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"McCarthy, M I"
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The early history of embodied cognition 1740-1920 : the Lebenskraft-debate and radical reality in German science, music, and literature
This book evaluates the early history of embodied cognition. It explores for the first time the life-force (Lebenskraft) debate in Germany, which was manifest in philosophical reflection, medical treatise, scientific experimentation, theoretical physics, aesthetic theory, and literary practice esp. 1740-1920. The history of vitalism is considered in the context of contemporary discourses on radical reality (or deep naturalism). We ask how animate matter and cognition arise and are maintained through agent-environment dynamics (Whitehead) or performance (Pickering). This book adopts a nonrepresentational approach to studying perception, action, and cognition, which Anthony Chemero designated radical embodied cognitive science. From early physiology to psychoanalysis, from the microbiome to memetics, appreciation of body and mind as symbiotically interconnected with external reality has steadily increased. Leading critics explore here resonances of body, mind, and environment in medical history (Reil, Hahnemann, Hirschfeld), science (Haller, Goethe, Ritter, Darwin, L. Büchner), musical aesthetics (E.T.A. Hoffmann, Wagner), folklore (Grimm), intersex autobiography (Baer), and stories of crime and aberration (Nordau, Döblin). Science and literature both prove to be continually emergent cultures in the quest for understanding and identity. This book will appeal to intertextual readers curious to know how we come to be who we are and, ultimately, how the Anthropocene came to be.
Book
Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes
Aims/hypothesis
MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility.
Methods
Using microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto–Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (
n
= 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions.
Results
We found 29 significantly differentiated microRNAs (
p
adjusted
< 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (
p
adjusted
= 0.0005) and miR-27a (
p
adjusted
= 0.006) were upregulated in adipose tissue; miR-195 (
p
adjusted
= 0.006) and miR-103 (
p
adjusted
= 0.04) were upregulated in liver; and miR-10b (
p
adjusted
= 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (
p
= 0.008), miR-27a (
p
= 0.02) and the previously reported miR-29a (
p
= 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes.
Conclusion
The expression patterns of miR-222, miR-27a, miR-195, miR-103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto–Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes.
Journal Article
Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis
Aims/hypothesis
FTO
gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the
FTO
rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of
FTO
genotype on BMI and weight in PCOS.
Methods
A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis.
Results
A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19
z
score units (95% CI 0.13, 0.24;
p
= 2.26 × 10
−11
) and body weight by a mean of 0.20
z
score units (95% CI 0.14, 0.26;
p
= 1.02 × 10
−10
). This translated into an approximately 3.3 kg/m
2
increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between
FTO
genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations.
Conclusions/interpretation
The effect of
FTO
SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between
FTO
and the metabolic context or polygenic background of PCOS.
Journal Article
Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants
Aims/hypothesis According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. Methods We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F ST) for 17 type 2 diabetes and 13 obesity loci. Results We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F ST for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. Conclusions/interpretation Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues.
Journal Article
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts
Aims/hypothesis
In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (
ATM
) gene in multiple additional populations.
Methods
Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS,
n
= 929) and the Rotterdam Study (
n
= 182) from the Netherlands, and the CARDS Trial (
n
= 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA
1c
reduction and treatment success, defined as the ability to reach the treatment target of an HbA
1c
≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed.
Results
In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58,
p
= 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39,
p
= 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49,
p
= 0.016 and OR 1.25, 95% CI 1.33, 1.38,
p
= 7.8 × 10
−6
, respectively).
Conclusions/interpretation
A gene variant near
ATM
is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
Journal Article
FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians
Aims and hypothesis Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune. Methods We genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India. Results We observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13-1.40; p = 3 x 10⁻⁵). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01-0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09-0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06-1.37; p = 4.0 x 10⁻³), and also for waist circumference and other anthropometric variables. Conclusions Our study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.
Journal Article
A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes
Aims/hypothesis
An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype–phenotype relationship and compare different hsCRP assays.
Methods
High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (
n
= 457), glucokinase (GCK)-MODY (
n
= 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (
n
= 54) and type 2 diabetes (
n
= 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic.
Results
In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (
z
score −21.8,
p
< 5 × 10
−105
). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l,
p
< 5 × 10
−5
). High-sensitivity CRP values between assays were strongly correlated (
r
2
≥ 0.91,
p
≤ 1 × 10
−5
). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy.
Conclusions/interpretation
In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.
Journal Article
Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome
Aims/hypothesis Variants in the fat-mass and obesity-associated gene (FTO) influence susceptibility to type 2 diabetes via an effect on adiposity/obesity. Given the important role of obesity in the aetiology of both polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, our aim was to establish whether FTO variants are also implicated in PCOS susceptibility. Methods We performed a genetic association study of FTO variant rs9939609 using case-control analyses, conducted in 463 PCOS patients (geometric mean BMI 27.5 kg/m²) and 1,336 female controls (geometric mean BMI 25.3 kg/m²) of UK British/Irish origin. We also sought evidence for associations between FTO variation and circulating testosterone levels in 324 UK PCOS patients and 1,000 women from the Northern Finland Birth Cohort of 1966. Outcome measures included FTO rs9939609 genotype frequencies by participant group and androgen measures (testosterone, free androgen index) by genotype. Results There was a significant association between FTO genotype and PCOS status in the UK case-control analysis, which was attenuated by adjustment for BMI (Cochran-Armitage test, odds ratio [per minor allele copy] 1.30 [95% CI 1.12, 1.51], p = 7.2 x 10⁻⁴ [unadjusted], p = 2.9 x 10⁻³ [adjusted]). This association was most evident in obese PCOS patients (PCOS patients below median BMI vs UK controls, p = 0.11; above median BMI vs controls, p = 2.9 x 10⁻⁴). No relationship between FTO genotype and androgen levels was seen. Conclusions/interpretation We provide the first evidence that variants that predispose to common obesity also result in altered susceptibility to PCOS, confirming the mechanistic link between these conditions. The predominant effect of FTO variants on PCOS susceptibility is probably mediated through adiposity.
Journal Article
Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice
Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with diet-induced NAFLD.
Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.
In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD.
Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to diet-induced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.
Journal Article