Fat and fat-free mass of healthy Swedish children show tracking during early life, but there are differences.

AIM: Obesity may start early in life. We investigated relationships between size and body composition variables in infancy and at 4 years of age using valid estimates of body composition. The results were compared to those obtained when body mass index (BMI) was used to estimate body fatness at 4 years. METHODS: Using air displacement plethysmography, size, fat mass and fat-free mass were studied, between 2007 and 2015, in 253 full-term healthy Swedish children at 1 week, 12 weeks and 4 years of age. RESULTS: Positive associations between variables in infancy and at 4 years were found at 1 and 12 weeks for weight, height, BMI, fat-free mass and fat-free mass index (p ≤ 0.002) and for fat mass, per cent body fat and fat mass index (p ≤ 0.04) at 12 weeks. Fat mass gained during infancy correlated positively (p ≤ 0.031) with per cent fat mass, fat mass index and BMI, all at 4 years. In girls, gains in fat-free mass during infancy correlated with BMI (p = 0.0005) at 4 years. CONCLUSION: The results provide information regarding body composition trajectories during early life and demonstrate limitations of BMI as a proxy for body fatness when relating early weight gain to variables, relevant for later obesity risk.

Correction to: Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

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Correlates of ideal cardiovascular health in European adolescents: The HELENA study.

BACKGROUND AND AIMS: The ideal cardiovascular health (iCVH) construct consists of 4 health behaviors (smoking status, body mass index, physical activity and diet) and 3 health factors (total cholesterol, blood pressure and fasting glucose). A greater number of iCVH components in adolescence are related to better cardiovascular health, but little is known about the correlates of iCVH in adolescents. Thus, the aim of the study was to examine correlates of iCVH in European adolescents. METHODS AND RESULTS: The study comprised 637 European adolescents with complete iCVH data. Participants were part of the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, a cross-sectional, multicenter study conducted in 9 different European countries. Correlates investigated were sex and age, family affluence scale, maternal education, geographic location, sleep time, television viewing, duration of pregnancy, birth weight and breastfeeding. Younger adolescents, those whose mothers had medium/high education or those who watched television less than 2 h per day had a greater number of iCVH components compared to those who were older, had a mother with low education or watched television 2 h or more daily (P ≤ 0.01). CONCLUSION: Since in our study older adolescents had worse iCVH than younger adolescents, early promotion of cardiovascular health may be important. Future studies may also investigate the usefulness of limiting television viewing to promote iCVH. Finally, since adolescents of mothers with low education had poorer iCVH, it may be of special interest to tailor public health promotion to adolescents from families with low socioeconomic status.

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone.

Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site-specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro-, and macro-levels. INTRODUCTION: Osteoporosis is a degenerative disease resulting in reduced bone mineral density, structure, and strength. The overall aim was to explore the hypothesis that changes in loading environment result in site-specific adaptations at molecular/micro- and macro-scale in mouse bone. METHODS: Right tibiae of adult mice were subjected to well-defined cyclic axial loading for 2 weeks; left tibiae were used as physiologically loaded controls. The bones were analyzed with µCT (structure), reference point indentation (material properties), Raman spectroscopy (chemical), and small-angle X-ray scattering (mineral crystallization and structure). RESULTS: The cranial and caudal sites of tibiae are structurally and biochemically different within control bones. In response to loading, cranial and caudal sites increase in cortical thickness with reduced mineralization (-14 and -3%, p < 0.01, respectively) and crystallinity (-1.4 and -0.3%, p < 0.05, respectively). Along the length of the loaded bones, collagen content becomes more heterogeneous on the caudal site and the mineral/collagen increases distally at both sites. CONCLUSION: Bone structure and composition are heterogeneous, finely tuned, adaptive, and site-specifically responsive at the micro-scale to maintain optimal function. Manipulation of this heterogeneity may affect bone strength, relative to specific applied loads.

Moderate physical exercise results in increased cell activity in articular cartilage of the knee joint in rats.

BACKGROUND: Moderate exercise regimens have shown minor positive effects on matrix turnover in articular cartilage (AC), while effects at cellular level, e.g. proliferation, are scarcely described. AIM: The aim of this study was to investigate the effects of moderate exercise on cell proliferation and recruitment of cells possibly active in regeneration in different regions of cartilage in the rat knee joint. METHODS: Eighteen rats were orally given 5-bromo-2-deoxyuridine (BrdU) for 14 days for in vivo DNA labeling. Nine rats underwent treadmill training for 50 min/day, 5 days/week (exercise group), and 9 rats served as controls (no exercise). Animals were sacrificed after 14, 56 and 105 days, and knee joints were harvested. BrdU+ cells were visualized immunohistochemically (IHC) and counted in AC, posterior stem cell niche (PN), potential migration route (PMR; area between PN and the AC border), potential migration area (PMA; region between PN and AC including PN) and epiphyseal cartilage plate (EP) of the tibia and femur. RESULTS: Compared to controls, in the exercise group BrdU+ cells/mm(2) were increased on days 14 (p = 0.022) and 105 (p = 0.045) in AC of the tibia and on day 105 (p = 0.014) in AC of the femur. BrdU+ cell numbers were increased in the PMR region of the tibia on days 14 (p = 0.023) and 105 (p = 0.0018) and in the PMR region of the femur on day 105 (p = 0.0099) as well as in the PMA region of the tibia (p = 0.0008) and femur (p = 0.0080) on day 105. No significant differences in BrdU+ cells/mm(2) were seen in PN or EP between the groups at any time point. Regarding collagen 2A1 expression and proteoglycan accumulation, no significant differences between groups were detected. CONCLUSIONS: The results indicate increased cell activity in AC in response to physical exercise and may help to understand the complexity of AC regeneration in the normal mammal knee joint.

Nitric oxide increases cyclic GMP levels, AMP-activated protein kinase (AMPK)alpha1-specific activity and glucose transport in human skeletal muscle.

AIMS/HYPOTHESIS: We investigated the direct effect of a nitric oxide donor (spermine NONOate) on glucose transport in isolated human skeletal muscle and L6 skeletal muscle cells. We hypothesised that pharmacological treatment of human skeletal muscle with N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) would increase intracellular cyclic GMP (cGMP) levels and promote glucose transport. METHODS: Skeletal muscle strips were prepared from vastus lateralis muscle biopsies obtained from seven healthy men. Muscle strips were incubated in the absence or presence of 5 mmol/l spermine NONOate or 120 nmol/l insulin. The L6 muscle cells were treated with spermine NONOate (20 micromol/l) and incubated in the absence or presence of insulin (120 nmol/l). The direct effect of spermine NONOate and insulin on glucose transport, cGMP levels and signal transduction was determined. RESULTS: In human skeletal muscle, spermine NONOate increased glucose transport 2.4-fold (p < 0.05), concomitant with increased cGMP levels (80-fold, p < 0.001). Phosphorylation of components of the canonical insulin signalling cascade was unaltered by spermine NONOate exposure, implicating an insulin-independent signalling mechanism. Consistent with this, spermine NONOate increased AMP-activated protein kinase (AMPK)-alpha1-associated activity (1.7-fold, p < 0.05). In L6 muscle cells, spermine NONOate increased glucose uptake (p < 0.01) and glycogen synthesis (p < 0.001), an effect that was in addition to that of insulin. Spermine NONOate also elicited a concomitant increase in AMPK and acetyl-CoA carboxylase phosphorylation. In the presence of the guanylate cyclase inhibitor LY-83583 (10 micromol/l), spermine NONOate had no effect on glycogen synthesis and AMPK-alpha1 phosphorylation. CONCLUSIONS/INTERPRETATION: Pharmacological treatment of skeletal muscle with spermine NONOate increases glucose transport via insulin-independent signalling pathways involving increased intracellular cGMP levels and AMPK-alpha1-associated activity.

Human disk cells from degenerated disks and mesenchymal stem cells in co-culture result in increased matrix production.

Transplantation of mesenchymal stem cells (MSCs) has been suggested for disk degeneration, which is characterized by dysfunctional cells and low proteoglycan production. The aim of this study was to examine the effects of a 3D co-culture system using human disk cells (DCs) and MSCs on collagen and proteoglycan production. DCs and MSCs were expanded in monolayer and grown in pellet cultures for 7, 14 and 28 days and analyzed for hydroxyproline (HP), reflecting total collagen production, and glycosaminoglycan (GAG) accumulation. DCs and MSCs co-cultured at different ratios (25/75, 50/50 and 75%/25%) were examined for GAG accumulation. Collagen type II expression was analyzed immunohistochemically. In a second series, conditioned media were added to pellet cultures of degenerated DCs or MSCs. DCs from degenerated disks and MSCs demonstrated lower total collagen production than non-degenerated DC pellets. GAG production was comparable in DCs and MSCs, except in the youngest donor, with MSC producing about 10 times higher GAG/DNA. Co-cultures resulted in approximately 1.5 times higher GAG/DNA production than DCs. Increased collagen type II expression was seen in co-cultures compared to DC or MSC culture alone, except in the case with highly active MSCs. No positive effect of conditioned media was seen. In conclusion, co-culture of MSCs with degenerated DCs increased proteoglycan and collagen-type ceII production, indicating that in future clinical therapy MSCs can be transplanted without pre-differentiation in vitro. The lack of effect of conditioned media suggests that the positive effect of co-culture on matrix production is not due to soluble factors.

Determination of mechanical and rheological properties of a cell-loaded peptide gel during ECM production.

The development of an injectable biomaterial that supports cell survival and maintains or promotes nucleus pulposus (NP) phenotype could aid delivery of cells to degenerated NPs causing low back pain. Mesenchymal cells were loaded and grown in a synthetic peptide gel, PuraMatrix®. Cells were observed within the gels over 0-28 days, and accumulation of glycosaminoglycans were detected by histological staining. The mechanical properties of the cell-loaded constructs, and the change of the mechanical properties were studied using stress relaxation of the gels under compression and confinement. The PuraMatrix® gel was shown to relax fast on compression indicating that the fluid could easily flow out of the gel, and thus indicating the presence of large pores/voids. The presence of these pores/voids was further supported by high mobility of dextran molecules, determined using fluorescence recovery after photo bleaching. The stress required to deform the cell-loaded constructs to a specific strain increases at day 21, at which point the presence of glycosaminoglycans within the cell-loaded constructs was also observed. The results provide evidence of changes in mechanical properties of the PuraMatrix® matrix upon excretion of the extracellular matrix by the cells.

Longitudinal assessment of body composition in healthy Swedish children from 1 week until 4 years of age.

BACKGROUND/OBJECTIVES: Knowledge of longitudinal body composition development is required to identify the mechanisms behind childhood overweight and obesity and to prevent these conditions. However, accurate data on this development in early childhood are lacking. Our aim was to describe the longitudinal body composition development in healthy young Swedish children. SUBJECTS/METHODS: Body size and composition were assessed in 26 children using air-displacement plethysmography (1 and 12 weeks and 4.4 years of age) and isotope dilution (1.5 and 3 years of age) and compared with available reference data. RESULTS: Body fat (%) for boys (n=16) was 12.8±3.9 (1 week), 25.6±4.8 (12 weeks), 28.2±3.8 (1.5 years), 27.3±5.1 (3 years) and 26.1±3.5 (4.4 years). For girls (n=10) these values were 15.3±2.9, 25.7±3.9, 27.9±3.3, 26.3±7.2 and 26.0±5.3, respectively. These values were above the Fomon reference values at 1.5 years of age and later and higher than the Butte reference (P<0.05) for boys at 1.5 years of age. At all ages the coefficients of variation were higher for body fat (%) (12-30%) than for BMI (4-11%). CONCLUSIONS: At 4 years of age our children had more body fat than indicated by reference data. This high level may have already been established at 1.5 years of age but our small sample and the lack of appropriate reference data limit the possibility of drawing firm conclusions. Our results demonstrate the limitations of BMI when investigating overweight and obesity in early life and highlight the need for appropriate reference body composition data in infants and young children.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.125.

The direction of human mesenchymal stem cells into the chondrogenic lineage is influenced by the features of hydrogel carriers.

Low back pain is a major public health issue in the Western world, one main cause is believed to be intervertebral disc (IVD) degeneration. To halt/diminish IVD degeneration, cell therapy using different biomaterials e.g. hydrogels as cell carriers has been suggested. In this study, two different hydrogels were examined (in vitro) as potential cell carriers for human mesenchymal stem cells (hMSCs) intended for IVD transplantation. The aim was to investigate cell-survival and chondrogenic differentiation of hMSCs when cultured in hydrogels Puramatrix® or Hydromatrix® and potential effects of stimulation with growth hormone (GH). hMSCs/hydrogel cultures were investigated for cell-viability, attachment, gene expression of chondrogenic markers SOX9, COL2A1, ACAN and accumulation of extracellular matrix (ECM). In both hydrogel types, hMSCs were viable for 28days, expressed integrin ß1 which indicates adhesion of hMSCs. Differentiation was observed into chondrocyte-like cells, in a higher extent in hMSCs/Hydromatrix® cultures when compared to hMSCs/Puramatrix® hydrogel cultures. Gene expression analyses of chondrogenic markers verified results. hMSCs/hydrogel cultures stimulated with GH displayed no significant effects on chondrogenesis. In conclusion, both hydrogels, especially Hydromatrix® was demonstrated as a promising cell carrier in vitro for hMSCs, when directed into chondrogenesis. This knowledge could be useful in biological approaches for regeneration of degenerated human IVDs.

Seasonal patterns in self-reported peripartum depressive symptoms.

BACKGROUND: In the peripartum period, the literature on seasonality in depression is still scarce and studies present varying findings. The aims of this study were to investigate whether seasonal patterns in postpartum depressive symptoms previously identified in a Swedish study could be replicated in a larger study, as well as to assess seasonal patterns in depressive symptoms during pregnancy. METHODS: This was a nested case-control study comprised of 4129 women who participated in the BASIC project and gave birth at Uppsala University Hospital, Uppsala, Sweden, between February 2010 and December 2015. RESULTS: Women who gave birth in October-December 2011 had an increased odds of depressive symptoms at 6 weeks postpartum, when compared with women giving birth in April-June 2011 (aOR=2.42; 95% CI: 1.12-5.26). The same pattern was found among women with a history of depression. No other seasonal patterns for depressive symptoms during pregnancy or at 6 weeks postpartum were identified. CONCLUSIONS: In general, no consistent seasonal patterns were found in peripartum depressive symptoms. Whether the seasonal patterns found in some studies during certain years may be due to other factors relating to specific years and seasons, such as extreme climatic conditions or other particular events, warrants further investigation.

Parental body mass index and its association with body composition, physical fitness and lifestyle factors in their 4-year-old children: results from the MINISTOP trial.

BACKGROUND/OBJECTIVES: To examine the association between parental body mass index (BMI) and their offspring's body composition, physical fitness and lifestyle factors (that is, sedentary time, physical activity and diet). SUBJECTS/METHODS: A total of 307 preschoolers (4.5±0.1 years) and their parents (fathers: 38.1±5.1 years and mothers: 35.6±4.2 years) participated in this study. Parental BMI was calculated using self-reported weight and height. Preschoolers body composition was assessed using: BMI, fat mass percentage, fat mass index, fat-free mass index (measured via air-displacement plethysmography) and waist circumference. Physical fitness was assessed by the PREFIT fitness battery. Lifestyle factors were assessed using the ActiGraph wGT3x-BT (sedentary time and physical activity), and the mobile-phone based tool for energy balance in children (diet). RESULTS: Parental BMI were positively associated with their offspring's BMI (paternal BMI: standardised beta, ß=0.233, P<0.001; maternal BMI: ß=0.186, P=0.001), fat mass index (paternal BMI: ß=0.130, P=0.026; maternal BMI: ß=0.163, P=0.005), fat-free mass index (paternal BMI: ß=0.214, P<0.001; maternal BMI: ß=0.119, P=0.036) and waist circumference (paternal BMI: ß=0.178, P=0.001; maternal BMI: ß=0.179, P=0.001). A negative association was found between maternal BMI and their offspring's standing long jump test (ß=-0.132, P=0.022). Paternal BMI was associated with their offspring's sedentary time (ß=0.100, P=0.026), whereas parental BMI was not associated with neither physical activity nor diet (all P⩾0.104). CONCLUSIONS: Parental BMI was positively associated with their offspring's BMI, fat as well as fat-free mass index and waist circumference. Moreover, a higher paternal and maternal BMI were related to higher levels of sedentary time and a lower performance in the standing long jump test of their offspring, respectively.

Indirect effect of catecholamines on development of insulin resistance in skeletal muscle from diabetic rats.

The role of an increased sympathetic activation in the development of insulin resistance in diabetic skeletal muscle was investigated. Epitrochlearis muscles from rats with streptozocin-induced diabetes and from controls were incubated in vitro for 0.5-12.0 h. Diabetes decreased maximal insulin-stimulated (20 mU/ml) glucose transport capacity by 60% (P less than .001), but this decreased insulin responsiveness returned to normal on in vitro incubation (3.79 +/- 0.59 before vs. 8.92 +/- 0.64 mumol.ml-1.h-1 after 12 h of incubation). The reversal of decreased insulin responsiveness in diabetic muscles did not require the presence of insulin and was not affected by the presence of 5.0 x 10(-8) M of epinephrine. However, it was possible to partially prevent the development of insulin resistance with regard to glucose transport by treating the rats with the beta-adrenergic antagonist propranolol (0.5 mg/kg) every 12 h during the entire 72-h period in which the animals were kept diabetic (insulin responsiveness was 3.16 +/- 0.40 mumol.ml-1.h-1 for saline-injected group vs. 5.55 +/- 0.46 mumol.ml-1.h-1 for propranolol-treated group). This effect was not present after a single injection of the drug 2 h before the experiment or when propranolol treatment was withdrawn 12 h before the experiment. The beta-adrenergic blockade markedly reduced the plasma concentration of free fatty acids (0.5 +/- 0.01 mumol/ml for propranolol-treated rats vs. 1.1 +/- 0.1 mumol/ml for saline-treated rats; P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in the ratio of RNA encoding two isoforms of the insulin receptor between control and NIDDM patients. The RNA variant without Exon 11 predominates in both groups.

Two alternative forms of the insulin receptor with different affinities for insulin are expressed as a result of alternative splicing of RNA corresponding to exon 11 of the IR gene. The percentage of IR-RNA molecules without exon 11, encoding the high-affinity isoform, was determined by cDNA-mediated PCR amplification of RNA extracts from the quadriceps femoris muscle of healthy control subjects (n = 9) and NIDDM patients (n = 7). In both patients and control individuals, a majority of the IR-RNA molecules contained exon 11. In addition, the proportion of IR-RNA molecules without exon 11 was decreased in patients (21 +/- 1%) compared with control subjects (31 +/- 3%) (P = 0.018). Careful investigation of the kinetics of the PCR-based assay system, as well as the conditions for separation of the PCR products, allowed us to suggest a possible explanation of the discrepant results concerning the alternative splicing presented in previous reports. The diabetic subjects as a group had higher fasting insulin levels and lower insulin-mediated glucose uptake during a euglycemic-hyperinsulinemic clamp (P = 0.042). However, identification of the regulatory pathways leading to the splicing alteration in NIDDM patients requires further investigation.

Influence of physical training on formation of muscle capillaries in type I diabetes.

The effects of physical training on skeletal muscle morphology and enzyme activities were compared in 10 male, type I diabetic subjects and 10 healthy, male, control subjects. The training program consisted of running for 45 min, three times per week for 8 wk. Muscle biopsies were obtained before and after the training period from the lateral portion of the gastrocnemius muscle. Pretraining maximal oxygen uptake was similar in the two groups (diabetic subjects 42 +/- 1 versus control subjects 43 +/- 2 ml X kg-1 X min-1), and the training resulted in an identical increase (+ 13%, P less than 0.01). Muscle capillarization (number of capillaries per muscle fiber) increased on the average in the control group (+ 14 +/- 4%, P less than 0.01), but was unchanged in the diabetic group (0 +/- 4%). Capillary density, expressed as number of capillaries per unit muscle cross sectional area, also increased on the average in controls (8 +/- 4%, P less than 0.05) but failed to do so in the diabetic patients (-8 +/- 6%, NS). The activities of the mitochondrial enzymes citrate synthase (+ 26-27%, P less than 0.01-0.05) and succinate dehydrogenase (+ 24-25%, P less than 0.05) increased significantly and similarly in the two groups, whereas training did not result in significant changes in the activities of the glycolytic enzymes 6-phosphofructokinase and glyceraldehyde-phosphate dehydrogenase. Glycemic control in the diabetic group did not improve with the training, as evaluated from hemoglobin A1 and home-monitored blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment.

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.

Hyperglycemia activates glucose transport in rat skeletal muscle via a Ca(2+)-dependent mechanism.

We investigated the acute effect of hyperglycemia on 3-O-methylglucose transport in isolated rat epitrochlearis muscles. High levels of glucose (20 mmol/l) induced an approximately twofold increase in the rate of glucose transport when compared with muscles exposed to a low level of glucose (8 mmol/l) (P < 0.001). The hyperglycemic effect was additive to the effects of both insulin and exercise on the glucose transport rates. Dantrolene (25 mumol/l), a potent inhibitor of Ca2+ release from the sarcoplasmic reticulum, blocked the ability of hyperglycemia to increase glucose transport by 73% (P < 0.01). Although dantrolene had no effect on the non-insulin-stimulated or the insulin-stimulated glucose transport rates during normoglycemic conditions, the effect of exercise was completely blocked in the presence of dantrolene (P < 0.01). Inhibition of phosphatidylinositol (PI) 3-kinase by wortmannin (500 nmol/l) had no effect on the activation of glucose transport by hyperglycemia, whereas the insulin-stimulated glucose transport was completely abolished (P < 0.001). These findings suggest that hyperglycemia activates glucose transport by a Ca(2+)-dependent activation of glucose transport does not involve the activation of PI 3-kinase and is separate from the mass-action effect of glucose on glucose transport.

Increased peripheral insulin sensitivity and muscle mitochondrial enzymes but unchanged blood glucose control in type I diabetics after physical training.

Nine male, insulin-dependent diabetic patients participated in a 16-wk training program consisting of 1 h of jogging, running, ball games, and gymnastics, performed 2-3 times/wk. The training resulted in an 8% increase of maximal oxygen uptake (P less than 0.01). Insulin sensitivity as determined by the insulin clamp technique increased 20% (P less than 0.05). Glycosylated hemoglobin showed no change (10.4 +/- 0.7% versus 11.3 +/- 0.5%), 24-h urinary glucose excretion was not reduced, and home-monitored urine tests were unchanged. The frequency of hypoglycemic attacks did not change during the training period and body weight remained constant. There was a 14% fall in plasma cholesterol (P less than 0.01) and a rise in the proportion of HDL-cholesterol from 24 +/- 2% to 30 +/- 3% (P less than 0.01). Thigh muscle oxidative capacity increased, as indicated by a 24% increase in succinate dehydrogenase activity (P less than 0.05). The number of capillaries/muscle fiber increased 15% (P less than 0.01). However, as the mean muscle fiber cross-sectional area increased to a similar extent (11%, P less than 0.05), capillary density (cap x mm-2) was unchanged. In conclusion, this study demonstrates that physical training in insulin-dependent diabetics results in increased peripheral insulin sensitivity, a rise in muscle mitochondrial enzyme activities, decreased total plasma cholesterol levels, and unchanged blood glucose control. The findings suggest that in the absence of efforts to alter dietary regulation and insulin administration, physical training consisting of 2-3 weekly bouts of moderate exercise may not of itself improve blood glucose control in type I diabetes.

Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects.

The serine/threonine kinase Akt (PKB/Rac) has been implicated as playing a role in the insulin-signaling pathway to glucose transport. Little is known regarding the regulation of Akt kinase activity in insulin-sensitive tissues, such as skeletal muscle, or whether this regulation is altered in insulin-resistant states such as NIDDM. We examined the effect of insulin on Akt kinase activity in skeletal muscle from six NIDDM patients and six healthy subjects. Whole-body insulin sensitivity, assessed by the euglycemic-hyperinsulinemic clamp, was significantly lower in NIDDM subjects (P < 0.001), and this was accompanied by impaired in vitro insulin-stimulated glucose transport in skeletal muscle. In both groups, insulin induced a significant increase in Akt kinase activity, but the response to maximal insulin (60 nmol/l) was markedly reduced in skeletal muscle from NIDDM subjects (66% of control levels, P < 0.01). Impaired Akt kinase activity was not accompanied by decreased protein expression of Akt. Instead, a trend toward increased Akt expression was noted in skeletal muscle from NIDDM subjects (P < 0.1). These parallel defects in insulin-stimulated Akt kinase activity and glucose transport in diabetic skeletal muscle suggest that reduced Akt kinase activity may play a role in the development of insulin resistance in NIDDM.