Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial.

BACKGROUND: Authorities advocate that resistance and aerobic exercise are essential for reducing risk factors for chronic disease and disability in older adults. However, the incremental effects of combined resistance and aerobic exercise compared with either modality alone on risk factors for disease and disability is generally unknown. METHODS: Participants were 136 sedentary, abdominally obese older men and women recruited from September 30, 2002, through November 15, 2006, at Queen's University. Participants were randomized to 1 of the following 4 groups for 6 months: resistance exercise, aerobic exercise, resistance and aerobic exercise (combined exercise), or nonexercise control. Primary outcomes were analyzed by an intent-to-treat model and included changes in insulin resistance by hyperinsulinemic-euglycemic clamp and functional limitation using the average change in 4 tests combined (average z score). RESULTS: After controlling for age, sex, and baseline value, insulin resistance improved compared with controls in the aerobic exercise and the combined exercise groups but not in the resistance exercise group. Improvement (mean [SE]) in the combined exercise group was greater than in the resistance exercise group (9.2 [1.3] vs 1.8 [1.3] mg/mL/microIU per kilogram of skeletal muscle per minute x100 [P < .001]) but not in the aerobic exercise group (9.2 [1.3] vs 6.5 [1.3] mg/mL/microIU per kilogram of skeletal muscle per minute x100 [P = .46]). Functional limitation improved significantly in all groups compared with the control group. Improvement in the combined exercise group was greater than in the aerobic exercise group (0.5 [0.1] vs -0.0 [0.1]; standard units, z score [P = .003]) but not in the resistance exercise group. Improvement in the resistance exercise group was not different from the aerobic exercise group. CONCLUSION: The combination of resistance and aerobic exercise was the optimal exercise strategy for simultaneous reduction in insulin resistance and functional limitation in previously sedentary, abdominally obese older adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00520858.

Whole-body skeletal muscle mass is not related to glucose tolerance or insulin sensitivity in overweight and obese men and women.

The relationship between skeletal muscle mass, visceral adipose tissue, insulin sensitivity, and glucose tolerance was examined in 214 overweight or obese, but otherwise healthy, men (n = 98) and women (n = 116) who participated in various exercise and (or) weight-loss intervention studies. Subjects had a 75 g oral glucose tolerance test and (or) insulin sensitivity measures by a 3 h hyperinsulinemic-euglycemic clamp technique. Whole-body skeletal muscle mass and visceral adipose tissue were measured using a multi-slice magnetic resonance imaging protocol. Total body skeletal muscle mass was not associated with any measure of glucose metabolism in men or women (p > 0.10). These observations remained independent of age and total adiposity. Conversely, visceral adipose tissue was a significant predictor of various measures of glucose metabolism in both men and women with or without control for age and (or) total body fat (p < 0.05). Although skeletal muscle is a primary site for glucose uptake and deposition, these findings suggest that unlike visceral adipose tissue, whole-body skeletal muscle mass per se is not associated with either glucose tolerance or insulin sensitivity in overweight and obese men and women.

Association between dietary fat intake, liver fat, and insulin sensitivity in sedentary, abdominally obese, older men.

Whether dietary fat influences the interaction between liver fat, visceral adipose tissue (VAT), and metabolic risk is unclear. Thus, we sought to determine the independent associations between 1 and 10 d dietary fat intake, liver fat, and VAT on insulin sensitivity using a cross-sectional design. Liver fat score (LFS) was assessed by computed tomography and VAT by magnetic resonance imaging in 42 abdominally obese older men. Insulin sensitivity was measured by the hyperinsulinemic-euglycemic clamp technique. Diet composition was determined from self-recorded diet records for 1 and 10 d preceding the assessment of LFS. LFS was positively associated with the 10 d average fat and alcohol intake, but not with any 1 d average dietary variables. VAT (r = -0.36) and LFS (r = -0.32) were both negatively correlated with insulin sensitivity (p < 0.05). When LFS and VAT were entered in the same model, only VAT was an independent predictor of insulin sensitivity (p < 0.05). Control for the average 10 d alcohol consumption and fat intake improved the association between insulin sensitivity and LFS (from r = -0.32, p > 0.10 to r = -0.49, p < 0.05), but not VAT. In fact, after control for the 10 d dietary variables, both LFS and VAT were independent predictors of insulin sensitivity (p < 0.05). This was not true for any of the 1 d dietary intake variables. In conclusion, liver fat is associated with dietary fat intake and alcohol consumption over 10 d, but not 1 d. Furthermore, dietary habits may influence the relationship between liver fat and insulin sensitivity.

An exercise intervention without weight loss decreases circulating interleukin-6 in lean and obese men with and without type 2 diabetes mellitus.

Obesity and type 2 diabetes mellitus (T2DM) have been associated with a state of chronic low-grade inflammation. We examined the effect of exercise without weight loss on circulating inflammatory biomarkers in previously sedentary lean men and obese men with and without T2DM. Middle-aged men (8 lean, 8 obese, and 8 obese with T2DM) performed 60 minutes of aerobic exercise 5 times per week for 12 weeks without a reduction in body weight. Subjects underwent a hyperinsulinemic-euglycemic clamp before and after the 12-week exercise program to assess insulin sensitivity. Circulating interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein concentrations were measured by sandwich enzyme-linked immunosorbent assay before and after the exercise intervention. Body fat was measured using magnetic resonance imaging, and waist circumference was recorded for each subject pre- and postexercise intervention. Waist circumference and plasma IL-6 concentrations were significantly lower (P < .05) after exercise training despite no change in body weight or insulin sensitivity. There were no correlations between insulin sensitivity and IL-6. Fasting plasma PAI-1 concentration was significantly lower in the lean group compared with the obese group both pre- and postexercise intervention (P < .05). There were no changes in C-reactive protein or PAI-1 concentrations after exercise training. A 12-week exercise intervention led to reductions in waist circumference and fasting IL-6 concentrations in previously sedentary lean and obese men with or without T2DM, demonstrating significant changes in clinically relevant diabetes-related parameters despite no change in body weight.

Exercise without weight loss is an effective strategy for obesity reduction in obese individuals with and without Type 2 diabetes.

It is unclear whether chronic exercise without caloric restriction or weight loss is a useful strategy for obesity reduction in obese men with and without Type 2 diabetes (T2D). We examined the effects of exercise without weight loss on total and regional adiposity and skeletal muscle mass and composition in lean men and in obese men with and without T2D. Twenty-four men participated in 13 wk of supervised aerobic exercise, five times per week for 60 min at a moderate intensity (approximately 60% peak oxygen uptake). Total and regional body composition was measured by magnetic resonance imaging. Skeletal muscle composition was determined using computed tomography. Cardiorespiratory fitness was assessed using a graded maximal treadmill test. Body weight did not change within any group in response to exercise (P > 0.1). Significant reductions in total, abdominal subcutaneous, and visceral fat were observed within each group (P < 0.01). The reduction in total and abdominal subcutaneous fat was not different (P > 0.1) between groups; however, the reduction in visceral fat was greater (P < 0.01) in the obese and T2D groups by comparison to the lean group. A significant (P < 0.01) increase in total skeletal muscle, high-density muscle area, and mean muscle attenuation was observed independent of group, and these changes were not different between groups (P > 0.1). Accordingly, whole body fat-to-muscle ratio was increased (P < 0.01) independent of groups. In conclusion, regular exercise without weight loss is associated with a substantial reduction in total and visceral fat and in skeletal muscle lipid in both obesity and T2D.

Caffeine ingestion is associated with reductions in glucose uptake independent of obesity and type 2 diabetes before and after exercise training.

OBJECTIVE: We investigated the effect of caffeine ingestion on insulin sensitivity in sedentary lean men (n = 8) and obese men with (n = 7) and without (n = 8) type 2 diabetes. We also examined whether chronic exercise influences the relationship between caffeine and insulin sensitivity in these individuals. RESEARCH DESIGN AND METHODS: Subjects underwent two hyperinsulinemic-euglycemic clamp procedures, caffeine (5 mg/kg body wt) and placebo, in a double-blind, randomized manner before and after a 3-month aerobic exercise program. Body composition was measured by magnetic resonance imaging. RESULTS: At baseline, caffeine ingestion was associated with a significant reduction (P < 0.05) in insulin sensitivity by a similar magnitude in the lean (33%), obese (33%), and type 2 diabetic (37%) groups in comparison with placebo. After exercise training, caffeine ingestion was still associated with a reduction (P < 0.05) in insulin sensitivity by a similar magnitude in the lean (23%), obese (26%), and type 2 diabetic (36%) groups in comparison with placebo. Exercise was not associated with a significant increase in insulin sensitivity in either the caffeine or placebo trials, independent of group (P > 0.10). CONCLUSIONS: Caffeine consumption is associated with a substantial reduction in insulin-mediated glucose uptake independent of obesity, type 2 diabetes, and chronic exercise.

Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial.

OBJECTIVES: To determine the effects of equivalent diet- or exercise-induced weight loss and exercise without weight loss on subcutaneous fat, visceral fat, and insulin sensitivity in obese women. RESEARCH METHODS AND PROCEDURES: Fifty-four premenopausal women with abdominal obesity [waist circumference 110.1 +/- 5.8 cm (mean +/- SD)] (BMI 31.3 +/- 2.0 kg/m2) were randomly assigned to one of four groups: diet weight loss (n = 15), exercise weight loss (n = 17), exercise without weight loss (n = 12), and a weight-stable control group (n = 10). All groups underwent a 14-week intervention. RESULTS: Body weight decreased by approximately 6.5% within both weight loss groups and was unchanged in the exercise without weight loss and control groups. In comparison with controls, cardiorespiratory fitness improved within the exercise groups only (p < 0.01). Reduction in total, abdominal, and abdominal subcutaneous fat within the exercise weight loss group was greater (p < 0.001) than within all other groups. The reduction in total and abdominal fat within the diet weight loss and exercise without weight loss groups was greater than within controls (p < 0.001) but not different from each other (p > 0.05). Visceral fat decreased within all treatment groups (p < 0.008), and these changes were not different from each other. In comparison with the control group, insulin sensitivity improved within the exercise weight loss group alone (p < 0.001). DISCUSSION: Daily exercise without caloric restriction was associated with substantial reductions in total fat, abdominal fat, visceral fat, and insulin resistance in women. Exercise without weight loss was also associated with a substantial reduction in total and abdominal obesity.

N-telopeptide of type II collagen interacts with annexin V on human chondrocytes.

Type II collagen binds to chondrocytes through integrins and annexin V. While the potential integrin binding sites have been identified, it is unclear which domains bind to annexin V. Proteolytic fragments of collagen are known to modulate cell signaling pathways resulting in degradation of articular cartilage; it is unknown whether annexin V binds to the fragments. The focus of our study was to determine the binding of type II collagen and its fragments to chondrocytes using flow cytometry and fluorescence microscopy. The N-telopeptide binds to annexin V, whereas the C-telopeptide and triple helical peptides do not. These data suggest that the binding of the N-telopeptide of type II collagen is through annexin V, whereas binding of the C-telopeptide and the triple helical peptide to the surface of chondrocytes are potentially facilitated through other collagen receptors, such as integrins or cell-associated matrix proteins.

In vivo expression of a GST-fusion protein mediates the rapid generation of affinity matured monoclonal antibodies using DNA-based immunizations.

Previously we demonstrated the rapid generation of affinity matured monoclonal antibody (MAb) producing cell lines following gene gun delivery of DNA using a mammalian expression vector (pAlpha/hFc), which enables the expression of human Fc-chimera proteins in vivo. Here we compare the pAlpha/hFc vector to modified vectors that replace human IgG(1) with either a Glutathione-S-Transferase (GST) fusion protein or a mouse IgG(2c) (mFc) fusion protein. We report that in vivo expression of a GST-chimera results in the rapid generation of affinity matured MAbs, comparable with antibodies raised using the pAlpha/hFc vector, that were reactive with annexin V. The mFc vector failed to induce early antigen-specific B-cell responses suitable for MAb development.

Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior.

EphA2 is a transmembrane receptor tyrosine kinase that is up-regulated on many aggressive carcinoma cells. Despite its overexpression, the EphA2 on malignant cells fails to bind its ligand, ephrinA1, which is anchored to the membrane of adjacent cells. Unlike other receptor kinases, EphA2 demonstrates kinase activity that is independent of ligand binding. However, ligand binding causes EphA2 to negatively regulate tumor cell growth and migration. Herein, we translate knowledge of EphA2 into strategies that selectively target malignant cells. Using a novel approach to preserve extracellular epitopes and optimize antibody diversity, we generated monoclonal antibodies that identify epitopes on the extracellular domain of EphA2. EphA2 antibodies were selected for their abilities to inhibit behaviors that are unique to metastatic cells while minimizing damage to nontransformed cells. A subset of EphA2 monoclonal antibodies were found to inhibit the soft agar colonization by MDA-MB-231 breast tumor cells but did not affect monolayer growth by nontransformed MCF-10A breast epithelial cells. These EphA2 antibodies also prevented tumor cells from forming tubular networks on reconstituted basement membranes, which is a sensitive indicator of metastatic character. Biochemical analyses showed that biologically active antibodies induced EphA2 phosphorylation and subsequent degradation. Antisense-based targeting of EphA2 similarly inhibited soft agar colonization, suggesting that the antibodies repress malignant behavior by down-regulating EphA2. These results suggest an opportunity for antibody-based targeting of the many cancers that overexpress EphA2. Our studies also emphasize how tumor-specific cellular behaviors can be exploited to identify and screen potential therapeutic targets.