Mentalising skills in generic mental healthcare settings: can we make our day-to-day interactions more therapeutic?

Aims and methodCaring for patients with personality disorder is one of the biggest challenges in psychiatric work. We investigated whether mentalisation-based treatment skills (MBT-S) teaching improves clinicians' understanding of mentalising and attitudes towards personality disorder. Self-report questionnaires (Knowledge and Application of MBT (KAMQ) and Attitudes to Personality Disorder (APDQ)) were completed at baseline and after a 2-day MBT-S workshop. RESULTS: Ninety-two healthcare professionals completed questionnaires before and after training. The mean within-participant increase in scores from baseline to end-of-programme was 11.6 points (95% CI 10.0-13.3) for the KAMQ and 4.0 points (1.8-6.2) for the APDQ.Clinical implicationsMBT-S is a short intervention that is effective in improving clinicians' knowledge of personality disorder and mentalisation. That attitudes to personality disorder improved overall is encouraging in relation to the possibility of deeper learning in staff and, ultimately, improved care for patients with personality disorder.Declaration of interestNone.

Optimized wound closure using a biomechanical abdominal model.

BACKGROUND: Suturing techniques for midline abdominal wall incisions vary between surgeons. This study uses a biomechanical abdominal model to assess tissue stretch using different suturing techniques for midline laparotomy closure. METHODS: Deformation tests were performed on the linea alba of 48 porcine abdominal walls. Each pattern was tested three times at pressures ranging from 0 to 20 kPa using different continuous suturing techniques and a control. RESULTS: There was a sevenfold improvement when the best performing bite separation and bite width ([5, 16] mm) was compared with the most poorly performing combination ([15, 4] mm). The traditional bite and width separation ([10, 10] mm) and the recently proposed combination ([5, 5] mm) may not be optimal, and substantial improvements in surgical outcome may be achieved by changing to a [5,16]-mm combination. CONCLUSION: These findings suggest using a small bite separation (5 mm) and large bite width (16 mm) during abdominal wound closure may be optimal. Surgical relevance Suturing techniques for midline abdominal wall incisions vary between surgeons. This experimental study suggests substantial potential for improved tissue apposition by changing the suturing approach from the traditional clinical recommendation of 10 mm for both bite separation and bite width to a bite separation of 5 mm and a bite width of 16 mm. These findings support recent European Hernia Society guidelines and the recent randomized STITCH (Suture Techniques to Reduce the Incidence of The inCisional Hernia) trial, which found that small separations are more effective than large separations, but suggest that they should be combined with large bite depths.

Novel outreach settings to enhance sexually transmitted infection/HIV awareness, diagnosis and treatment in hard-to-reach populations.

Despite recent rises in the number of cases of sexually transmitted infections (STIs) such as syphilis and gonorrhoea in England and increasing rates of HIV diagnosis among several men who have sex with men populations, many individuals are still not engaging with sexual health services. The John Hunter Clinic for Sexual Health, Chelsea and Westminster Hospital, London set up outreach clinics at the two world's largest adult lifestyle exhibitions in 2013 and 2015. This was the first time that a sexual health screening and promotion service was available at these large-scale (over 10,000 attendees at each) adult lifestyle events. A total of 381 individuals underwent STI screening across the two events. Nineteen (5.0%) patients were diagnosed with an infection. Twelve (3.1%) patients with Chlamydia trachomatis, three (0.8%) patients with syphilis, one (0.3%) patient with Neisseria gonorrhoeae, one (0.3%) patient with HIV, one (0.3%) patient with hepatitis B and one (0.3%) patient with hepatitis C. All 19 patients were promptly contacted with their results and had arrangements made for treatment or were referred for specialist follow up. Where possible, contact tracing was also performed. Implementing such outreach-based projects is challenged by lack of on-site laboratory support, high staffing demands and potentially high costs. However, we achieved a total HIV screening uptake rate of 94.5% amongst our outreach clinic attendees (versus 67% nationally in conventional sexual health clinic attendees) with an HIV positivity rate of 0.3% (versus 0.2% nationally in high HIV prevalence band populations). Additionally, 30.7% had never been tested for HIV previously (versus 20.7% nationally). Our work demonstrates that these strategies can help to address issues related to lack of STI/HIV screening in hard-to-reach populations and promote risk reduction behaviour.

Exploring the relationship between α-actinin-3 deficiency and obesity in mice and humans.

Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. α-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.

Enhanced peroxisomal ß-oxidation is associated with prevention of obesity and glucose intolerance by fish oil-enriched diets.

OBJECTIVE: The effects of different amounts of omega 3-polyunsaturated fatty acids in diets with normal or high content of fat on lipid and carbohydrate metabolism were investigated. DESIGN AND METHODS: Mice were fed for 8 weeks on diets enriched with fish oil or lard at 10% or 60% of energy. Energy balance and energy expenditure were analyzed. Fatty acid (FA) oxidative capacity of the liver and the activity of enzymes involved in this pathway were assessed. RESULTS: Fish oil-fed mice had lower body weight and adiposity compared with lard-fed animals, despite having lower rates of oxygen consumption. Mice fed diets containing fish oil also displayed lower glycemia, reduced fat content in the liver, and improved glucose tolerance compared with lard-fed animals. The fish oil-containing diets increased markers of hepatic peroxisomal content and increased the generation of metabolites derived from FA ß-oxidation in liver homogenates. In contrast, no changes were observed in the content of mitochondrial electron transport chain proteins or carnitine palmitoyl transferase-1 in the liver, indicating little direct effect of fish oil on mitochondrial metabolism. CONCLUSION: Collectively, our findings suggest that the energy inefficient oxidation of FAs in peroxisomes may be an important mechanism underlying the protection against obesity and glucose intolerance of fish oil administration.

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding.

AIMS/HYPOTHESIS: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD). METHODS: C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle. RESULTS: Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance. CONCLUSIONS/INTERPRETATION: HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding.

AIMS/HYPOTHESIS: Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated strain-dependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). METHODS: Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. RESULTS: BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. CONCLUSIONS/INTERPRETATION: Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies.

Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.

Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic clamp. After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3ß. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.

The adaptor protein APPL1 increases glycogen accumulation in rat skeletal muscle through activation of the PI3-kinase signalling pathway.

APPL1 is an adaptor protein that binds to both AKT and adiponectin receptors and is hypothesised to mediate the effects of adiponectin in activating downstream effectors such as AMP-activated protein kinase (AMPK). We aimed to establish whether APPL1 plays a physiological role in mediating glycogen accumulation and insulin sensitivity in muscle and the signalling pathways involved. In vivo electrotransfer of cDNA- and shRNA-expressing constructs was used to over-express or silence APPL1 for 1 week in single tibialis cranialis muscles of rats. Resulting changes in glucose and lipid metabolism and signalling pathway activation were investigated under basal conditions and in high-fat diet (HFD)- or chow-fed rats under hyperinsulinaemic-euglycaemic clamp conditions. APPL1 over-expression (OE) caused an increase in glycogen storage and insulin-stimulated glycogen synthesis in muscle, accompanied by a modest increase in glucose uptake. Glycogen synthesis during the clamp was reduced by HFD but normalised by APPL1 OE. These effects are likely explained by APPL1 OE-induced increase in basal and insulin-stimulated phosphorylation of IRS1, AKT, GSK3ß and TBC1D4. On the contrary, APPL1 OE, such as HFD, reduced AMPK and acetyl-CoA carboxylase phosphorylation and PPARγ coactivator-1α and uncoupling protein 3 expression. Furthermore, APPL1 silencing caused complementary changes in glycogen storage and phosphorylation of AMPK and PI3-kinase pathway intermediates. Thus, APPL1 may provide a means for crosstalk between adiponectin and insulin signalling pathways, mediating the insulin-sensitising effects of adiponectin on muscle glucose disposal. These effects do not appear to require AMPK. Activation of signalling mediated via APPL1 may be beneficial in overcoming muscle insulin resistance.

Differential regulation of adaptive and apoptotic unfolded protein response signalling by cytokine-induced nitric oxide production in mouse pancreatic beta cells.

AIMS/HYPOTHESIS: Pro-inflammatory cytokines such as IL-1ß, IFN-γ and TNF-α may contribute to pancreatic beta cell destruction in type 1 diabetes. A mechanism requiring nitric oxide, which is generated by inducible nitric oxide synthase (iNOS), in cytokine-induced endoplasmic reticulum (ER) stress and apoptosis has been proposed. Here, we tested the role of nitric oxide in cytokine-induced ER stress and the subsequent unfolded protein response (UPR) in beta cells. METHODS: Isolated islets from wild-type and iNos (also known as Nos2) knockout (iNos ( -/- )) mice, and MIN6 beta cells were incubated with IL-1ß, IFN-γ and TNF-α for 24-48 h. N (G)-methyl-L: -arginine was used to inhibit nitric oxide production in MIN6 cells. Protein levels and gene expression were assessed by western blot and real-time RT-PCR. RESULTS: In islets and MIN6 cells, inhibition of nitric oxide production had no effect on the generation of ER stress by cytokines, as evidenced by downregulation of Serca2b (also known as Atp2a2) mRNA and increased phosphorylation of PKR-like ER kinase, Jun N-terminal kinase (JNK) and eukaryotic translation initiation factor 2 α subunit. However, nitric oxide regulated the pattern of UPR signalling, which delineates the cellular decision to adapt to ER stress or to undergo apoptosis. Inhibition of nitric oxide production led to reduced expression of pro-apoptotic UPR markers, Chop (also known as Ddit3), Atf3 and Trib3. In contrast, adaptive UPR markers (chaperones, foldases and degradation enhancers) were increased. Further analysis of mouse islets showed that cytokine-induced Chop and Atf3 expression was also dependent on JNK activity. CONCLUSIONS/INTERPRETATION: The mechanism by which cytokines induce ER stress in mouse beta cells is independent of nitric oxide production. However, nitric oxide may regulate the switch between adaptive and apoptotic UPR signalling.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1ß involves reductions in long-chain acyl-CoA levels and oxidative stress.

AIMS/HYPOTHESIS: To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1ß [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. METHODS: Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1ß in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1ß on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. RESULTS: Pgc-1ß gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1ß. In rats fed a HFD, increasing the levels of Pgc-1ß partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. CONCLUSIONS: Our data show that an increase in Pgc-1ß expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo.

AIMS/HYPOTHESIS: A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. METHODS: L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow- and fat-fed rats and the effects on glucose and lipid metabolism evaluated. RESULTS: Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow- and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with body-fat content and insulin sensitivity. CONCLUSIONS/INTERPRETATION: Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.

The Ski proto-oncogene regulates body composition and suppresses lipogenesis.

OBJECTIVE: The Ski gene regulates skeletal muscle differentiation in vitro and and in vivo. In the c-Ski overexpression mouse model there occurs marked skeletal muscle hypertrophy with decreased adipose tissue mass. In this study, we have investigated the underlying molecular mechanisms responsible for the increased skeletal muscle and decreased adipose tissue mass in the c-Ski mouse. APPROACH: Growth and body composition analysis (tissue weights and dual energy X-ray absorptiometry) coupled with skeletal muscle and white adipose gene expression and metabolic phenotyping in c-Ski mice and wild-type (WT) littermate controls was performed. RESULTS: The growth and body composition studies confirmed the early onset of accelerated body growth, with increased lean mass and decreased fat mass in the c-Ski mice. Gene expression analysis in skeletal muscle from c-Ski mice compared with WT mice showed significant differences in myogenic and lipogenic gene expressions that are consistent with the body composition phenotype. Skeletal muscle of c-Ski mice had significantly repressed Smad1, 4, 7 and myostatin gene expression and elevated myogenin, myocyte enhancer factor 2, insulin-like growth factor-1 receptor and insulin-like growth factor-2 expression. Strikingly, expression of the mRNAs encoding the master lipogenic regulators, sterol-regulatory enhancer binding protein 1c (SREBP1c), and the nuclear receptor liver X-receptor-alpha, and their downstream target genes, SCD-1 and FAS, were suppressed in skeletal muscle of c-Ski mice, as were the expressions of other nuclear receptors involved in adipogenesis and metabolism, such as peroxisome proliferator-activated receptor-gamma, glucocorticoid receptor and retinoic acid receptor-related orphan receptor-alpha. Transfection analysis demonstrated Ski repressed the SREBP1c promoter. Moreover, palmitate oxidation and oxidative enzyme activity was increased in skeletal muscle of c-Ski mice. These results suggest that the Ski phenotype involves attenuated lipogenesis, decreased myostatin signalling, coupled to increased myogenesis and fatty acid oxidation. CONCLUSION: Ski regulates several genetic programs and signalling pathways that regulate skeletal muscle and adipose mass to influence body composition development, suggesting that Ski may have a role in risk for obesity and metabolic disease.

Diverse roles for protein kinase C delta and protein kinase C epsilon in the generation of high-fat-diet-induced glucose intolerance in mice: regulation of lipogenesis by protein kinase C delta.

AIMS/HYPOTHESIS: This study aimed to determine whether protein kinase C (PKC) delta plays a role in the glucose intolerance caused by a high-fat diet, and whether it could compensate for loss of PKCepsilon in the generation of insulin resistance in skeletal muscle. METHODS: Prkcd (-/-), Prkce (-/-) and wild-type mice were fed high-fat diets and subjected to glucose tolerance tests. Blood glucose levels and insulin responses were determined during the tests. Insulin signalling in liver and muscle was assessed after acute in vivo insulin stimulation by immunoblotting with phospho-specific antibodies. Activation of PKC isoforms in muscle from Prkce (-/-) mice was assessed by determining intracellular distribution. Tissues and plasma were assayed for triacylglycerol accumulation, and hepatic production of lipogenic enzymes was determined by immunoblotting. RESULTS: Both Prkcd (-/-) and Prkce (-/-) mice were protected against high-fat-diet-induced glucose intolerance. In Prkce (-/-) mice this was mediated through enhanced insulin availability, while in Prkcd (-/-) mice the reversal occurred in the absence of elevated insulin. Neither the high-fat diet nor Prkcd deletion affected maximal insulin signalling. The activation of PKCdelta in muscle from fat-fed mice was enhanced by Prkce deletion. PKCdelta-deficient mice exhibited reduced liver triacylglycerol accumulation and diminished production of lipogenic enzymes. CONCLUSIONS/INTERPRETATION: Deletion of genes encoding isoforms of PKC can improve glucose intolerance, either by enhancing insulin availability in the case of Prkce, or by reducing lipid accumulation in the case of Prkcd. The absence of PKCepsilon in muscle may be compensated by increased activation of PKCdelta in fat-fed mice, suggesting that an additional role for PKCepsilon in this tissue is masked.

Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase.

The worldwide prevalence of type 2 diabetes (T2D) and related disorders of the metabolic syndrome (MS) has reached epidemic proportions. Insulin resistance (IR) is a major perturbation that characterizes these disorders. Extra-adipose accumulation of lipid, particularly within the liver and skeletal muscle, is closely linked with the development of IR. The AMP-activated protein kinase (AMPK) pathway plays an important role in the regulation of both lipid and glucose metabolism. Through its effects to increase fatty acid oxidation and inhibit lipogenesis, AMPK activity in the liver and skeletal muscle could be expected to ameliorate lipid accumulation and associated IR in these tissues. In addition, AMPK promotes glucose uptake into skeletal muscle and suppresses glucose output from the liver via insulin-independent mechanisms. These characteristics make AMPK a highly attractive target for the development of strategies to curb the prevalence and costs of T2D. Recent insights into the regulation of AMPK and mechanisms by which it modulates fuel metabolism in liver and skeletal muscle are discussed here. In addition, we consider the arguments for and against the hypothesis that dysfunctional AMPK contributes to IR. Finally we review studies which assess AMPK as an appropriate target for the prevention and treatment of T2D and MS.

Young people with intellectual disabilities attending mainstream and segregated schooling: perceived stigma, social comparison and future aspirations.

BACKGROUND: Mainstream schooling is a key policy in the promotion of social inclusion of young people with learning disabilities. Yet there is limited evidence about the school experience of young people about to leave mainstream as compared with segregated education, and how it impacts on their relative view of self and future aspirations. METHODS: Sixty young people with mild to moderate intellectual disabilities in their final year of secondary school participated in this study. Twenty-eight individuals came from mainstream schools and 32 attended segregated school. They completed a series of self-report measures on perceptions of stigma, social comparison to a more disabled and non-disabled peer and the likelihood involved in attaining their future goals. RESULTS: The majority of participants from both groups reported experiencing stigmatized treatment in the local area where they lived. The mainstream group reported significant additional stigma at school. In terms of social comparisons, both groups compared themselves positively with a more disabled peer and with a non-disabled peer. While the mainstream pupils had more ambitious work-related aspirations, both groups felt it equally likely that they would attain their future goals. Although the participants from segregated schools came from significantly more deprived areas and had lower scores on tests of cognitive functioning, neither of these factors appeared to have an impact on their experience of stigma, social comparisons or future aspirations. CONCLUSIONS: Irrespective of schooling environment, the young people appeared to be able to cope with the threats to their identities and retained a sense of optimism about their future. Nevertheless, negative treatment reported by the children was a serious source of concern and there is a need for schools to promote the emotional well-being of pupils with intellectual disabilities.

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin.

AIMS/HYPOTHESIS: Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [(3)H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion. METHODS: Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours. RESULTS: Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake. CONCLUSIONS/INTERPRETATION: These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.

Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with Type 2 diabetes.

AIM/HYPOTHESIS: We determined the effect of exercise training on insulin sensitivity and muscle lipids (triglyceride [TG(m)] and long-chain fatty acyl CoA [LCACoA] concentration) in patients with Type 2 diabetes. METHODS: Seven patients with Type 2 diabetes and six healthy control subjects who were matched for age, BMI, % body fat and VO(2)peak participated in a 3 days per week training program for 8 weeks. Insulin sensitivity was determined pre- and post-training during a 120 min euglycaemic-hyperinsulinaemic clamp and muscle biopsies were obtained before and after each clamp. Oxidative enzyme activities [citrate synthase (CS), beta-hydroxy-acyl-CoA (beta-HAD)] and TG(m) were determined from basal muscle samples pre- and post training, while total LCACoA content was measured in samples obtained before and after insulin-stimulation, pre- and post training. RESULTS: The training-induced increase in VO(2)peak (approximately 20%, p<0.01) was similar in both groups. Compared with control subjects, insulin sensitivity was lower in the diabetic patients before and after training (approximately 60%; p<0.05), but was increased to the same extent in both groups with training (approximately 30%; p<0.01). TG(m) was increased in patients with Type 2 diabetes (170%; p<0.05) before, but was normalized to levels observed in control subjects after training. Basal LCACoA content was similar between groups and was unaltered by training. Insulin-stimulation had no detectable effect on LCACoA content. CS and beta-HAD activity were increased to the same extent in both groups in response to training ( p<0.001). CONCLUSION/INTERPRETATION: We conclude that the enhanced insulin sensitivity observed after short-term exercise training was associated with a marked decrease in TG(m) content in patients with Type 2 diabetes. However, despite the normalization of TG(m )to levels observed in healthy individuals, insulin resistance was not completely reversed in the diabetic patients.

The role of intramuscular lipid in insulin resistance.

There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.

Muscle long-chain acyl CoA esters and insulin resistance.

A common observation in animal models and in humans is that accumulation of muscle triglyceride is associated with the development of insulin resistance. In animals, this is true of genetic models of obesity and nutritional models of insulin resistance generated by high-fat feeding, infusion of lipid, or infusion of glucose. Although there is a strong link between the accumulation of triglycerides (TG) in muscle and insulin resistance, it is unlikely that TG are directly involved in the generation of muscle insulin resistance. There are now other plausible mechanistic links between muscle lipid metabolites and insulin resistance, in addition to the classic substrate competition proposed by Randle's glucose-fatty acid cycle. The first step in fatty acid metabolism (oxidation or storage) is activation to the long-chain fatty acyl CoA (LCACoA). This review covers the evidence suggesting that cytosolic accumulation of this active form of lipid in muscle can lead to impaired insulin signaling, impaired enzyme activity, and insulin resistance, either directly or by conversion to other lipid intermediates that alter the activity of key kinases and phosphatases. Actions of fatty acids to bind specific nuclear transcription factors provide another mechanism whereby different lipids could influence metabolism.