Sex-related differences of fatty acid-binding protein 4 and leptin levels in atrial fibrillation.

AIMS: Adiposity plays a key role in the pathogenesis of atrial fibrillation (AF). Our aim was to study the sex differences in adipokines levels according to AF burden. METHODS AND RESULTS: Two independent cohorts of patients were studied: (i) consecutive patients with AF undergoing catheter ablation (n = 217) and (ii) a control group (n = 105). (i) Adipokines, oxidative stress, indirect autonomic markers, and leucocytes mRNA levels were analysed; (ii) correlation between biomarkers was explored with heatmaps and Kendall correlation coefficients; and (iii) logistic regression and random forest model were used to determine predictors of AF recurrence after ablation. Our results showed that: (i) fatty acid-binding protein 4 (FABP4) and leptin levels were higher in women than in men in both cohorts (P < 0.01). In women, FABP4 levels were higher on AF cohort (20 ± 14 control, 29 ± 18 paroxysmal AF and 31 ± 17 ng/mL persistent AF; P < 0.01). In men, leptin levels were lower on AF cohort (22 ± 15 control, 13 ± 16 paroxysmal AF and 13 ± 11 ng/mL persistent AF; P < 0.01). (ii) In female with paroxysmal AF, there was a lower acetylcholinesterase and higher carbonic anhydrase levels with respect to men (P < 0.05). (iii) Adipokines have an important role on discriminate AF recurrence after ablation. In persistent AF, FABP4 was the best predictor of recurrence after ablation (1.067, 95% confidence interval 1-1.14; P = 0.046). CONCLUSION: The major finding of the present study is the sex-based differences of FABP4 and leptin levels according to AF burden. These adipokines are associated with oxidative stress, inflammatory and autonomic indirect markers, indicating that they may play a role in AF perpetuation.

Electron-Pair Distribution in Chemical Bond Formation.

The chemical formation process has been studied from relaxation holes, Δh(u), resulting from the difference between the radial intracule density and the nonrelaxed counterpart, which is obtained from atomic radial intracule densities and the pair density constructed from the overlap of the atomic densities. Δh(u) plots show that the internal reorganization of electron pairs prior to bond formation and the covalent bond formation from electrons in separate atoms are completely recognizable processes from the shape of the relaxation hole, Δh(u). The magnitude of Δh(u), the shape of Δh(u) ∀ u < Req, and the distance between the minimum and the maximum in Δh(u) provide further information about the nature of the chemical bond formed. A computational affordable approach to calculate the radial intracule density from approximate pair densities has been also suggested, paving the way to study electron-pair distributions in larger systems.

Microsatellite instable vs stable colon carcinomas: analysis of tumour heterogeneity, inflammation and angiogenesis.

BACKGROUND: Microsatellite instability (MSI) accounts for 15% of all colorectal tumours. Several specific clinicopathologicals (e.g., preference for the proximal colon over the distal colon, improved prognosis and altered response to chemotherapeutics) are described for this subset of tumours. This study aimed to analyse morphological, inflammatory and angiogenic features of MSI vs microsatellite stable (MSS) tumours. METHODS: Twenty-seven MSS and 29 MSI, TNM stage matched, colorectal tumours were selected from the archive of the Department of Pathology, UZ Leuven. Morphology was analysed on haematoxylin-eosin sections. Immunohistochemistry for CD3, CD4, CD8, CD20 and CD68 was used to map tumour infiltration in both a digital and traditional microscope-based manner for all distinct morphological components of the tumour. CD31 immunostains were performed to assess angiogenesis. RESULTS: Morphological tumour heterogeneity was a marked feature of MSI tumours, occurring in 53% of the cases as compared with 11% of the MSS tumours (P<0.001). Digital immune quantification showed an increased number of tumour-infiltrating cytotoxic T-lymphocytes (CD8+) in MSI compared with MSS tumours for both the tumour (P=0.02) and peritumoural area (P=0.03). Traditional microscope-based quantification confirmed these results (P<0.001 for both) and, in addition, revealed large numbers of CD68+ macrophages in the peritumoural area of MSI cancers (P=0.001). Moreover, traditional microscope-based analysis was able to distinguish between lymphocytes directly infiltrating the tumoural glands (intra-epithelial) and those infiltrating only the neoplastic stroma around the glands (intratumoural). Quantification showed high numbers of intra-epithelial CD3+, CD4+, CD8+, CD20+ and CD68+ cells in MSI compared with MSS cancers (P<0.001, P=0.01, P<0.001, P<0.001 and P=0.006, respectively). Higher microvessel density (MVD) was observed in MSI tumours compared with their MSS counterpart. CONCLUSIONS: Mixed morphology, reflecting tumour heterogeneity, is an important feature of MSI tumours and may have both diagnostic and therapeutic impact. The inflammatory reaction also presented with significant differences in MSI vs MSS colorectal tumours. MSI cancers showed mainly infiltration by cytotoxic T-cells in both the tumour and the close border around the tumour, as well as increased intra-epithelial infiltration in contrast to MSS tumours. The type of immune cell and the compartment it resides in (intratumoural or intra-epithelial) depend both on MSI status and morphology. Finally, MSI tumours showed a higher angiogenic capacity represented by an increased MVD, hinting for possible therapeutic consequences.

Symbolic dynamics marker of heart rate variability combined with clinical variables enhance obstructive sleep apnea screening.

Many sleep centres try to perform a reduced portable test in order to decrease the number of overnight polysomnographies that are expensive, time-consuming, and disturbing. With some limitations, heart rate variability (HRV) has been useful in this task. The aim of this investigation was to evaluate if inclusion of symbolic dynamics variables to a logistic regression model integrating clinical and physical variables, can improve the detection of subjects for further polysomnographies. To our knowledge, this is the first contribution that innovates in that strategy. A group of 133 patients has been referred to the sleep center for suspected sleep apnea. Clinical assessment of the patients consisted of a sleep related questionnaire and a physical examination. The clinical variables related to apnea and selected in the statistical model were age (p < 10(-3)), neck circumference (p < 10(-3)), score on a questionnaire scale intended to quantify daytime sleepiness (p < 10(-3)), and intensity of snoring (p < 10(-3)). The validation of this model demonstrated an increase in classification performance when a variable based on non-linear dynamics of HRV (p < 0.01) was used additionally to the other variables. For diagnostic rule based only on clinical and physical variables, the corresponding area under the receiver operating characteristic (ROC) curve was 0.907 (95% confidence interval (CI) = 0.848, 0.967), (sensitivity 87.10% and specificity 80%). For the model including the average of a symbolic dynamic variable, the area under the ROC curve was increased to 0.941 (95% = 0.897, 0.985), (sensitivity 88.71% and specificity 82.86%). In conclusion, symbolic dynamics, coupled with significant clinical and physical variables can help to prioritize polysomnographies in patients with a high probability of apnea. In addition, the processing of the HRV is a well established low cost and robust technique.

Epithelial expression of FHL2 is negatively associated with metastasis-free and overall survival in colorectal cancer.

BACKGROUND: Four-and-a-half LIM domains protein 2 (FHL2) is a component of the focal adhesion structures and has been suggested to have a role in cancer progression. It has been shown to be overexpressed in the colorectal cancer (CRC). METHODS: Here, we examined a possible prognostic value of FHL2 in CRC. Immunohistochemistry for FHL2 was performed on 296 CRCs without distant metastases at the time of surgery. Staining in the epithelial compartment was quantitatively evaluated using image analysis, and results were related to clinical variables. Antibody specificity was tested using small-interfering RNA transfection in hTERT-immortalised myofibroblasts. RESULTS: Varying degrees of cytoplasmic FHL2 expression by neoplastic epithelial cells were detectable in all cases. Higher FHL2 expression in the epithelial compartment was an independent adverse prognostic factor. Multivariate Cox analysis shows that expression in the tumour invasion front (P<0.001) as well as in the centre of the tumour (P<0.001) was associated with metachronous metastases independently of the clinicopathological variables; expression in the tumour invasion front was also associated with overall survival independently of the clinicopathological variables (P<0.01). CONCLUSION: Higher FHL2 expression is involved in CRC progression and correlates with the development of metachronous metastases and overall survival, suggesting that FHL2 is an independent adverse prognostic indicator for CRC.

The intrapair electron correlation in natural orbital functional theory.

A previously proposed [M. Piris, X. Lopez, F. Ruipérez, J. M. Matxain, and J. M. Ugalde, J. Chem. Phys. 134, 164102 (2011)] formulation of the two-particle cumulant, based on an orbital-pairing scheme, is extended here for including more than two natural orbitals. This new approximation is used to reconstruct the two-particle reduced density matrix (2-RDM) constrained to the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. In this way, we have derived an extended version of the Piris natural orbital functional 5 (PNOF5e). An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is also used to generate the PNOF5e. The theory is applied to the homolytic dissociation of selected diatomic molecules: H2, LiH, and Li2. The Bader's theory of atoms in molecules is used to analyze the electron density and the presence of non-nuclear maxima in the case of a set of light atomic clusters: Li2, Li3(+), Li4(2+), and H3(+). The improvement of PNOF5e over PNOF5 was observed by visualizing the electron densities.

Molecular dynamics simulations of iron- and aluminum-loaded serum transferrin: protonation of Tyr188 is necessary to prompt metal release.

Serum transferrin (sTf) carries iron in blood serum and delivers it into cells by receptor-mediated endocytosis. The protein can also bind other metals, including aluminum. The crystal structures of the metal-free and metal-loaded protein indicate that the metal release process involves an opening of the protein. In this process, Lys206 and Lys296 lying in the proximity of each other form the dilysine pair or, so-called, dilysine trigger. It was suggested that the conformational change takes place due to variations of the protonation state of the dilysine trigger at the acidic endosomal pH. In 2003, Rinaldo and Field (Biophys. J. 85, 3485-3501) proposed that the dilysine trigger alone can not explain the opening and that the protonation of Tyr188 is required to prompt the conformational change. However, no evidence was supplied to support this hypothesis. Here, we present several 60 ns molecular dynamics simulations considering various protonation states to investigate the complexes formed by sTf with Fe(III) and Al(III). The calculations demonstrate that only in those systems where Tyr188 has been protonated does the protein undergo the conformational change and that the dilysine trigger alone does not lead to the opening. The simulations also indicate that the metal release process is a stepwise mechanism, where the hinge-bending motion is followed by the hinge-twisting step. Therefore, the study demonstrates for the first time that the protonation of Tyr188 is required for the release of metal from the metal loaded sTf and provides valuable information about the whole process.

Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes.

AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress may play a role in cytokine-mediated beta cell death in type 1 diabetes, but it remains controversial whether ER stress markers are present in islets from type 1 diabetic individuals. Therefore, we evaluated by immunostaining the expression of markers of the three main branches of the ER stress response in islets from 13 individuals with and 15 controls without type 1 diabetes (eight adults and seven children). METHODS: Antibodies against the ER stress markers C/EBP homologous protein (CHOP), immunoglobulin heavy chain (BIP) and X-box binding protein 1 (XBP-1) were validated using HeLa cells treated with the ER stressor thapsigargin. These antibodies were then used to stain serial sections of paraffin-embedded pancreas from type 1 diabetic and non-diabetic individuals; samples were also immunostained for CD45, insulin and glucagon. Immunostaining intensities of the ER stress markers were quantified using a software-based, unbiased quantitative approach. RESULTS: Islets from individuals with type 1 diabetes showed increased levels of CHOP and, at least for insulitis-positive and beta cell-containing islets, BIP. XBP-1 expression was not, however, increased. CONCLUSIONS/INTERPRETATION: Islet cells from individuals with type 1 diabetes display a partial ER stress response, with evidence of the induction of some, but not all, components of the unfolded protein response.

Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolising enzyme that induces immune tolerance by modulating T-cell responses. Carcinomas may create an immunosuppressive state via IDO1 expression. Here we examined a possible contribution of IDO1 on this phenomenon and investigated whether IDO1 has prognostic value in colorectal cancer (CRC). METHODS: IDO1 expression was investigated by quantitative PCR and western blotting in three colon cancer cell lines, in basal state and after interferon (IFN)-γ stimulation. Semi-quantitative immunohistochemistry was used to evaluate IDO1 expression in 265 pT1-4N0-2Mx-staged CRCs. Results were related to clinical variables and correlated with amounts of CD3(+) and CD8(+) T lymphocytes, which were quantitatively evaluated using image analysis. RESULTS: In vitro expression of IDO1 depended on IFN-γ stimulation. Higher IDO1 expression at the tumour invasion front was an independent adverse prognostic factor in pT1-4N1Mx-staged CRC. It was associated with overall survival (P=0.001) and with metachronous metastases (P=0.018). IDO1 expression was not associated with the presence of CD3(+) or CD8(+) T lymphocytes. CONCLUSION: Higher IDO1 expression at the tumour invasion front is involved in CRC progression and correlates with impaired clinical outcome, suggesting that IDO1 is an independent prognostic indicator for CRC.

Aluminum speciation in biological environments. The deprotonation of free and aluminum bound citrate in aqueous solution.

Citrate is the main low mass molecule chelator of aluminum in serum, and knowledge of the interaction mode of this organic molecule with this cation is necessary to understand aluminum speciation in biosystems. However, the 1:1 complexation of citric acid to Al(III) is a complex process due to the myriad of coordination sites and protonation states of this molecule. Moreover, due to the acidic character of the complex, its entire experimental characterization is elusive. The system is also challenging from a computational point of view, due to the difficulties in getting a balanced estimation of the large range of solvation free energies encountered for the different protonation states of a multiprotic acid in both situations, complexed and uncomplexed with a trivalent cation. Herein, the deprotonation process of the free citric acid in solution and that interacting with Al(III) have been investigated considering all possible coordination modes and protonation states of the citric acid. All the structures were optimized in solution combining the B3LYP density function method with the polarizable continuum IEFPCM model. In addition, different schemes have been employed to obtain reliable solvation energies. Taking into account the most stable isomer of each protonation state, the pK(a) values were computationally estimated for the free citric acid and that interacting with Al(III), showing a good agreement with the experimental data. All these results shed light on how the deprotonation process of the citric acid takes place, and show that Al(III) not only increases the acidity of the molecule, but also changes qualitatively the deprotonation pattern of the citric acid. This information is highly relevant to understand aluminum speciation in biological environments, for which citrate is the main low molecular weight chelator, and responsible for its cellular in-take.

Non-Born-Oppenheimer electronic and nuclear densities for a Hooke-Calogero three-particle model: non-uniqueness of density-derived molecular structure.

We consider the calculation of non-Born-Oppenheimer, nBO, one-particle densities for both electrons and nuclei. We show that the nBO one-particle densities evaluated in terms of translationally invariant coordinates are independent of the wavefunction describing the motion of center of mass of the whole system. We show that they depend, however, on an arbitrary reference point from which the positions of the vectors labeling the particles are determined. We examine the effect that this arbitrary choice has on the topology of the one-particle density by selecting the Hooke-Calogero model of a three-body system for which expressions for the one-particle densities can be readily obtained in analytic form. We extend this analysis to the one-particle densities obtained from full Coulomb interaction wavefunctions for three-body systems. We conclude, in view of the fact that there is a close link between the choice of the reference point and the topology of one-particle densities that the molecular structure inferred from the topology of these densities is not unique. We analyze the behavior of one-particle densities for the Hooke-Calogero Born-Oppenheimer, BO, wavefunction and show that topological transitions are also present in this case for a particular mass value of the light particles even though in the BO regime the nuclear masses are infinite. In this vein, we argue that the change in topology caused by variation of the mass ratio between light and heavy particles does not constitute a true indication in the nBO regime of the emergence of molecular structure.

Homolytic molecular dissociation in natural orbital functional theory.

The dissociation of diatomic molecules of the 14-electron isoelectronic series N(2), O(2)(2+), CO, CN(-) and NO(+) is examined using the Piris natural orbital functional. It is found that the method describes correctly the dissociation limit yielding an integer number of electrons on the dissociated atoms, in contrast to the fractional charges obtained when using the variational two-particle reduced density matrix method under the D, Q and G positivity necessary N-representability conditions. The chemistry of the considered systems is discussed in terms of their dipole moments, natural orbital occupations and bond orders as well as atomic Mulliken populations at the dissociation limit. The values obtained agree well with accurate multiconfigurational wave function based CASSCF results and the available experimental data.

Pro-oxidant activity of aluminum: stabilization of the aluminum superoxide radical ion.

The pro-oxidant activity of aluminum, a nonredox metal, through superoxide formation is studied by theoretical methods, determining the ESR g-tensor values of O2(•­) with a variety of metals and the reaction energies for Al3+ superoxide affinity in solution. First, the intrinsic ability of aluminum to induce a splitting of the πg levels is compared to that of other significant biological metals, such as Na+, K+, Mg2+, and Ca2+. Additional properties such as bond lengths, ionization potentials, and electron affinities are also determined, and the coherency with the trends observed from ESR g-tensor values is analyzed. As it corresponds to the high charge and its small size, there is a strong interaction between Al3+ and the superoxide. We predict that this strong inherent interaction remains when aluminum is microsolvated. Finally, we analyze the possibility of Al3+ superoxide formation in solution, leading to the conclusion that substitution of the first coordination shell water molecules is plausible, but not of hydroxides. This points to the possibility of Al3+ superoxide formation in solution, which would be pH-dependent. Taking into account the earlier established linear relationship between metal­superoxide interactions and promoting effects in electron-transfer reactions, our work reinforces the idea that the presence of aluminum in biological systems could lead to an important pro-oxidant activity through a superoxide formation mechanism.

A natural orbital functional for multiconfigurational states.

An explicit formulation of the Piris cumulant λΔ,Π matrix is described herein, and used to reconstruct the two-particle reduced density matrix (2-RDM). Then, we have derived a natural orbital functional, the Piris Natural Orbital Functional 5, PNOF5, constrained to fulfill the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. This functional yields a remarkable accurate description of systems bearing substantial (near)degeneracy of one-particle states. The theory is applied to the homolitic dissociation of selected diatomic molecules and to the rotation barrier of ethylene, both paradigmatic cases of near-degeneracy effects. It is found that the method describes correctly the dissociation limit yielding an integer number of electrons on the dissociated atoms. PNOF5 predicts a barrier of 65.6 kcal/mol for the ethylene torsion in an outstanding agreement with Complete Active Space Second-order Perturbation Theory (CASPT2). The obtained occupation numbers and pseudo one-particle energies at the ethylene transition state account for fully degenerate π orbitals. The calculated equilibrium distances, dipole moments, and binding energies of the considered molecules are presented. The values obtained are accurate comparing those obtained by the complete active space self-consistent field method and the experimental data.

Gender-affirming hormone therapy in cystic fibrosis - A case of new Pseudomonas infection.

BACKGROUND: Little is known about the impact of hormone therapy on transgender youth with Cystic Fibrosis (CF). This case report describes an 18-year-old affirmed female with CF who was treated with hormone therapy associated in timing with new growth of Pseudomonas aeruginosa in her sputum culture. DISCUSSION: We highlight important considerations, including the impact of gender-affirming hormone therapy on overall CF disease course. Evidence supports that females with CF have worse outcomes than males, which are partly attributed to estrogen effects. Pseudomonas aeruginosa is one of the most prevalent pathogens in people with CF. Here, we highlight a transfemale who grows Pseudomonas aeruginosa for the first time since her youth, nearly 1 year after starting estrogen therapy. This is consistent with previous literature of an association between high estrogen levels and Pseudomonas aeruginosa prevalence, but has never been evaluated in a transgender population. CONCLUSION: Through this case, we demonstrate the need for additional research to understand the relationship between gender-affirmative hormone transition and CF care and management.

Impact of cadaveric practices on arthroscopic knee training for Orthopaedic Surgery and Traumatology residents. / Impacto de las prácticas cadavéricas en la formación artroscópica de rodilla de los residentes de Cirugía Ortopédica y Traumatología.

BACKGROUND AND OBJECTIVES: There currently is a considerable variability in the content of training programs and courses for orthopaedic surgeons in training. Besides this, there is still no consensus regarding which is the most effective methodology for improving learning of the technique or for its qualitative evaluation. A study was carried out to assess the influence of carrying out a cadaveric practical course on the acquisition of arthroscopic technical skills in fifth-year residents. MATERIAL AND METHODS: A knee arthroscopy cadaveric course was performed in which 48 students participated. Different technical aspects during a knee arthroscopy, as well as the residents skill and the execution time were evaluated before and after the course using a specific questionnaire. RESULTS: There was a significant statistic improvement between the initial and final evaluation, increasing from 11,7 till 17,1 (maximum 20) points. Also, a significant improvement in all the parameters analysed was observed; the identification of anatomic structures (p = 0.001), the palpation of specific structures (p = 0.032), and the time necessary for the arthroscopic knee check (p = 0.015). CONCLUSIONS: A knee arthroscopy cadaveric course improves significantly the technical skills of surgeons in training.

Performance of PNOF3 for reactivity studies: X[BO] and X[CN] isomerization reactions (X = H, Li) as a case study.

Natural Orbital Functional Theory in its PNOF3 implementation is used to investigate the potential energy surfaces of four isomerization reactions: (i) BOH to HBO; (ii) BOLi to LiBO; (iii) CNH to HCN; and (iv) CNLi to LiCN. These reactions are taken as a case study to illustrate the potentiality of PNOF3 to yield the correct topology for reactions sensible to electron correlation. The perfomance of PNOF3 to yield accurate reaction barriers and isomerization energies is also discussed. We have found that PNOF3 shows promising behaviour in the description of these delicate PESs, and yield the correct trends in isomerization energies and reaction barriers, although the latter trends tend to be somewhat lower than the ones calculated at highly correlated levels of theory. The present results show that PNOF3 can give a balanced description of electron correlation in both equilibrium and non-equilibrium structures.

Communications: Accurate description of atoms and molecules by natural orbital functional theory.

The spin-conserving density matrix functional theory is used to propose an improved natural orbital functional. The Piris reconstruction functional, PNOF, which is based on an explicit form of the two-particle cumulant lambda(Delta,Lambda) satisfying necessary positivity conditions for the two-particle reduced density matrix, is used to reconstruct the latter. A new approach Lambda((3)), as well as an extension of the known Delta(alphabeta) to spin-uncompensated systems lead to PNOF3. The theory is applied to the calculation of the total energies of the first- and second-row atoms (H-Ne) and a number of selected small molecules. The energy differences between the ground state and the lowest-lying excited state with different spin for these atoms, and the atomization energies of the considered molecules are also presented. The obtained values agree remarkably well with their corresponding both CCSD(T, full) and experimental values.

Communication: The role of the positivity N-representability conditions in natural orbital functional theory.

The positivity conditions for the N-representability of the reduced density matrices are considered to propose a new natural orbital functional. The Piris reconstruction functional, which is based on an explicit form of the two-particle cumulant λ(Δ,Π) is used to reconstruct the two-particle reduced density matrix. A new approach for Π matrix, satisfying rigorously D, Q, and G necessary conditions, leads to Piris Natural Orbital Functional 4 (PNOF4). The theory is applied to the dissociation of selected diatomic molecules. The equilibrium distances, dipole moments, harmonic frequencies, anharmonicity constants, and binding energies of the considered molecules are presented. The values we have obtained are very accurate results comparing with the experimental data.

Family history of diabetes impacts on interactions between minimal model estimates of insulin sensitivity and glucose effectiveness.

AIMS/HYPOTHESIS: Insulin resistance and glucose effectiveness (S(G)) are major determinants of glucose tolerance and independently predict the development of type 2 diabetes in individuals with a family history of disease. We examined the inter-relationship between insulin sensitivity (S(I)) and S(G) in offspring of two parents with type 2 diabetes and in individuals with no family history of diabetes. METHODS: Fifty non-diabetic individuals, including 26 offspring of two type 2 diabetic parents (family history, FH+) and 24 with no family history of diabetes (FH-) similar in gender, age, ethnicity and body mass index (BMI) were studied. Each subject underwent a 100-g oral glucose tolerance test (OGTT) and insulin modified frequently sampled intravenous glucose tolerance, analysed using the Bergman's minimal model (MINMOD). RESULTS: Thirteen subjects of the FH+ group and nine of the FH- group had impaired glucose tolerance (IGT). S(I) and S(G) were independent variables in the FH+ group, while they correlated highly with each other in the FH- group (r = 0.69, p = 0.0002). The relationship between S(I) and S(G) persisted when analysing the IGT and normal glucose tolerance subgroups separately, demonstrating that these associations were not because of differences in glycaemia. Consistently, S(G) strongly correlated with additional measures of insulin resistance only in the FH- group, including fasting insulin (r = 0.56, p = 0.004), homeostasis model assessment of insulin resistance (r = 0.57 p = 0.003) and BMI (r = 0.66, p = 0.0004). CONCLUSIONS: These results demonstrate that familial factors impart important physiological differences in the inter-relationship between insulin-dependent and insulin-independent glucose disposal, which may be important in modulating risk for development of disease.