Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.Studies in human and rodent models have revealed deleterious effects of excess lipid availability on peripheral insulin sensitivity (1,2). Intracellular increases in fatty acid metabolites, such as diacylglycerol (DAG) and ceramide, may play critical roles in mediating lipid-induced insulin resistance by inducing serine phosphorylation of insulin-receptor substrate 1 (IRS-1) (3–6) and consequently inhibiting downstream signaling to GLUT4 translocation. However, recent reports challenge such causality. These studies revealed unaltered signal transduction at the level of IRS-1, IRS-1–associated phosphatidylinositol-3-kinase (PI3K) activity, Akt, and TBC1 domain family member 4 (TBC1D4) phosphorylation (phospho-Akt-substrate [PAS] an unspecific antibody recognizing phosphorylated Akt substrate motifs), after 2–7 h of lipid infusion (7–11). When DAG and/or ceramide levels were reported, no changes in skeletal muscle DAG or ceramide levels were found after lipid infusion (7,11).We recently showed that lactate release in human skeletal muscle is augmented along with reduced respiratory exchange ratio (RER) values during lipid infusion (11). This could indicate suppressed activity of the pyruvate dehydrogenase (PDH) complex, which in turn could lead to a reduction in glucose uptake according to the Randle cycle (12). Here, we wished to investigate whether this increase in leg lactate release and reduced RER values were accompanied by altered regulation of PDH, measured by site-specific phosphorylation.Exercise increases peripheral insulin sensitivity (13–15). After an acute bout of exercise, the ability for insulin to stimulate glucose uptake in skeletal muscle is increased several hours into recovery (14,16). This effect can be ascribed to adaptations in the exercised muscle rather than changes in systemic factors (13,17,18) and is observed in both healthy and insulin-resistant states (e.g., obesity) (19) and type 2 diabetes (20). A recent study has shown that a single bout of exercise can prevent subsequent lipid-induced impairments in whole-body glucose tolerance assessed by an intravenous glucose tolerance test (IVGTT) (2). It was hypothesized that repartitioning fatty acids toward intramuscular triacylglycerol (IMTG) synthesis and storage rather than DAG or ceramide might be a primary mediator of the beneficial effects of exercise on lipid-induced impairments in glucose tolerance (2). Enhanced insulin sensitivity after a bout of exercise is associated with increased GLUT4 recruitment to the plasma membrane (21) and not with altered protein synthesis (e.g., GLUT4 protein) (22), but has not been associated with altered signal transduction through the insulin receptor, IRS-1, PI3K, or Akt (13,22,23). Recently, the hypothesis was put forward (24) that the guanosine triphosphatase (GTPase) activating proteins TBC1 domain family member 1 (TBC1D1) and 4 (TBC1D4) might serve as points of convergence for insulin dependent and independent signaling pathways to GLUT4 translocation. In agreement with this hypothesis, PAS phosphorylation of TBC1D4 is elevated along with insulin-stimulated glucose uptake for up to 27 h after exercise in skeletal muscle of rats (25), and we recently showed that phosphorylation of TBC1D4 on specific residues was elevated 4 h after a single bout of exercise in human skeletal muscle (26).TBC1D4/D1 are multikinase substrates proposed to be involved in contraction- and insulin-stimulated glucose uptake in mice (27,28), and exercise and insulin both substantially increase TBC1D4/D1 phosphorylation in human skeletal muscle (29,30). TBC1D4/D1 contain several phosphorylation sites distinctly phosphorylated by various kinases, including Akt and 5′AMP-activated protein kinase (AMPK) (28,31–33). Phosphorylation of TBC1D4/D1 and subsequent 14-3-3 binding is proposed to lead to inactivation of the GTPase-activating proteins, decreasing their inhibitory function on the GLUT4 translocation process and thus, potentially, increasing the GLUT4 capacity of the surface membrane.In the current study we tested the hypothesis that prior exercise prevents subsequent lipid-induced insulin resistance in human skeletal muscle through regulation of the signaling molecules TBC1D4/TBC1D1.     

Important risk factors and attributable risk of vertebral fractures in the population-based Tromsø study

ABSTRACT: BACKGROUND: Vertebral fractures, the most common type of osteoporotic fractures, are associated with increased risk of subsequent fracture, morbidity, and mortality. The aim of this study was to examine the contribution of important risk factors to the variability in vertebral fracture risk. METHODS: Vertebral fracture was ascertained by VFA method (DXA, GE Lunar Prodigy) in 2887 men and women, aged between 38 and 87 years, in the population-based Tromso Study 2007/2008. Bone mineral density (BMD; g/cm2) at the hip was measured by DXA. Lifestyle information was collected by questionnaires. Multivariable logistic regression model, with anthropometric and lifestyle factors included, was used to assess the association between each or combined risk factors and vertebral fracture risk. Population attributable risk was estimated for combined risk factors in the final multivariable model. RESULTS: In both sexes, age (odds ratio [OR] per 5 year increase: 1.32; 95% CI 1.19-1.45 in women and 1.21; 95% CI 1.10-1.33 in men) and BMD (OR per SD decrease: 1.60; 95% CI 1.34-1.90 in women and1.40; 95% CI 1.18-1.67 in men) were independent risk factors for vertebral fracture. At BMD levels higher than 0.85 g/cm2, men had a greater risk of fracture than women (OR 1.52; 95% CI 1.14-2.04), after adjusting for age. In women and men, respectively, approximately 46% and 33% of vertebral fracture risk was attributable to advancing age (more than 70 years) and low BMD (less than 0.85 g/cm2), with the latter having a greater effect than the former. CONCLUSIONS: These data confirm that age and BMD are major risk factors for vertebral fracture risk. However, in both sexes the two factors accounted for less than half of fracture risk. The identification of individuals with vertebral fracture is still a challenge.     

Cortisol levels and psychosocial factors in preadolescent children

Regarding the relationship between psychosocial factors and health, one model of explanation states that psychosocial stress constitutes a principal mediator connecting psychosocial factors to health outcome, affecting the body through psychobiological mechanisms. This relationship has scarcely been studied in children. In the present study the relation between diurnal cortisol secretion and psychosocial factors [socio‐economic status (SES), immigrant status and impact of psychiatric symptoms] was investigated in a normal population of 6–12 year old children (n = 273). Salivary cortisol levels were measured in the early morning, late morning and in the evening during three consecutive days. Parents answered demographic questionnaires and teachers answered psychiatric questionnaires concerning the children. Children exposed to one or more of the factors of psychosocial load (n = 117) had significantly higher morning (p < 0.001) and evening (p = 0.029) cortisol levels as well as total daily cortisol secretion [measured by the area under the curve (AUC), p = 0.003] compared to the group of children with none of the factors (n = 156). Different psychosocial stressors seemed to influence different parts of the diurnal cortisol curve. In conclusion, this study indicates that even children exposed to a moderate degree of psychosocial load differ in their cortisol levels compared to non‐exposed children. Copyright © 2006 John Wiley & Sons, Ltd.     

Increased risk of PTLD in lung transplant recipients with cystic fibrosis

Background

Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry.

Age‐ and Sex‐Dependent Changes of Intra‐articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis

The objective of this cross‐sectional study was to define normal sex‐ and age‐dependent values of intra‐articular bone mass and microstructures in the metacarpal heads of healthy individuals by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra‐articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR‐pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra‐articular (intracapsular) bone margins. These data were applied in measuring intra‐articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra‐articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra‐articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm³) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra‐articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex‐ and age‐adjusted controls. Standard sex‐ and age‐dependent values for physiological intra‐articular bone were defined. Postmenopausal state and RA led to significant decrease of intra‐articular bone. © 2016 American Society for Bone and Mineral Research.     

Congenital biliary atresia: liver injury begins at birth

Background

The timing of onset of liver injury in biliary atresia (BA) is not known, although in approximately 10% of cases, biliary pathologic condition associated with the biliary atresia splenic malformation syndrome must begin well before birth.

Methods

The study involved retrospective case-note review for infants with definite BA who underwent laparotomy within first week of life.

Results

Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial.

Conclusion

This suggests that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory and ultimately fibrotic response.     

Comparison of kyphoplasty and vertebroplasty in the treatment of fresh vertebral compression fractures

Introduction  As life expectancy in the population rises, osteoporotic fractures are seen most frequently in the proximal femur and the vertebral column. In balloon kyphoplasty and vertebroplasty, we have two minimally invasive treatment procedures available. Although they have both been controversially discussed in studies, they have seldom been directly compared. Materials and methods  Between 2002 and 2004, patients with fresh thoracic or lumbar single-segment vertebral compression fractures not involving neurological deficits were treated by balloon kyphoplasty (n = 30) or vertebroplasty(n = 30) using PMMA cement, and the results of the two interventions were compared in a prospective, nonrandomised cohort study. Surgery was indicated when patients had painful, dislocated fractures of type A1 and type A3 according to Magerl’s classification. The outcome of treatment was assessed with special reference to the angle of kyphosis, back pain (VAS), health-related quality of life (SF-36) and complications. Results  At the time of the follow-up examination, significant improvement in the angle of kyphosis was found to have been achieved both by kyphoplasty and by vertebroplasty (P < 0.001 and P = 0.002, respectively). Comparison showed that correction of the angle was significantly (P < 0.001) better in the kyphoplasty group. Both surgical procedures led to significant (P < 0.001) attenuation of the patients’ pain; no difference was observed between the groups in the degree of pain relief achieved. There was no demonstrable correlation in either group between the preoperative pain experienced by the patients and the degree of dislocation of their fractures. In both study groups, the quality of life was in keeping with that of a reference group matched for age and sex. Cement leakage was observed in 7% of patients after kyphoplasty and in 33% of patients after vertebroplasty (P = 0.021). Adjacent-level fractures were checked for, but occurred in only one patient in the vertebroplasty group. Conclusion  The two surgical procedures were both followed by significant pain relief, and the quality of life was similar regardless of the procedure used. Balloon kyphoplasty led to an ongoing reduction of freshly fractured vertebrae and was followed by a lower rate of cement leakage.     

Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1

The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.