Bone Marrow Metabolism Is Impaired in Insulin Resistance and Improves After Exercise Training

Abstract Context Exercise training improves bone mineral density, but little is known about the effects of training on bone marrow (BM) metabolism. BM insulin sensitivity has been suggested to play an important role in bone health and whole-body insulin sensitivity. Objective To study the effects of exercise training on BM metabolism. Design Randomized controlled trial. Setting Clinical research center. Participants Sedentary healthy (n = 28, 40–55 years, all males) and insulin resistant (IR) subjects (n = 26, 43–55 years, males/females 16/10) Intervention Two weeks of sprint interval training or moderate-intensity continuous training Main outcome measures We measured femoral, lumbar, and thoracic BM insulin-stimulated glucose uptake (GU) and fasting free fatty acid uptake (FFAU) using positron-emission tomography and bone turnover markers from plasma. Results At baseline, GU was highest in lumbar, followed by thoracic, and lowest in femoral BM (all Ps < 0.0001). FFAU was higher in lumbar and thoracic than femoral BM (both Ps < 0.0001). BM FFAU and femoral BM GU were higher in healthy compared to IR men and in females compared to males (all Ps < 0.05). Training increased femoral BM GU similarly in all groups and decreased lumbar BM FFAU in males (all Ps < 0.05). Osteocalcin and PINP were lower in IR than healthy men and correlated positively with femoral BM GU and glycemic status (all Ps < 0.05). Conclusions BM metabolism differs regarding anatomical location. Short-term training improves BM GU and FFAU in healthy and IR subjects. Bone turnover rate is decreased in insulin resistance and associates positively with BM metabolism and glycemic control. Clinical Trial Registration Number NCT01344928.

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Short-term interval training alters brain glucose metabolism in subjects with insulin resistance

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17734998 ◽

2017 ◽

Vol 38 (10) ◽

pp. 1828-1838 ◽

Cited By ~ 7

Author(s):

Sanna M Honkala ◽

Jarkko Johansson ◽

Kumail K Motiani ◽

Jari-Joonas Eskelinen ◽

Kirsi A Virtanen ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Interval Training ◽

Insulin Level ◽

Whole Body ◽

Moderate Intensity ◽

Acid Uptake ◽

Short Term ◽

Continuous Training ◽

Sedentary Subjects

Brain insulin-stimulated glucose uptake (GU) is increased in obese and insulin resistant subjects but normalizes after weight loss along with improved whole-body insulin sensitivity. Our aim was to study whether short-term exercise training (moderate intensity continuous training (MICT) or sprint interval training (SIT)) alters substrates for brain energy metabolism in insulin resistance. Sedentary subjects ( n = 21, BMI 23.7–34.3 kg/m2, age 43–55 y) with insulin resistance were randomized into MICT ( n = 11, intensity≥60% of VO2peak) or SIT ( n = 10, all-out) groups for a two-week training intervention. Brain GU during insulin stimulation and fasting brain free fatty acid uptake (FAU) was measured using PET. At baseline, brain GU was positively associated with the fasting insulin level and negatively with the whole-body insulin sensitivity. The whole-body insulin sensitivity improved with both training modes (20%, p = 0.007), while only SIT led to an increase in aerobic capacity (5%, p = 0.03). SIT also reduced insulin-stimulated brain GU both in global cortical grey matter uptake (12%, p = 0.03) and in specific regions ( p < 0.05, all areas except the occipital cortex), whereas no changes were observed after MICT. Brain FAU remained unchanged after the training in both groups. These findings show that short-term SIT effectively decreases insulin-stimulated brain GU in sedentary subjects with insulin resistance.

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Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00303.2014 ◽

2014 ◽

Vol 307 (7) ◽

pp. E571-E579 ◽

Cited By ~ 9

Author(s):

Andrew M. Cheng ◽

Norma Rizzo-DeLeon ◽

Carole L. Wilson ◽

Woo Je Lee ◽

Sanshiro Tateya ◽

...

Keyword(s):

Insulin Resistance ◽

Bone Marrow ◽

Insulin Sensitivity ◽

Vascular Tissue ◽

Vascular Inflammation ◽

Physiological Role ◽

Whole Body ◽

Aortic Tissue ◽

Protective Effects ◽

Downstream Mediator

Among the pleotropic effects of endothelial nitric oxide (NO) is protection against vascular inflammation during high-fat diet (HFD) feeding. The current work investigated the role of the enzyme vasodilatory-stimulated phosphoprotein (VASP) as a downstream mediator of the anti-inflammatory effect of NO signaling in vascular tissue. Relative to mice fed a low-fat diet (LFD), levels of VASP Ser239 phosphorylation, a marker of VASP activation, were dramatically reduced in aortic tissue of mice with obesity induced by consuming a HFD. As reported previously, the effect of the HFD was associated with increased aortic inflammation, as measured by increased NF-κB-dependent gene expression, and reduced vascular insulin sensitivity (including insulin-stimulated phosphorylation of eNOS and Akt). These effects of the HFD were recapitulated by VASP knockout, implying a physiological role for VASP to constrain inflammatory signaling and thereby maintain vascular insulin sensitivity. Conversely, overexpression of VASP in endothelial cells blocked inflammation and insulin resistance induced by palmitate. The finding that transplantation of bone marrow from VASP-deficient donors into normal recipients does not recapitulate the vascular effects of whole body VASP deficiency suggests that the protective effects of this enzyme are not mediated in immune or other bone marrow-derived cells. These studies implicate VASP as a downstream mediator of the NO/cGMP pathway that is both necessary and sufficient to protect against vascular inflammation and insulin resistance. As such, this work identifies VASP as a potential therapeutic target in the treatment of obesity-related vascular dysfunction.

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Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in Men Classified as Overweight or Obese

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz104 ◽

2019 ◽

Vol 105 (3) ◽

pp. 660-676 ◽

Cited By ~ 2

Author(s):

Robert M Edinburgh ◽

Helen E Bradley ◽

Nurul-Fadhilah Abdullah ◽

Scott L Robinson ◽

Oliver J Chrzanowski-Smith ◽

...

Keyword(s):

Insulin Sensitivity ◽

Exercise Training ◽

Whole Body ◽

Moderate Intensity ◽

Type I ◽

Training Study ◽

Exercise Timing ◽

Lipid Utilization ◽

Acute Study ◽

Intramuscular Lipid

Abstract Context Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. Objective To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism. Design (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study). Setting General community. Participants Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study). Interventions Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion. Results Acute Study—exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: –3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (–1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study—postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs –21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05). Conclusions Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.

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Improved insulin sensitivity after a single bout of exercise is curvilinearly related to exercise energy expenditure

Clinical Science ◽

10.1042/cs20070134 ◽

2007 ◽

Vol 114 (1) ◽

pp. 59-64 ◽

Cited By ~ 48

Author(s):

Faidon Magkos ◽

Yannis Tsekouras ◽

Stavros A. Kavouras ◽

Bettina Mittendorfer ◽

Labros S. Sidossis

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Energy Expenditure ◽

Peak Oxygen Consumption ◽

Whole Body ◽

Moderate Intensity ◽

Model Assessment ◽

Single Bout ◽

Exercise Energy Expenditure ◽

Exercise Induced

A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12–48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in insulin sensitivity is not known. We hypothesized that the exercise-induced increase in whole-body insulin sensitivity, assessed with HOMAIR (homoeostasis model assessment of insulin resistance), is directly related to the energy expended during exercise. We studied 30 recreationally active non-obese men (age, 27±5 years; body mass index, 24±2 kg/m2) in the post-absorptive state on two separate occasions: once after exercising at 60% of V̇O22peak (peak oxygen consumption) for 30–120 min on the preceding afternoon (expending a total of 1.28–5.76 MJ) and once after an equivalent period of rest. Blood samples were obtained the following morning. Exercise-induced changes in HOMAIR were curvilinearly related to exercise energy expenditure (r=−0.666, P=0.001) with a threshold of approx. 3.77 MJ (900 kcal) for improvements in HOMAIR to be manifested. In particular, HOMAIR was reduced by 32±24% (P=0.003) in subjects who expended more than 3.77 MJ during exercise, but did not change for those who expended fewer than 3.77 MJ (−2±21%; P=0.301). Furthermore, the magnitude of change in HOMAIR after exercise was directly associated with baseline (i.e. resting) HOMAIR (r=−0.508, P=0.004); this relationship persisted in multivariate analysis. We conclude that improved whole-body insulin resistance after a single bout of exercise is curvilinearly related to exercise energy expenditure, and requires unfeasible amounts of exercise for most sedentary individuals.

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Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake

Journal of Applied Physiology ◽

10.1152/japplphysiol.00431.2016 ◽

2017 ◽

Vol 122 (5) ◽

pp. 1188-1197 ◽

Cited By ~ 4

Author(s):

Kumail K. Motiani ◽

Anna M. Savolainen ◽

Jari-Joonas Eskelinen ◽

Jussi Toivanen ◽

Tamiko Ishizu ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Exercise Training ◽

Glucose Uptake ◽

Interval Training ◽

Fatty Acid Uptake ◽

Whole Body ◽

Moderate Intensity ◽

Acid Uptake ◽

Continuous Training

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy, middle-aged, sedentary men were randomized for 2 wk of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [18F]FDG and [18F]FTHA. In addition, effects of HIIT and MICT on intestinal GLUT2 and CD36 protein expression were studied in rats. Training improved aerobic capacity ( P = 0.001) and whole body insulin sensitivity ( P = 0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon (HIIT = 0%; MICT = 37%) ( P = 0.02 for time × training) and tended to increase in the jejunum (HIIT = −4%; MICT = 13%) ( P = 0.08 for time × training). Fasting free fatty acid uptake decreased in the duodenum in both groups (HIIT = −6%; MICT = −48%) ( P = 0.001 time) and tended to decrease in the colon in the MICT group (HIIT = 0%; MICT = −38%) ( P = 0.08 for time × training). In rats, both training groups had higher GLUT2 and CD36 expression compared with control animals. This study shows that already 2 wk of MICT enhances insulin-stimulated glucose uptake, while both training modes reduce fasting free fatty acid uptake in the intestine in healthy, middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism. NEW & NOTEWORTHY This is the first study where the effects of exercise training on the intestinal substrate uptake have been investigated using the most advanced techniques available. We also show the importance of exercise intensity in inducing these changes.

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Bone mineral density and explanatory factors in children and adults with juvenile dermatomyositis at long term follow-up; a cross sectional study

Pediatric Rheumatology ◽

10.1186/s12969-021-00543-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Henriette Schermacher Marstein ◽

Kristin Godang ◽

Berit Flatø ◽

Ivar Sjaastad ◽

Jens Bollerslev ◽

...

Keyword(s):

Bone Turnover ◽

Inflammatory Markers ◽

Juvenile Dermatomyositis ◽

Inflammatory Myopathy ◽

Disease Onset ◽

Whole Body ◽

Mineral Density ◽

Z Scores

Abstract Background Juvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy in children and adolescents. Both the disease and its treatment with glucocorticoids may negatively impact bone formation. In this study we compare BMD in patients (children/adolescence and adults) with long-standing JDM with matched controls; and in patients, explore how general/disease characteristics and bone turnover markers are associated with BMD. Methods JDM patients (n = 59) were examined median 16.8y (range 6.6–27.0y) after disease onset and compared with 59 age/sex-matched controls. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD of the whole body and lumbar spine (spine) in all participants, and of ultra-distal radius, forearm and total hip in participants ≥20y only. Markers of bone turnover were analysed, and associations with outcomes explored. Results Reduced BMD Z-scores (<−1SD) were found in 19 and 29% of patients and 7 and 9% of controls in whole body and spine, respectively (p-values < 0.05). BMD and BMD Z-scores for whole body and spine were lower in all patients and for < 20y compared with their respective controls. In participants ≥20y, only BMD and BMD Z-score of forearm were lower in the patients versus controls. In patients, BMD Z-scores for whole body and/or spine were found to correlate negatively with prednisolone use at follow-up (yes/no) (age < 20y), inflammatory markers (age ≥ 20y) and levels of interferon gamma-induced protein 10 (IP-10) (both age groups). In all patients, prednisolone use at follow-up (yes/no) and age ≥ 20y were independent correlates of lower BMD Z-scores for whole body and spine, respectively. Conclusion In long-term JDM, children have more impairment of BMD than adults in spine and whole-body. Associations with BMD were found for both prednisolone and inflammatory markers, and a novel association was discovered with the biomarker of JDM activity, IP-10.

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Effect of training on insulin binding to rat skeletal muscle sarcolemmal vesicles

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.250.5.e570 ◽

1986 ◽

Vol 250 (5) ◽

pp. E570-E575

Author(s):

G. K. Grimditch ◽

R. J. Barnard ◽

S. A. Kaplan ◽

E. Sternlicht

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Insulin Binding ◽

Whole Body ◽

Rat Skeletal Muscle ◽

Binding Studies ◽

Muscle Enzyme ◽

Intravenous Glucose ◽

High Affinity

We examined the hypothesis that the exercise training-induced increase in skeletal muscle insulin sensitivity is mediated by adaptations in insulin binding to sarcolemmal (SL) insulin receptors. Insulin binding studies were performed on rat skeletal muscle SL isolated from control and trained rats. No significant differences were noted between groups in body weight or fat. An intravenous glucose tolerance test showed an increase in whole-body insulin sensitivity with training, and specific D-glucose transport studies on isolated SL vesicles indicated that this was due in part to adaptations in skeletal muscle. Enzyme marker analyses revealed no differences in yield, purity, or contamination of SL membranes between the two groups. Scatchard analyses indicated no significant differences in the number of insulin binding sites per milligram SL protein on the high-affinity (15.0 +/- 4.1 vs. 18.1 +/- 6.4 X 10(9)) or on the low-affinity portions (925 +/- 80 vs. 884 +/- 106 X 10(9)) of the curves. The association constants of the high-affinity (0.764 +/- 0.154 vs. 0.685 +/- 0.264 X 10(9) M-1) and of the low affinity sites (0.0096 +/- 0.0012 vs. 0.0102 +/- 0.0012 X 10(9) M-1) also were similar. These results do not support the hypothesis that the increased sensitivity to insulin after exercise training is due to changes in SL insulin receptor binding.

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Carbohydrate Restriction with or without Exercise Training Improves Blood Pressure and Insulin Sensitivity in Overweight Women

Healthcare ◽

10.3390/healthcare9060637 ◽

2021 ◽

Vol 9 (6) ◽

pp. 637

Author(s):

Shengyan Sun ◽

Zhaowei Kong ◽

Qingde Shi ◽

Haifeng Zhang ◽

On-Kei Lei ◽

...

Keyword(s):

Blood Pressure ◽

Insulin Sensitivity ◽

Exercise Training ◽

Fasting Glucose ◽

Training Group ◽

Moderate Intensity ◽

Cardiometabolic Health ◽

Carbohydrate Restriction ◽

Obese Women ◽

Low Carbohydrate Diet

Objective: The purpose of this study was to evaluate the effects of a 4-week low-carbohydrate diet (LC) with or without exercise training on cardiometabolic health-related profiles in overweight/obese women. Methods: Fifty overweight/obese Chinese women (age: 22.2 ± 3.3 years, body mass index (BMI): 25.1 ± 3.1 kg·m−2) were randomized to either a LC control group (LC-CON, n = 16), a LC and high-intensity interval training group (LC-HIIT, n = 17), or a LC and moderate-intensity continuous training group (LC-MICT, n = 17). All groups consumed LC for 4 weeks, while the LC-HIIT and LC-MICT groups followed an additional five sessions of HIIT (10 × 6 s cycling sprints and 9 s rest intervals, 2.5 min in total) or MICT (cycling continuously at 50–60% of peak oxygen uptake (VO2peak) for 30 min) weekly. Blood pressure, fasting glucose, insulin sensitivity, and several metabolic or appetite regulating hormones were measured before and after intervention. Results: Significant reductions in body weight (− ~2.5 kg, p < 0.001, η2 = 0.772) and BMI (− ~1 unit, p < 0.001, η2 = 0.782) were found in all groups. Systolic blood pressure was reduced by 5–6 mmHg (p < 0.001, η2 = 0.370); fasting insulin, leptin, and ghrelin levels were also significantly decreased (p < 0.05), while insulin sensitivity was improved. However, there were no significant changes in fasting glucose, glucagon, and gastric inhibitory peptide levels. Furthermore, no group differences were found among the three groups, suggesting that extra training (i.e., LC-HIIT and LC-MICT) failed to trigger additional effects on these cardiometabolic profiles. Conclusions: The short-term carbohydrate restriction diet caused significant weight loss and improved blood pressure and insulin sensitivity in the overweight/obese women, although the combination with exercise training had no additional benefits on the examined cardiometabolic profiles. Moreover, the long-term safety and effectiveness of LC needs further study.

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Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00369.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. H1423-H1438 ◽

Cited By ~ 19

Author(s):

Petra Haberzettl ◽

James P. McCracken ◽

Aruni Bhatnagar ◽

Daniel J. Conklin

Keyword(s):

Insulin Resistance ◽

Bone Marrow ◽

Particulate Matter ◽

Insulin Sensitivity ◽

Ambient Air ◽

Air Pollutant ◽

Ambient Air Pollution ◽

Endothelial Progenitor ◽

Insulin Sensitizer ◽

Circulating Levels

Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1+/Sca-1+ cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/particulate-matter-induced-vascular-insulin-resistance/ .

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Hepatokine ERAP1 impairs skeletal muscle insulin sensitivity via ADRB2/PKA pathway

10.21203/rs.3.rs-37586/v1 ◽

2020 ◽

Author(s):

Feifan Guo ◽

Yuguo Niu ◽

Haizhou Jiang ◽

Hanrui Yin ◽

Fenfen Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Neutralizing Antibodies ◽

Leptin Receptor ◽

Whole Body ◽

C2c12 Myotubes ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Sensitivity ◽

Pka Pathway

Abstract The current study aimed to investigate the role of endoplasmic reticulum aminopeptidase 1 (ERAP1), a novel hepatokine, in whole-body glucose metabolism. Here, we found that hepatic ERAP1 levels were increased in insulin-resistant leptin-receptor-mutated (db/db) and high-fat diet (HFD)-fed mice. Consistently, hepatic ERAP1 overexpression attenuated skeletal muscle (SM) insulin sensitivity, whereas knockdown ameliorated SM insulin resistance. Furthermore, serum and hepatic ERAP1 levels were positively correlated, and recombinant mouse ERAP1 or conditioned medium with high ERAP1 content (CM-ERAP1) attenuated insulin signaling in C2C12 myotubes, and CM-ERAP1 or HFD-induced insulin resistance was blocked by ERAP1 neutralizing antibodies. Mechanistically, ERAP1 reduced ADRB2 expression and interrupted ADRB2-dependent signaling in C2C12 myotubes. Finally, ERAP1 inhibition via global knockout or the inhibitor thimerosal improved insulin sensitivity. Together, ERAP1 is a hepatokine that impairs SM and whole-body insulin sensitivity, and its inhibition might provide a therapeutic strategy for diabetes, particularly for those with SM insulin resistance.

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