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S O'Rahilly

Publications and source records attributed to S O'Rahilly.

At least 19 recordsLinked to original sources
PubMed2007

Adiponectin receptor genes: mutation screening in syndromes of insulin resistance and association studies for type 2 diabetes and metabolic traits in UK populations.

AIMS/HYPOTHESIS: Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. Several reports suggest that genetic variants in the adiponectin gene are associated with circulating levels of adiponectin, insulin sensitivity and type 2 diabetes risk. Recently two receptors for adiponectin have been cloned. Genetic studies have yielded conflicting results on the role of these genes and type 2 diabetes predisposition. In this study we aimed to evaluate the potential role of genetic variation in these genes in syndromes of severe insulin resistance, type 2 diabetes and in related metabolic traits in UK Europid populations. MATERIALS AND METHODS: Exons and splice junctions of the adiponectin receptor 1 and 2 genes (ADIPOR1; ADIPOR2) were sequenced in patients from our severe insulin resistance cohort (n=129). Subsequently, 24 polymorphisms were tested for association with type 2 diabetes in population-based type 2 diabetes case-control studies (n=2,127) and with quantitative traits in a population-based longitudinal study (n=1,721). RESULTS: No missense or nonsense mutations in ADIPOR1 and ADIPOR2 were detected in the cohort of patients with severe insulin resistance. None of the 24 polymorphisms (allele frequency 2.3-48.3%) tested was associated with type 2 diabetes in the case-control study. Similarly, none of the polymorphisms was associated with fasting plasma insulin, fasting and 2-h post-load plasma glucose, 30-min insulin increment or BMI. CONCLUSIONS/INTERPRETATION: Genetic variation in ADIPOR1 and ADIPOR2 is not a major cause of extreme insulin resistance in humans, nor does it contribute in a significant manner to type 2 diabetes risk and related traits in UK Europid populations.

Diabetes Mellitus, Type 2↗
PubMed2007

PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge.

AIMS/HYPOTHESIS: The peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein, encoded by the PPARGC1A gene, transcriptionally activates a complex pathway of lipid and glucose metabolism and is expressed primarily in tissues of high metabolic activity such as liver, heart and exercising oxidative skeletal muscle fibre. Ppargc1a-null mice develop systemic dyslipidaemia and hepatic steatosis. In humans, NEFAs downregulate PPARGC1A expression in skeletal muscle. Furthermore, a common non-synonymous coding variant at PPARGC1A (Gly482Ser, rs8192678) is associated with decreased PPARGC1A mRNA levels and increased type 2 diabetes risk. MATERIALS AND METHODS: In a population-based sample of 691 healthy middle-aged Europids we assessed whether Gly482Ser is associated with levels of NEFA when fasting and in response to an oral glucose challenge. We also assessed the potential effect-modifying role of adipose tissue mass on these phenotypes. RESULTS: After adjustment for age, sex, fat mass and fat-free mass, the Ser482 allele associated with higher NEFA at 30 min and 2 h and with NEFA AUC (all values p 0.6). CONCLUSIONS/INTERPRETATION: Our observations indicate that NEFA clearance is blunted following a glucose load in carriers of the PPARCG1A Ser482 allele. This association is augmented by obesity.

Adipose Tissue↗
PubMed2007

Human obesity and insulin resistance: lessons from experiments of nature.

Examination of individuals with 'extreme phenotypes' has revealed some rare monogenic disorders that were previously unknown. This identification can shed light on physiological pathways that are also important in normal physiology and how their impairment leads to more common, milder, multigenic forms of the disease. Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance.

Diabetes Mellitus, Type 2↗
PubMed2006

PARL Leu262Val is not associated with fasting insulin levels in UK populations.

AIMS/HYPOTHESIS: PARL, the gene encoding presenilins-associated rhomboid-like protein, maps to chromosome 3q27 within a quantitative trait locus that influences components of the metabolic syndrome. Recently, an amino acid substitution (Leu262Val, rs3732581) in PARL was associated with fasting plasma insulin levels in a US white population (N=1031). This variant was also found to modify the positive association between age and fasting insulin. The aim of this study was to test whether these findings could be replicated in two UK population-based cohorts. METHODS: Participants from the Medical Research Council Ely and Hertfordshire cohort studies were genotyped for this variant using a SNaPshot primer extension assay and Taqman assay respectively. Full phenotypic and genotypic data were available for 3,666 study participants. RESULTS: Based on a dominant model, we found no association between the Leu262Val polymorphism and fasting insulin levels (p=0.79) or BMI (p=0.98). We did not observe the previously reported interaction between age and genotype on fasting insulin (p=0.14). CONCLUSIONS/INTERPRETATION: Despite having greater statistical power, our data do not support the previously reported association between PARL Leu262Val and fasting plasma insulin levels, a measure of insulin resistance. Our findings indicate that this variant is unlikely to be an important contributor to insulin resistance in UK populations.

Aged↗
PubMed2006

Polymorphisms in the gene encoding sterol regulatory element-binding factor-1c are associated with type 2 diabetes.

AIMS/HYPOTHESIS: The sterol regulatory element-binding factor (SREBF)-1c is a transcription factor involved in the regulation of lipid and glucose metabolism. We have previously found evidence that a common SREBF1c single-nucleotide polymorphism (SNP), located between exons 18c and 19c, is associated with an increased risk of type 2 diabetes. The present study aimed to replicate our previously reported association in a larger case-control study and to examine an additional five SREBF1c SNPs for their association with diabetes risk and plasma glucose concentrations. METHODS: We genotyped six SREBF1c SNPs in two case-control studies (n=1,938) and in a large cohort study (n=1,721) and tested for association with type 2 diabetes and with plasma glucose concentrations (fasting and 120-min post-glucose load), respectively. RESULTS: In the case-control studies, carriers of the minor allele of the previously reported SNP (rs11868035) had a significantly increased diabetes risk (odds ratio [OR]=1.20 [95% CI 1.04-1.38], p=0.015). Also, three other SNPs (rs2236513, rs6502618 and rs1889018), located in the 5' region, were significantly associated with diabetes risk (OR > or =1.21, p< or =0.006). Furthermore, two SNPs (rs2236513 and rs1889018) in the 5' region were weakly (p<0.09) associated with plasma glucose concentrations in the cohort study. Rare homozygotes had increased (p< or =0.05) 120-min post-load glucose concentrations compared with carriers of the wild-type allele. Haplotype analyses showed significant (p=0.04) association with diabetes risk and confirmed the single SNP analyses. CONCLUSIONS/INTERPRETATION: In summary, we replicated our previous finding and found evidence for SNPs in the 5' region of the SREBF1c gene to be associated with the risk of type 2 diabetes and plasma glucose concentration.

Aged↗
PubMed2006

Studies of the SIM1 gene in relation to human obesity and obesity-related traits.

OBJECTIVE: The single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor, which plays a critical role in the development of the paraventricular nucleus (PVN) of the hypothalamus. SIM1-deficient mice have a hypocellular PVN and are severely obese with increased food intake. DESIGN: We examined whether variants in the SIM1 gene might be associated with severe early-onset obesity in humans. Two hundred and seventy-seven subjects with hyperphagia and severe, early-onset obesity were screened. Association studies with common single-nucleotide polymorphisms (SNPs) in the SIM1 gene were performed in two population-based cohorts. RESULTS: One novel missense mutation, I128T, was found in one obese subject and not in 192 controls. However, the variant did not co-segregate with obesity in the family. Four SNPs, IVS4+83GA, P352T, A371V and T653T, were also identified. The two common SNPs, P352T and A371V, which are in complete linkage disequilibrium, were genotyped in 981 subjects from a population-based cohort, the Ely Study. An allele frequency of 0.13 was observed. Male subjects carrying the P352T/A371V haplotype were found to have a slightly higher body mass index (BMI; P=0.038). Female subjects homozygous for the haplotype gained more weight over a period of 4.5 and 10 years (P=0.003 and P=0.02, respectively). The association studies were repeated in another population-based cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC) - Norfolk Study with 4869 subjects successfully genotyped. Male subjects homozygous for the P352T/A371V haplotype had slightly higher BMI (P=0.04). CONCLUSION: Mutations in SIM1 are not commonly found in humans with severe early-onset obesity. The relationship between the common variants in SIM1 with BMI and body weight gain deserves further exploration in other populations.

Basic Helix-Loop-Helix Proteins↗
PubMed2006

Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity.

OBJECTIVE: The neurotrophin receptor TrkB has been implicated in the regulation of energy homeostasis in rodents. We have previously identified four rare missense mutations in the gene encoding TrkB, NTRK2, in 198 severely obese children with developmental delay. We have now undertaken a more detailed analysis of the in vitro functional consequences of the mutations identified: I98V, P660L, T821A and Y722C. DESIGN: Wild-type and mutant TrkB receptor constructs were stably transfected into PC12 cells and the signaling responses to the endogenous ligand, brain-derived neurotrophic factor (BDNF), were examined by Western blotting of cell lysates. In the case of Y722C, PC12 cells stably expressing this mutant were studied for their ability to respond to BDNF by promoting neurite outgrowth and cell survival. RESULTS: Further functional characterization of the previously reported Y722C TrkB mutation reveals impaired activation of mitogen-activated protein kinase, phospholipase C-gamma and Akt, as well as reduced BDNF-induced neurite outgrowth and cell survival in stably transfected PC12 cell lines. However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type. CONCLUSION: We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF. Thus, impaired hypothalamic neurogenesis may contribute to the severe hyperphagia and obesity seen in the individual harboring the Y722C variant. The other three rare TrkB variants do not show reduced autophosphorylation or impaired downstream signaling in vitro and, as yet, it is unclear whether these variants contribute to obesity in these patients.

Age of Onset↗
PubMed2006

Elevated plasma adiponectin in humans with genetically defective insulin receptors.

CONTEXT: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity. OBJECTIVE: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance. DESIGN/SETTING: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States. PARTICIPANTS: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls. OUTCOME MEASURES: Fasting plasma insulin, adiponectin, and leptin were measured. RESULTS: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)]. CONCLUSIONS: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.

Adiponectin↗
PubMed2006

Psychiatric co-morbidities in patients attending specialist obesity services in the UK.

BACKGROUND: The prevalence of obesity is rising, but little is known about its psychosocial correlates. AIM: To assess psychological co-morbidities and impairment of quality of life in obese individuals seeking treatment at two specialist centres in the UK. DESIGN: Retrospective analysis of anthropometric and questionnaire data collected at initial clinic visit. METHODS: Patients attending for a first visit between April 2004 and March 2005 completed questionnaires that included scales for measurement of anxiety and depression (Hospital Anxiety and Depression Scale), eating disorder-behaviour (Eating Disorder Inventory 2), assessment of body image (Body Image Assessment for Obesity) and quality of life (Impact of Weight on Quality of Life-Lite). We examined the relationships between variables measured on these scales and anthropometric data. RESULTS: Of 253 questionnaires evaluated, there were elevated scores for depression in 48%, and elevated scores for anxiety in 56%. Twenty-two percent demonstrated scores suggestive of a personality trait that overlaps with an eating disorder; an additional 11.5% had an elevated score for bulimia. About a third of individuals had significant impaired quality of life in the areas of examined. DISCUSSION: Psychological co-morbidities are common in obese individuals attending specialist weight-management clinics, and may merit consideration at (or before) commencement of a weight loss programme.

Adult↗
PubMed2006

WNT10B mutations in human obesity.

AIMS/HYPOTHESIS: Recent studies suggest that wingless-type MMTV integration site family, member 10B (WNT10B) may play a role in the negative regulation of adipocyte differentiation in vitro and in vivo. In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene. SUBJECTS AND METHODS: We studied 96 subjects with severe obesity of early onset (less than 10 years of age) from the UK Genetics of Obesity Study and 115 obese Italian subjects of European origin. RESULTS: One proband with early-onset obesity was found to be heterozygous for a C256Y mutation, which abrogated the ability of WNT10B to activate canonical WNT signalling and block adipogenesis and was not found in 600 control alleles. All relatives of the proband who carried this allele were either overweight or obese. Three other rare missense variants were found in obese probands, but these did not clearly cosegregate with obesity in family studies and one (P301S), which was found in three unrelated subjects with early-onset obesity, had normal functional properties. CONCLUSIONS/INTERPRETATION: These mutations represent the first naturally occurring missense variants of WNT10B. While the pedigree analysis in the case of C256Y WNT10B does not provide definitive proof of a causal link of this variant with obesity, the finding of a non-functioning WNT10B allele in a human family affected by obesity should encourage further study of this gene in other obese populations.

Adipocytes↗
PubMed2006

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes.

AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. MATERIALS AND METHODS: Gly482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. RESULTS: In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482Ser and BMI, fasting glucose or fasting insulin. CONCLUSIONS/INTERPRETATION: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.

Blood Glucose↗
PubMed2006

Hypercalcaemia associated with granulomatous lymphadenitis and elevated 1,25 dihydroxyvitamin D concentration in a dog.

A seven-year-old Labrador was presented with weight loss and mild generalised lymphadenopathy. Histopathology of an excised lymph node by the referring veterinarian demonstrated granulomatous lymphadenitis. At the time of referral, fine-needle aspirates of the lymph nodes confirmed the presence of ongoing granulomatous inflammation. Further investigations revealed marked hypercalcaemia, a low parathyroid hormone concentration, a parathyroid hormone related protein concentration within the reference range, and an elevated serum concentration of 1,25 dihydroxyvitamin D. An underlying cause of the granulomatous lymphadenitis could not be identified. The clinical signs, hypercalcaemia and elevated serum concentrations of 1,25 dihydroxyvitamin D resolved following prednisolone treatment. In contrast to dogs, hypercalcaemia occurred secondarily to granulomatous disease and elevated 1,25 dihydroxyvitamin D concentrations is a well-recognised condition in human beings. To the authors' knowledge, this is the first case report to describe elevated serum calcium and 1,25 dihydroxyvitamin D concentrations in a dog with histologically confirmed granulomatous disease.

Animals↗
PubMed2005

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.

AIMS/HYPOTHESIS: The proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources. MATERIALS AND METHODS: The G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls. RESULTS: There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16). CONCLUSIONS/INTERPRETATION: The present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.

Adult↗
PubMed2005

A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms.

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.

Amino Acid Sequence↗
PubMed2004

Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).

Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.

Animals↗
PubMed2004

Hypoketotic hypofattyacidaemic hypoinsulinaemic hypoglycaemia in a child with hemihypertrophy? A new syndrome.

BACKGROUND: Recurrent and persistent hypoketotic, hypofattyacidaemic hypoglycaemia in infancy and childhood is most frequently due to hyperinsulinism of infancy. This biochemical profile can also be due to non-islet cell tumour hypoglycaemia or circulating insulin-receptor autoantibodies. Hyperinsulinaemic hypoglycaemia is also seen in children with the Beckwith-Wiedemann syndrome, where it is usually transient. METHODS/RESULTS: We report a novel case of child with hemihypertrophy and severe persistent hypoketotic, hypofattyacidaemic hypoinsulinaemic hypoglycaemia. No 'big' pro-IGF2 forms or circulating insulin-receptor antibodies were found. Glucose and protein isotope turnover studies showed marked suppression of hepatic glucose production during fasting. There was no evidence for constitutive autophosphorylation of the insulin or IGF-1 receptor, and no evidence for up-regulation of IGF-1 receptor. CONCLUSION: The precise pathophysiology of this novel case is still unclear.

Abnormalities, Multiple↗