Charles J. Tanner

Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women

OBJECTIVE To determine whether circulating metabolic intermediates are related to insulin resistance and β-cell dysfunction in individuals at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry–based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates. RESULTS The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (SI) (R2 = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R2 = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R2 = 0.39). Sex differences were found for metabolic predictors of SI and DI. CONCLUSIONS In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.

Effects of Exercise Training Intensity on Pancreatic β-Cell Function

OBJECTIVE Insulin resistance and β-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on β-cell function are less well studied. RESEARCH DESIGN AND METHODS Sedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (Si), acute insulin response to glucose (AIRg), and the disposition index (DI = Si × AIRg) were modeled from an intravenous glucose tolerance test. RESULTS Compared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved Si and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in Si but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose. CONCLUSIONS To the extent that the DI accurately reflects β-cell function, we observed that both moderate- and vigorous-intensity exercise training improved β-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk.

Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT

While the benefits of exercise are clear, many unresolved issues surround the optimal exercise prescription. Many organizations recommend aerobic training (AT) and resistance training (RT), yet few studies have compared their effects alone or in combination. The purpose of this study, part of Studies Targeting Risk Reduction Interventions Through Defined Exercise-Aerobic Training and/or Resistance Training (STRRIDE/AT/RT), was to compare the effects of AT, RT, and the full combination (AT/RT) on central ectopic fat, liver enzymes, and fasting insulin resistance [homeostatic model assessment (HOMA)]. In a randomized trial, 249 subjects [18-70 yr old, overweight, sedentary, with moderate dyslipidemia (LDL cholesterol 130-190 mg/dl or HDL cholesterol ≤ 40 mg/dl for men or ≤ 45 mg/dl for women)] performed an initial 4-mo run-in period. Of these, 196 finished the run-in and were randomized into one of the following 8-mo exercise-training groups: 1) RT, which comprised 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set, 2) AT, which was equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O(2) uptake, and 3) full AT + full RT (AT/RT), with 155 subjects completing the intervention. The primary outcome variables were as follows: visceral and liver fat via CT, plasma liver enzymes, and HOMA. AT led to significant reductions in liver fat, visceral fat, alanine aminotransferase, HOMA, and total and subcutaneous abdominal fat (all P < 0.05). RT resulted in a decrease in subcutaneous abdominal fat (P < 0.05) but did not significantly improve the other variables. AT was more effective than RT at improving visceral fat, liver-to-spleen ratio, and total abdominal fat (all P < 0.05) and trended toward a greater reduction in liver fat score (P < 0.10). The effects of AT/RT were statistically indistinguishable from the effects of AT. These data show that, for overweight and obese individuals who want to reduce measures of visceral fat and fatty liver infiltration and improve HOMA and alanine aminotransferase, a moderate amount of aerobic exercise is the most time-efficient and effective exercise mode.

Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle.

The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, approximately 75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15-17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased (P < 0. 05) significantly (means +/- SE, 7.8 +/- 0.5 vs. 9.8 +/- 0.8 mg. kg(-1). min(-1)), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly (P < 0.05) with exercise (3.1 +/- 0.8-fold) compared with the sedentary condition (1.3 +/- 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, ≈75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15-17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased ( P < 0.05) significantly (means ± SE, 7.8 ± 0.5 vs. 9.8 ± 0.8 mg ⋅ kg-1 ⋅ min-1), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly ( P < 0.05) with exercise (3.1 ± 0.8-fold) compared with the sedentary condition (1.3 ± 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.

Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.

The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P < or = 0.05) at 16-24 h with all of the exercise prescriptions. S(I) decreased to sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P < or = 0.05) in the prescriptions utilizing 200 min/wk (low volume/moderate intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

Mechanism for Improved Insulin Sensitivity after Gastric Bypass Surgery

CONTEXT Surgical treatments of obesity have been shown to induce rapid and prolonged improvements in insulin sensitivity. OBJECTIVE The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. DESIGN We performed a cross-sectional, nonrandomized, controlled study. SETTING This study was conducted jointly between the Departments of Exercise Science and Physiology at East Carolina University in Greenville, North Carolina. SUBJECTS Subjects were recruited into four groups: 1) lean [body mass index (BMI) < 25 kg/m(2); n = 93]; 2) weight-matched (BMI = 25 to 35 kg/m(2); n = 310); 3) morbidly obese (BMI > 35 kg/m(2); n = 43); and 4) postsurgery patients (BMI approximately 30 kg/m(2); n = 40). Postsurgery patients were weight stable 1 yr after surgery. MAIN OUTCOME MEASURES Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. RESULTS Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and weight-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and weight-matched groups. IRS1-pSer(312) in the postsurgery group was lower than morbidly obese and weight-matched groups. Inhibitor kappaBalpha was higher in the postsurgery vs. the morbidly obese and weight-matched controls, indicating reduced inhibitor of kappaB kinase beta activity. CONCLUSIONS Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the weight-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addition to, weight loss. Improved insulin sensitivity is related to reduced inhibitor of kappaB kinase beta activity and enhanced insulin signaling in muscle.

Muscle insulin receptor concentrations in obese patients post bariatric surgery: relationship to hyperinsulinemia

OBJECTIVE: Obesity results in insulin resistance. Bariatric surgery for obese individuals induces weight loss, improves insulin sensitivity, and lowers insulin levels. We investigated the mechanisms of this improvement.DESIGN: Insulin receptor (IR) content, IR signaling, and adiponectin levels were measured in nine morbidly obese subjects before and after bariatric surgery.SUBJECTS: Seven female and two male, average age 44±2y, BMI >40 kg/m2 and/or at least 100 lbs over ideal body weight, undergoing elective bariatric surgery.MEASUREMENTS: Before surgery BMI, fasting plasma glucose, adiponectin, and insulin levels were measured. A fasting muscle biopsy was obtained from the vastus lateralis for IR concentration and autophosphorylation activity measurements. These procedures were repeated 1 y after surgery.RESULTS: At 1 y after surgery, the subjects had lost an average of 48.3±5.6 kg (P<0.001), insulin sensitivity had significantly increased as determined by the minimal model (SI 0.72±0.18 vs 3.86±1.43, P<0.05), and IR content had increased two-fold in muscle (2.1±0.4 vs 4.3±0.7 ng/mg protein, P<0.01). The increase in IR content was related to fasting insulin levels. In the subjects with the lowest IR function, there was also an increase in IR function. Plasma adiponectin increased by 40% following weight loss (7.4±1.6 pre vs 10.3±1.3 mg/ml post, P<0.05). There was no significant change in muscle content of the IR inhibitor, PC-1.CONCLUSION: Increased IR content, most likely regulated by insulin levels, may be one contributor to the increased insulin sensitivity that occurs when morbidly obese patients undergo bariatric surgery.

Effect of intense training on plasma leptin in male and female swimmers

PURPOSE The purpose of this study was to determine whether fasting plasma leptin concentration was altered with an increase in training volume in competitive male and female athletes. METHODS Intercollegiate male (N = 9) and female (N = 12) swimmers were examined during the preseason and at two times during the mid-season (mid-season 1 and mid-season 2) when training volume was relatively high (33,000 m.wk(-1)). Body composition (hydrostatic weighing), energy intake and expenditure, and fasting plasma leptin concentration were measured. RESULTS In the women, there was a significant (P < 0.05) decline in fat mass (2 kg) with the increase in training volume, which was not accompanied by a reduction in fasting leptin (12.8 +/- 1.5 vs 11.0 +/- 1.2 vs 11.0 +/- 1.5 ng.mL(-1) for preseason, mid-season 1, and mid-season 2, respectively). In the men, there were no significant changes in body composition, body mass, or fasting leptin (4.4 +/- 0.8 vs 4.3 +/- 0.8 vs 4.6 +/- 0.8 ng.mL(-1), respectively). CONCLUSION These findings suggest 1) plasma leptin is not sensitive to an increase in training volume and 2) leptin may not be indicative of changes in fat mass with an increase in training volume in female athletes. These data suggest that leptin may not be useful in monitoring relative training stress in athletes.

Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery

Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery–induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity.

The Effects of Hydrotherapy on Anxiety, Pain, Neuroendocrine Responses, and Contraction Dynamics During Labor

Background: Hydrotherapy (immersion or bathing) is used worldwide to promote relaxation and decrease parturient anxiety and pain in labor, but the psychophysiological effects of this intervention remain obscure. Design: A pretest—posttest design with repeated measures was used to examine the effects of hydrotherapy on maternal anxiety and pain, neuroendocrine responses, plasma volume shift (PVS), and uterine contractions (CXs) during labor. Correlations among variables were examined at three time points (preimmersion and twice during hydrotherapy). Methods: Eleven term women (mean age 24.5 years) in spontaneous labor were immersed to the xiphoid in 37 °C water for 1 hr. Blood samples and measures of anxiety and pain were obtained under dry baseline conditions and repeated at 15 and 45 min of hydrotherapy. Uterine contractions were monitored telemetrically. Results: Hydrotherapy was associated with decreases in anxiety, vasopressin (V), and oxytocin (O) levels at 15 and 45 min (all ps < .05). There were no significant differences between preimmersion and immersion pain or cortisol (C) levels. Pain decreased more for women with high baseline pain than for women with low baseline levels at 15 and 45 min. Cortisol levels decreased twice as much at 15 min of hydrotherapy for women with high baseline pain as for those with low baseline pain. β-endorphin (βE) levels increased at 15 min but did not differ between baseline and 45 min. During immersion, CX frequency decreased. A positive PVS at 15 min was correlated with contraction duration. Conclusions: Hydrotherapy during labor affects neuroendocrine responses that modify psychophysiological processes.