Resistance Training Increases White Matter Density in Frail Elderly Women.

We aimed to investigate the effects of maternal obesity on brain structure and metabolism in frail women, and their reversibility in response to exercise. We recruited 37 frail elderly women (20 offspring of lean/normal-weight mothers (OLM) and 17 offspring of obese/overweight mothers (OOM)) and nine non-frail controls to undergo magnetic resonance and diffusion tensor imaging (DTI), positron emission tomography with Fluorine-18-fluorodeoxyglucose (PET), and cognitive function tests (CERAD). Frail women were studied before and after a 4-month resistance training, and controls were studied once. White matter (WM) density (voxel-based morphometry) was higher in OLM than in OOM subjects. Exercise increased WM density in both OLM and OOM in the cerebellum in superior parietal regions in OLM and in cuneal and precuneal regions in OOM. OLM gained more WM density than OOM in response to intervention. No significant results were found from the Freesurfer analysis, nor from PET or DTI images. Exercise has an impact on brain morphology and cognition in elderly frail women.

Preoperative Posterior Tilt Increases the Risk of Later Conversion to Arthroplasty After Osteosynthesis for Femoral Neck Fracture.

BACKGROUND: Femoral neck fractures (FNFs) are one of the most common injuries in the elderly. Treatment is either internal fixation or primary arthroplasty. The main aim of this study is to assess the risk factors associated with fixation failure leading to further arthroplasty in FNFs treated with cannulated screws. METHODS: Data on internal fixations of FNFs performed at Turku University Hospital between January 1, 2012 and December 31, 2017 were collected retrospectively from the patient database. Radiographical measurements were performed for preoperative displacement and posterior tilt, postoperative displacement, reduction quality, and implant shaft angle. RESULTS: Altogether 301 cases were included in the study. The overall reoperation rate was 25% and conversion to arthroplasty was performed in 16% of cases. In the multiple variant analysis, adjusted for age and gender, nondisplaced fractures with a 0°-20° preoperative posterior tilt had a significantly lower risk of later conversion to arthroplasty than did nondisplaced fractures with a ≤0° or ≥20° posterior tilt (odds ratio [OR] 4.0, 95% confidence interval [Cl] 1.8-8.6, P = .0005) and displaced fractures (OR 7.2, 95% CI 3.0-17.4, P < .0001). No statistically significant association was found between preoperatively nondisplaced fractures with a <0° or ≥20° posterior tilt and displaced fractures (OR 0.6, 95% Cl 0.2-1.3, P = .2). CONCLUSION: Displaced fractures and fractures with a preoperative posterior tilt of <0° or ≥20° have a considerably increased risk of reoperation and conversion to arthroplasty. Primary arthroplasty should be considered as treatment for displaced FNFs and fractures with >20° or <0° posterior tilt, especially in fragile patients, to avoid further operations.

Predicting Skeletal Muscle and Whole-Body Insulin Sensitivity Using NMR-Metabolomic Profiling.

PURPOSE: Abnormal lipoprotein and amino acid profiles are associated with insulin resistance and may help to identify this condition. The aim of this study was to create models estimating skeletal muscle and whole-body insulin sensitivity using fasting metabolite profiles and common clinical and laboratory measures. MATERIAL AND METHODS: The cross-sectional study population included 259 subjects with normal or impaired fasting glucose or type 2 diabetes in whom skeletal muscle and whole-body insulin sensitivity (M-value) were measured during euglycemic hyperinsulinemic clamp. Muscle glucose uptake (GU) was measured directly using [18F]FDG-PET. Serum metabolites were measured using nuclear magnetic resonance (NMR) spectroscopy. We used linear regression to build the models for the muscle GU (Muscle-insulin sensitivity index [ISI]) and M-value (whole-body [WB]-ISI). The models were created and tested using randomly selected training (n = 173) and test groups (n = 86). The models were compared to common fasting indices of insulin sensitivity, homeostatic model assessment-insulin resistance (HOMA-IR) and the revised quantitative insulin sensitivity check index (QUICKI). RESULTS: WB-ISI had higher correlation with actual M-value than HOMA-IR or revised QUICKI (ρ = 0.83 vs -0.67 and 0.66; P < 0.05 for both comparisons), whereas the correlation of Muscle-ISI with the actual skeletal muscle GU was not significantly stronger than HOMA-IR's or revised QUICKI's (ρ = 0.67 vs -0.58 and 0.59; both nonsignificant) in the test dataset. CONCLUSION: Muscle-ISI and WB-ISI based on NMR-metabolomics and common laboratory measurements from fasting serum samples and basic anthropometrics are promising rapid and inexpensive tools for determining insulin sensitivity in at-risk individuals.

Dynamic changes in p66Shc mRNA expression in peripheral blood mononuclear cells following resistance training intervention in old frail women born to obese mothers: a pilot study.

The p66Shc gerontogene may affect healthspan by promoting fat accumulation. We assessed changes of p66Shc-mRNA in peripheral tissues in relation to maternal obesity and the moderating effects of resistance-training (RT) exercise in elderly frail women. Thirty-seven women participated in a 4-month RT program. Twenty were offspring of lean/normal weight mothers and 17 were offspring of overweight/obese mothers (OOM). P66Shc was assessed in peripheral blood mononuclear cells (PBMC) and in subcutaneous adipose tissue (SAT) before and after RT. Overall, OOM showed elevated p66Shc mRNA levels in the PBMC. Independently from maternal obesity, following RT there was a decrease in p66Shc expression in PBMC but not in SAT, particularly in subjects with a high body mass index. Results suggest that maternal obesity has long-term effects on the expression of genes involved in mitochondrial function and fat deposition and that RT modifies p66Shc expression in PBMC with greater effects in obese subjects.ClinicalTrials.gov ID: NCT01931540.

Changes in bone metabolism after bariatric surgery by gastric bypass or sleeve gastrectomy.

Bariatric surgery results in rapid weight loss and beneficial metabolic effects, but may have negative effects on the skeleton. The objective of this prospective study was to evaluate changes in bone metabolism in response to bariatric surgery with two surgical techniques. 46 morbidly obese subjects (mean 44.9years, BMI 42.1) with (n=19) or without (n=27) type 2 diabetes (T2DM) at baseline underwent either Roux-en-Y gastric bypass (RYGB, n=21) or sleeve gastrectomy (SG, n=25). Bone turnover markers (CTX, PINP, TRAcP5b, TotalOC and ucOC) were measured before and six months after surgery. Volumetric bone mineral density (vBMD) at lumbar spine and vertebral bone marrow (VBM) fat were measured in 21 subjects (7 RYGB and 14 SG) with three-dimensional quantitative computer tomography and 1H MR spectroscopy, respectively. 25 non-obese subjects were recruited as controls (mean 45.8years, BMI 23.0) and assessed at a single cross-sectional visit. Obese subjects had significantly lower bone turnover at baseline when compared to non-obese controls. Bone metabolic markers markedly increased post-operatively (p<0.0001 for all). The activation of bone remodeling was significantly higher after RYGB than after SG and was particularly observed in patients, whose type 2 diabetes was in remission after weight loss. There was no change in volumetric BMD or marrow fat at lumbar spine six months after surgery in our sample. In conclusion, severe obesity decreases bone remodeling, which is activated after bariatric surgery. The increase in bone turnover after surgery is affected by the choice of surgical technique and by the post-surgery remission of T2DM.

Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers.

Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring's mother's obesity status. 37 frail elderly females (mean age 71.9 ± 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI ≤ 26.3 kg/m2) and 17 were offspring of obese/overweight mothers (OOM, maternal BMI ≥ 28.1 kg/m2) were studied before and after a four-month individualized resistance training intervention. Nine age- and sex-matched non-frail controls (maternal BMI ≤ 26.3 kg/m2) were studied at baseline. Femoral bone marrow (FBM) and vertebral bone marrow (VBM) insulin sensitivity were measured using [18F]fluoro-2-deoxy-D-glucose positron emission tomography with computer tomography under hyperinsulinemic euglycemic clamp. We found that bone marrow insulin sensitivity was not related to maternal obesity status but FBM insulin sensitivity correlated with whole body insulin sensitivity (R = 0.487, p = 0.001). A four-month resistance training intervention increased FBM insulin sensitivity by 47% (p = 0.006) only in OOM, while VBM insulin sensitivity remained unchanged regardless of the maternal obesity status. In conclusion, FBM and VBM glucose metabolism reacts differently to a four-month resistance training intervention in elderly women according to their maternal obesity status. TRIAL REGISTRATION: ClinicalTrials.gov NCT01931540.

Bone mineral density is increased after a 16-week resistance training intervention in elderly women with decreased muscle strength.

OBJECTIVE: Non-pharmacological interventions are important in reducing risk for osteoporotic fractures. We investigated the effects of a 16-week individualized resistance training intervention on bone mineral density (BMD), bone turnover markers and 10-year relative risk (RR) for osteoporotic fracture. DESIGN: Interventional study with a follow-up. METHODS: In total, 37 elderly women (mean age 71.9 ± 3.1 years) with decreased muscle strength participated in the resistance training intervention three times per week with 60 min per session for 16 weeks under the supervision of a licensed physiotherapist. Total hip BMD with quantitative CT, bone markers (sclerostin, osteocalcin, CTX, PINP, IGF-1, 25(OH)-D) and 10-year RR for osteoporotic fracture were measured at baseline, post-intervention and at 1-year follow-up after the end of the intervention. Eleven age- and sex-matched controls did not participate in the intervention but were studied at baseline and at 1-year follow-up. RESULTS: Resistance training seemed to increase total hip BMD by 6% (P = 0.005). Sclerostin (P < 0.001) and total osteocalcin (P = 0.04) increased while other bone markers remained unchanged. A 10-year RR for major osteoporotic and hip fracture remained unchanged. At follow-up total hip BMD (P < 0.001) decreased back to the baseline level with a simultaneous decrease in serum sclerostin (P = 0.045), CTX (P < 0.001) and an increase in 25(OH)-D (P < 0.001), 10-year RR for major osteoporotic (P = 0.002) and hip fracture (P = 0.01). CONCLUSIONS: Our findings suggest an important role of continuous supervised resistance training for the prevention of osteoporotic fractures in elderly women with decreased muscle strength.

Resistance training enhances insulin suppression of endogenous glucose production in elderly women.

An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty-five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo resistance training program. Endogenous glucose production (EGP) and hepatic and visceral fat glucose uptake were measured during euglycemic hyperinsulinemia with [(18)F]fluorodeoxyglucose and positron emission tomography. Ectopic fat was measured using magnetic resonance spectroscopy and imaging. We found that the training intervention reduced EGP during insulin stimulation [from 5.4 (interquartile range 3.0, 7.0) to 3.9 (-0.4, 6.1) µmol·kg body wt(-1)·min(-1), P = 0.042] in the whole study group. Importantly, the reduction was higher among those whose EGP was more insulin resistant at baseline (higher than the median) [-5.6 (7.1) vs. 0.1 (5.4) µmol·kg body wt(-1)·min(-1), P = 0.015]. Furthermore, the decrease in EGP was associated with telomere elongation (r = -0.620, P = 0.001). The resistance training intervention did not change either hepatic or visceral fat glucose uptake or the amounts of ectopic fat. Maternal obesity did not influence the studied measures. In conclusion, resistance training improves suppression of EGP in elderly women. The finding of improved insulin sensitivity of EGP with associated telomere lengthening implies that elderly women can reduce their risk for type 2 diabetes and cardiovascular disease with resistance training.

Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers.

AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women. METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI ≤26.3 kg/m2) and 17 were frail offspring of overweight/obese mothers (OOM,BMI ≥28.1 kg/m2), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using 18F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic­euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR. RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p=0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p=0.004 and p=0.013, respectively), and increased muscle mass in both groups (p <0 .01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (ρ ≥ 0.53; p ≤ 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (ρ ≥ −0.61; p ≤ 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers. Trial registration: ClinicalTrials.gov NCT01931540.

Bone marrow fat unsaturation in young adults is not affected by present or childhood obesity, but increases with age: A pilot study.

OBJECTIVES: Obesity increases bone marrow fat (BMF) content. The association between early obesity and bone marrow fatty acid composition is unknown. We measured BMF unsaturation index (UI) in normal-weight and overweight young adults with a known weight status in early childhood and tested the relationship between BMF UI and exercise history, glycemic state, and other clinical characteristics. METHODS: The study included 18 normal-weight (BMI <25 kg/m(2); 2 males, 16 females) and 17 overweight (BMI ≥25 kg/m(2); 9 males, 8 females) young adults aged 15-27 years. BMF UI was assessed with magnetic resonance proton spectroscopy optimized to reduce water interference. Exercise information was obtained with a pedometer accompanied with the history of recent physical activity. Blood samples (insulin, glucose, HbA1c) and body characteristics (BMI, waist-to-hip ratio, body fat composition) were assessed. RESULTS: BMF UI was not affected by obesity at the time of study or before age 7 years. BMF UI increased with age in normal-weight and overweight subjects (R=0.408, p=0.015) but did not associate with gender, physical activity or body fat composition; a suggestive association was observed with glucose (R=-0.289, p=0.10). CONCLUSIONS: The association of BMF UI with age in early adulthood may represent normal maturation of bone marrow. There was a trend toward an association with blood glucose, warranting further studies.

The effects of acute hyperinsulinemia on bone metabolism.

Insulin signaling in bone-forming osteoblasts stimulates bone formation and promotes the release of osteocalcin (OC) in mice. Only a few studies have assessed the direct effect of insulin on bone metabolism in humans. Here, we studied markers of bone metabolism in response to acute hyperinsulinemia in men and women. Thirty-three subjects from three separate cohorts (n=8, n=12 and n=13) participated in a euglycaemic hyperinsulinemic clamp study. Blood samples were collected before and at the end of infusions to determine the markers of bone formation (PINP, total OC, uncarboxylated form of OC (ucOC)) and resorption (CTX, TRAcP5b). During 4 h insulin infusion (40 mU/m(2) per min, low insulin), CTX level decreased by 11% (P<0.05). High insulin infusion rate (72 mU/m(2) per min) for 4 h resulted in more pronounced decrease (-32%, P<0.01) whereas shorter insulin exposure (40 mU/m(2) per min for 2 h) had no effect (P=0.61). Markers of osteoblast activity remained unchanged during 4 h insulin, but the ratio of uncarboxylated-to-total OC decreased in response to insulin (P<0.05 and P<0.01 for low and high insulin for 4 h respectively). During 2 h low insulin infusion, both total OC and ucOC decreased significantly (P<0.01 for both). In conclusion, insulin decreases bone resorption and circulating levels of total OC and ucOC. Insulin has direct effects on bone metabolism in humans and changes in the circulating levels of bone markers can be seen within a few hours after administration of insulin.

Clever-1/stabilin-1 controls cancer growth and metastasis.

PURPOSE: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown. EXPERIMENTAL DESIGN: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma. RESULTS: Clever-1-deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity. CONCLUSION: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer.

Vertebral bone marrow glucose uptake is inversely associated with bone marrow fat in diabetic and healthy pigs: [(18)F]FDG-PET and MRI study.

OBJECTIVES: Diabetes induces osteoporosis and during osteoporosis, vertebral bone marrow (VBM) adipose tissue amount increases. The association between this adiposity and bone marrow metabolism is unclear. Here, we compared VBM glucose metabolism and fat content in healthy and diabetic pigs, in vivo, using positron emission tomography (PET), in-phase and out-of-phase magnetic resonance imaging and magnetic resonance proton spectroscopy ((1)H MR spectroscopy). MATERIALS/METHODS: Eleven pigs (n=11) were used. The intervention group had five diabetic and the control group had six healthy pigs. To measure metabolism, PET-imaging with [(18)F]fluoro-deoxy-glucose ([(18)F]FDG) intravenous tracer was used. 1.5-T MRI with (1)H spectroscopy, in-phase and out-of-phase imaging and chemical TAG analysis of the VBM were performed. RESULTS: We found a significant inverse correlation between VBM glucose uptake (GU) and VBM fat content (R=-0.800, p<0.01) and TAG concentration assay (R=-0.846, p<0.05). There was a trend, although non-significant, of a linear correlation between VBM (1)H MR spectroscopy and TAG concentration (R=0.661) and (1)H MR spectroscopy and in-phase and out-of-phase MR imaging (R=0.635). CONCLUSIONS: VBM glucose metabolism coupled with VBM fat content may impact diabetic induced osteoporosis.