Owner-Specific Quality of Life (DOQOL), and Canine Behavioral Assessment and Research questionnaires at 3 months. Cardiorespiratory endurance, lower body strength, daily steps, and time spent engaging in moderate physical activity all increased compared to the baseline levels. Body weight decreased among veterans whose body mass index was ≥30 (n = 11). The PAS and DOQOL scores indicated high attachment and positive effects on quality of life after having a dog in the home, with all veterans agreeing that having a dog improved the number of social activities they performed. We conclude that providing a companion dog to veterans not inclined to participate in gym-based exercise is an effective alternative method of promoting health and wellness in this population.

Exercise with calorie restriction improves insulin sensitivity and glycogen synthase activity in obese postmenopausal women with impaired glucose tolerance.

Our objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in normal (NGT) vs. impaired glucose-tolerant (IGT) obese postmenopausal women and to determine whether an increase in insulin activation of GS is associated with an improvement in insulin sensitivity (M) following calorie restriction (CR) and/or aerobic exercise plus calorie restriction (AEX + CR) in women with NGT and IGT. We did a longitudinal, clinical intervention study of CR compared with AEX + CR. Overweight and obese women, 49-76 yr old, completed 6 mo of CR (n = 46) or AEX + CR (n = 50) with Vo(2 max), body composition, and glucose tolerance testing. Hyperinsulinemic euglycemic (80 mU·m(-2)·min(-1)) clamps (n = 73) and skeletal muscle biopsies (before and during clamp) (n = 58) were performed before and after the interventions (n = 50). After 120 min of hyperinsulinemia during the clamp, GS fractional activity and insulin's effect to increase GS fractional activity (insulin - basal) were significantly lower in IGT vs. NGT (P < 0.01) at baseline. GS total activity increased during the clamp in NGT (P < 0.05), but not IGT, at baseline. CR and AEX + CR resulted in a significant 8% weight loss with reductions in total fat mass, visceral fat, subcutaneous fat, and intramuscular fat. Overall, M increased (P < 0.01), and the change in M (postintervention - preintervention) was associated with the change in insulin-stimulated GS fractional activity (partial r = 0.44, P < 0.005). In IGT, the change (postintervention - preintervention) in insulin-stimulated GS total activity was greater following AEX + CR than CR alone (P < 0.05). In IGT, insulin-stimulated GS-independent (P < 0.005) and fractional activity (P = 0.06) increased following AEX + CR. We conclude that the greatest benefits at the whole body and cellular level (insulin activation of GS) in older women at highest risk for diabetes are derived from a lifestyle intervention that includes exercise and diet.

Effects of Proximity between Companion Dogs and Their Caregivers on Heart Rate Variability Measures in Older Adults: A Pilot Study.

Heart rate variability (HRV) is a noninvasive tool used to evaluate autonomic nervous system function and is affected by age, stress, postural changes, and physical activity. Dog ownership has been associated with higher 24-hr HRV and increased physical activity compared to nonowners. The current pilot study was designed to evaluate the effects of proximity to a dog in real time (minute-by-minute) on older dog caregivers' HRV measures and stress index during normal daily life over a 24-hr period. Eleven caregivers (56-83 years of age) wore ActiGraph GT9X Link accelerometers and camntech electrocardiogram monitors, and 11 dogs wore PetPace Collars and ActiGraph monitors to determine (a) proximity (absence or presence of Received Signal Strength Indicator, RSSI), (b) heart rate and HRV measures, (c) position (lying vs. sitting vs. standing), and (d) physical activity in the 11 dyads. Twenty-four hour HRV (SDNN index) and physical activity in the caregivers and dogs were related. Stress index was lower, and HRV parameters (SDNN, rMSDD, high frequency power (HF)) were higher when an RSSI signal was detected (presence of dog) compared to no RSSI signal (absence of dog) in the caregivers while inactive (lying + sitting + standing combined). HRV parameters (rMSDD and HF) were lower in the caregivers while standing and sitting compared to lying. The results from this pilot study support the hypothesis that spending time in the presence of a companion dog increases caregivers' HRV throughout the day and suggest that proximity to a dog may contribute to overall improvements in 24-hr HRV and cardiac health in dog caregivers.

Insulin Resistance in Skeletal Muscle of Chronic Stroke.

A stroke can lead to reduced mobility affecting skeletal muscle mass and fatty infiltration which could lead to systemic insulin resistance, but this has not been examined and the mechanisms are currently unknown. The objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in paretic (P) and nonparetic (NP) skeletal muscle in chronic stroke, and to compare to nonstroke controls. Participants were mild to moderately disabled adults with chronic stroke (n = 30, 60 ± 8 years) and sedentary controls (n = 35, 62 ± 8 years). Insulin sensitivity (M) and bilateral GS activity were determined after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Stroke subjects had lower aerobic capacity than controls, but M was not significantly different. Insulin-stimulated activities of GS (independent, total, fractional), as well as absolute differences (insulin minus basal) and the percent change (insulin minus basal, relative to basal) in GS activities, were all significantly lower in P versus NP muscle. Basal GS fractional activity was 3-fold higher, and the increase in GS fractional activity during the clamp was 2-fold higher in control versus P and NP muscle. Visceral fat and intermuscular fat were associated with lower M. The effect of in vivo insulin to increase GS fractional activity was associated with M in control and P muscle. A reduction in insulin action on GS in paretic muscle likely contributes to skeletal muscle-specific insulin resistance in chronic stroke.

Companion Dog Foster Caregiver Program for Older Veterans at the VA Maryland Health Care System: A Feasibility Study.

Veterans experience mental health conditions at a disproportionate rate compared to their civilian counterparts, and approximately 60% of older veterans who receive their care through the United States Department of Veterans Affairs (VA) do not meet physical activity (PA) recommendations. We tested the Veterans as Foster Ambassadors program at the VA Maryland Health Care System to examine whether fostering a companion dog would improve PA and function, heart rate variability (HRV), balance, and quality of life (QOL) in older veterans. Participants wore an accelerometer for ≥10 days during each phase (30 day baseline vs. 60 day foster period) to measure daily PA (n = 4). Six-minute walk (6MW) and balance testing (n = 4) and 24 h heart rate (HR) and HRV (n = 2) were determined at baseline and during the foster period. Compared to baseline, there were significant increases in (a) distance during the 6MW, (b) daily steps, and (c) time spent in moderate activity during the foster period. 24 h HR decreased and time- and frequency-domain measures of HRV significantly increased in a veteran with post-traumatic stress disorder during the foster period compared to baseline. All veterans offered positive feedback about the program and indicated that it was beneficial to them. The results from this pilot study provide evidence that fostering a companion dog can improve PA, health, and QOL in older veterans. Future research conducted with a larger sample size to validate the results is warranted.

Combining Actigraph Link and PetPace Collar Data to Measure Activity, Proximity, and Physiological Responses in Freely Moving Dogs in a Natural Environment.

Although several studies have examined the effects of an owner's absence and presence on a dog's physiological responses under experimental conditions over short periods of time (minutes), little is known about the effects of proximity between humans and freely moving dogs under natural conditions over longer periods of time (days). The first aim of our study was to determine whether the combined data generated from the PetPace Collar and Actigraph Link accelerometer provide reliable pulse, respiration, and heart rate variability results during sedentary, light-moderate, and vigorous bouts in 11 freely moving dogs in a foster caretaker environment over 10⁻15 days. The second aim was to determine the effects of proximity (absence and presence of caretaker) and distance (caretaker and dog within 0⁻2 m) on the dogs' physiological responses. Aim 1 results: Pulse and respiration were higher during light-moderate bouts compared to sedentary bouts, and higher at rest while the dogs were standing and sitting vs. lying. Heart rate variability (HRV) was not different between activity levels or position. Aim 2 results: During sedentary bouts, pulse and respiration were higher, and HRV lower, when there was a proximity signal (caretaker present) compared to no proximity signal (caretaker absent). Using multiple regression models, we found that activity, position, distance, and signal presence were predictors of physiological response in individual dogs during sedentary bouts. Our results suggest that combining data collected from Actigraph GT9X and PetPace monitors will provide useful information, both collectively and individually, on dogs' physiological responses during activity, in various positions, and in proximity to their human caretaker.

Resistance training reduces inflammation and fatigue and improves physical function in older breast cancer survivors.

OBJECTIVE: Resistance training (RT) reduces fatigue and improves physical function and quality of life (QOL) in breast cancer survivors (BCS). This may be related to reductions in systemic and tissue-specific inflammation. This pilot study examines the hypothesis that RT induces changes in systemic and tissue-specific inflammation that contribute to improvements in physical and behavioral function in postmenopausal BCS. METHODS: Eleven BCS (60 ±â€Š2 years old, body mass index 30 ±â€Š1 kg/m, mean ±â€ŠSEM) underwent assessments of fatigue (Piper Fatigue Scale), physical function, QOL (SF-36), glucose and lipid metabolism, and systemic, skeletal muscle, and adipose tissue inflammation (n = 9) before and after 16 weeks of moderate-intensity whole-body RT. RESULTS: Muscle strength improved by 25% to 30% (P < 0.01), QOL by 10% (P = 0.04), chair stand time by 15% (P = 0.01), 6-minute walk distance by 4% (P = 0.03), and fatigue decreased by 58% (P < 0.01), fasting insulin by 18% (P = 0.04), and diastolic and systolic blood pressure by approximately 5% (P = 0.04) after RT. BCS with the worst fatigue and QOL demonstrated the greatest improvements (absolute change vs baseline: fatigue: r = -0.95, P < 0.01; QOL: r = -0.82, P < 0.01). RT was associated with an approximately 25% to 35% relative reduction in plasma and adipose tissue protein levels of proinflammatory interleukin (IL)-6sR, serum amyloid A, and tumor necrosis factor-α, and 75% relative increase in muscle pro-proliferative, angiogenic IL-8 protein content by 75% (all P < 0.05). BCS with the highest baseline proinflammatory cytokine levels had the greatest absolute reductions, and the change in muscle IL-8 correlated directly with improvements in leg press strength (r = 0.53, P = 0.04). CONCLUSIONS: These preliminary results suggest that a progressive RT program effectively lowers plasma and tissue-specific inflammation, and that these changes are associated with reductions in fatigue and improved physical and behavioral function in postmenopausal BCS.

Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women.

OBJECTIVE: The effects of 6-month weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity. METHODS: Fat (gluteal and abdominal) lipoprotein lipase (LPL), skeletal muscle LPL, acyl-CoA synthase (ACS), ß-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n = 104) and before and after WL (n = 34) and AEX+WL (n = 37). RESULTS: After controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M value) and inversely related to G120 , fasting insulin, and homeostatic model assessment of insulin resistance. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2 max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios. CONCLUSIONS: Six-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity.

Effects of aerobic and resistive exercise training on glucose disposal and skeletal muscle metabolism in older men.

BACKGROUND: Aging is associated with insulin resistance, primarily as a result of physical inactivity and increased abdominal obesity. We hypothesized that aerobic (AEX) or resistive (RT) exercise training would result in comparable improvements in glucose disposal in older men, but that there would be different metabolic adaptations in skeletal muscle. METHODS: Thirty-nine older (63+/-1 years, mean+/-standard error of the mean), overweight and obese (body mass index=30.3+/-0.4 kg/m2) men were assigned to AEX (treadmill walking and/or jogging, n=19) or RT (upper and lower body, n=20) programs 3 d/wk for 6 months, with 9 completing AEX and 13 completing RT. Testing before and after the exercise programs included body composition, euglycemic-hyperinsulinemic clamps, and vastus lateralis muscle biopsies. RESULTS: Maximal oxygen consumption (VO2max) increased by 16% after AEX (p<.01), while leg and arm muscle strength increased by 45+/-5% and 27+/-5% after RT (p<.0001). Although participants were monitored to maintain their body weight during the exercise program, body weight decreased by 2% after AEX (p<.05), and increased by 2% after RT (p<.05). Whole-body glucose disposal, determined during the last 30 minutes of a 2-hour 480 pmol/m2/min euglycemic-hyperinsulinemic clamp, increased comparably by 20%-25% after AEX (51+/-5 to 61+/-5 microM/kgfat-free mass/min, p<.05) and RT (49+/-3 to 58+/-3 microM/kgfat-free mass/min, p<.05). The increase in vastus lateralis muscle glycogen synthase fractional activity in response to insulin stimulation was significantly higher after AEX compared to after RT (279+/-59% compared to 100+/-28% change, p<.05). Neither AEX nor RT altered muscle glycogen synthase total activity, glycogen content, or levels of phosphotidylinositol 3-kinase. CONCLUSION: These results suggest that AEX and RT result in comparable improvements in glucose metabolism in older men, whereas an increase in insulin activation of glycogen synthase occurred only with AEX. These improvements in insulin sensitivity could reduce the risk of metabolic syndrome and type 2 diabetes and attenuate the development of cardiovascular disease.

Skeletal muscle cellular metabolism in older HIV-infected men.

Skeletal muscle mitochondrial dysfunction may contribute to low aerobic capacity. We previously reported 40% lower aerobic capacity in HIV-infected men compared to noninfected age-matched men. The objective of this study was to compare skeletal muscle mitochondrial enzyme activities in HIV-infected men on antiretroviral therapy (55 ± 1 years of age, n = 10 African American men) with age-matched controls (55 ± 1 years of age, n = 8 Caucasian men), and determine their relationship with aerobic capacity. Activity assays for mitochondrial function including enzymes involved in fatty acid activation and oxidation, and oxidative phosphorylation, were performed in homogenates prepared from vastus lateralis muscle. Hydrogen peroxide (H2O2), cardiolipin, and oxidized cardiolipin were also measured. ß-hydroxy acyl-CoA dehydrogenase (ß-HAD) (38%) and citrate synthase (77%) activities were significantly lower, and H2O2 (1.4-fold) and oxidized cardiolipin (1.8-fold) were significantly higher in HIV-infected men. VO2peak (mL/kg FFM/min) was 33% lower in HIV-infected men and was directly related to ß-HAD and citrate synthase activity and inversely related to H2O2 and oxidized cardiolipin. Older HIV-infected men have reduced oxidative enzyme activity and increased oxidative stress compared to age-matched controls. Further research is crucial to determine whether an increase in aerobic capacity by exercise training will be sufficient to restore mitochondrial function in older HIV-infected individuals.

Skeletal muscle insulin resistance in obesity-associated type 2 diabetes in monkeys is linked to a defect in insulin activation of protein kinase C-zeta/lambda/iota.

Rhesus monkeys frequently develop obesity and insulin resistance followed by type 2 diabetes when allowed free access to chow. This insulin resistance is partly due to defective glucose transport into skeletal muscle. In this study, we examined signaling factors required for insulin-stimulated glucose transport in muscle biopsies taken during euglycemic-hyperinsulinemic clamps in nondiabetic, obese prediabetic, and diabetic monkeys. Insulin increased activities of insulin receptor substrate (IRS)-1-dependent phosphatidylinositol (PI) 3-kinase and its downstream effectors, atypical protein kinase Cs (aPKCs) (zeta/lambda/iota) and protein kinase B (PKB) in muscles of nondiabetic monkeys. Insulin-induced increases in glucose disposal and aPKC activity diminished progressively in prediabetic and diabetic monkeys. Decreases in aPKC activation appeared to be at least partly due to diminished activation of IRS-1-dependent PI 3-kinase, but direct activation of aPKCs by the PI 3-kinase lipid product PI-3,4,5-(PO(4))(3) was also diminished. In conjunction with aPKCs, PKB activation was diminished in prediabetic muscle but, differently from aPKCs, seemed to partially improve in diabetic muscle. Interestingly, calorie restriction and avoidance of obesity largely prevented development of defects in glucose disposal and aPKC activation. Our findings suggest that defective activation of aPKCs contributes importantly to obesity-dependent development of skeletal muscle insulin resistance in prediabetic and type 2 diabetic monkeys.

Increased Skeletal Muscle Capillarization Independently Enhances Insulin Sensitivity in Older Adults After Exercise Training and Detraining.

Intramuscular signaling and glucose transport mechanisms contribute to improvements in insulin sensitivity after aerobic exercise training. This study tested the hypothesis that increases in skeletal muscle capillary density (CD) also contribute to exercise-induced improvements in whole-body insulin sensitivity (insulin-stimulated glucose uptake per unit plasma insulin [M/I]) independent of other mechanisms. The study design included a 6-month aerobic exercise training period followed by a 2-week detraining period to eliminate short-term effects of exercise on intramuscular signaling and glucose transport. Before and after exercise training and detraining, 12 previously sedentary older (65 ± 3 years) men and women underwent research tests, including hyperinsulinemic-euglycemic clamps and vastus lateralis biopsies. Exercise training increased Vo2max (2.2 ± 0.2 vs. 2.5 ± 0.2 L/min), CD (313 ± 13 vs. 349 ± 18 capillaries/mm(2)), and M/I (0.041 ± 0.005 vs. 0.051 ± 0.007 µmol/kg fat-free mass/min) (P < 0.05 for all). Exercise training also increased the insulin activation of glycogen synthase by 60%, GLUT4 expression by 16%, and 5' AMPK-α1 expression by 21%, but these reverted to baseline levels after detraining. Conversely, CD and M/I remained 15% and 18% higher after detraining, respectively (P < 0.05), and the changes in M/I (detraining minus baseline) correlated directly with changes in CD in regression analysis (partial r = 0.70; P = 0.02). These results suggest that an increase in CD is one mechanism contributing to sustained improvements in glucose metabolism after aerobic exercise training.

Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction.

Mortality and morbidity were examined in 117 laboratory-maintained rhesus monkeys studied over approximately 25 years (8 dietary-restricted [DR] and 109 ad libitum-fed [AL] monkeys). During the study, 49 AL monkeys and 3 DR monkeys died. Compared with the DR monkeys, the AL monkeys had a 2.6-fold increased risk of death. Hyperinsulinemia led to a 3.7-fold increased risk of death (p <.05); concordantly, the risk of death decreased by 7%, per unit increase in insulin sensitivity (M). There was significant organ pathology in the AL at death. The age at median survival in the AL was approximately 25 years compared with 32 years in the DR. The oldest monkey was a diabetic female (AL) that lived to be 40 years of age. These results suggest that dietary restriction leads to an increased average age of death in primates, associated with the prevention of hyperinsulinemia and the mitigation of age-related disease.

Elevated plasma cell membrane glycoprotein levels and diminished insulin receptor autophosphorylation in obese, insulin-resistant rhesus monkeys.

In obese humans, insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein (PC-1) and decreased insulin receptor (IR) tyrosine kinase activity in skeletal muscle. PC-1 overexpression inhibits IR tyrosine kinase and possibly other downstream signaling events. The rhesus monkey in captivity is susceptible to obesity with concomitant insulin resistance. In the present study we analyzed obese (n = 10, 29.4% +/- 1.2% body fat) and non-obese (n = 12, 19.4% +/- 1.9% body fat) rhesus monkeys. Glucose clearance during an euglycemic hyperinsulinemic (400 mU/m(2) body surface area/min) clamp was lower for the obese group (non-obese, 9.7 +/- 0.9; obese, 3.2 +/- 0.7 mg/kg fat-free mass [FFM]/min; P <.01). We performed vastus lateralis muscle biopsies prior to and during the clamp. We measured PC-1 levels in these muscle samples to determine whether PC-1 content is elevated in this primate model of insulin resistance. PC-1 levels were determined by assay of phosphodiesterase activity and specific PC-1 enzyme-linked immunosorbent assay (ELISA). In the obese group, both PC-1 content and activity were 2-fold higher than in the non-obese group (P <.05). In order to investigate the ability of insulin to stimulate IR signaling in vivo in these 2 groups of monkeys, we then measured tyrosine autophosphorylation of the IR by specific ELISA. The increase in IR autophosphorylation in the non-obese group was twice that of the obese group (fold increase over basal: non-obese, 3.7 +/- 0.3; obese, 1.9 +/- 0.6; P <.05). We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle.

Aerobic exercise plus weight loss improves insulin sensitivity and increases skeletal muscle glycogen synthase activity in older men.

The purpose of this study was to determine the effects of 6-month aerobic exercise training + weight loss (AEX + WL) on basal and insulin activation of glycogen synthase, basal citrate synthase activity, and Akt and AS160 phosphorylation in older, overweight/obese insulin-resistant men (n = 14; 63 ± 2 years; body mass index, 32 ± kg/m(2)). Muscle samples of the vastus lateralis were collected before and during a 3-hour 80 mU/m(2)/min hyperinsulinemic-euglycemic clamp. AEX + WL increased VO2max by 11% (p < .05) and decreased body weight (-9%, p < .001). AEX + WL increased basal citrate synthase activity by 46% (p < .01) and insulin activation of independent (2.9-fold) and fractional (2.3-fold) activities (both p < .001) of glycogen synthase. AEX + WL had no effect on phosphorylation of Akt or AS160. Glucose utilization (M) improved 25% (p < .01), and the change tended to be related to the increase in insulin activation of glycogen synthase fractional activity (r = .50, p = .08) following AEX + WL. In summary, AEX + WL has a robust effect on insulin activation of skeletal muscle glycogen synthase activity that likely contributes to improved glucose utilization in older insulin-resistant men.