Restricted mating dispersal and strong breeding group structure in a mid-sized marsupial mammal (Petrogale penicillata)

Ecological genetic studies have demonstrated that spatial patterns of mating dispersal, the dispersal of gametes through mating behaviour, can facilitate inbreeding avoidance and strongly influence the structure of populations, particularly in highly philopatric species. Elements of breeding group dynamics, such as strong structuring and sex-biased dispersal among groups, can also minimize inbreeding and positively influence levels of genetic diversity within populations. Rock-wallabies are highly philopatric mid-sized mammals whose strong dependence on rocky terrain has resulted in series of discreet, small colonies in the landscape. Populations show no signs of inbreeding and maintain high levels of genetic diversity despite strong patterns of limited gene flow within and among colonies. We used this species to investigate the importance of mating dispersal and breeding group structure to inbreeding avoidance within a 'small' population. We examined the spatial patterns of mating dispersal, the extent of kinship within breeding groups, and the degree of relatedness among brush-tailed rock-wallaby breeding pairs within a colony in southeast Queensland. Parentage data revealed remarkably restricted mating dispersal and strong breeding group structuring for a mid-sized mammal. Breeding groups showed significant levels of female kinship with evidence of male dispersal among groups. We found no evidence for inbreeding avoidance through mate choice; however, anecdotal data suggest the importance of life history traits to inbreeding avoidance between first-degree relatives. We suggest that the restricted pattern of mating dispersal and strong breeding group structuring facilitates inbreeding avoidance within colonies. These results provide insight into the population structure and maintenance of genetic diversity within colonies of the threatened brush-tailed rock-wallaby.

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders. © 2011 Elsevier Inc.

Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their firstdegree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states. Copyright © 2009 Society for Neuroscience.

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

Sense-making in theory and practice: a metatheoretical foundation and application for health information seeking

This thesis attempts to provide deeper historical and theoretical grounding for sense-making, thereby illustrating its applicability to practical information seeking research. In Chapter One I trace the philosophical origins of Brenda Dervin’s theory known as “sense making,” reaching beyond current scholarship that locates the origins of sense-making in twentieth-century Phenomenology and Communication theory and find its rich ontological, epistemological, and etymological heritage that dates back to the Pre-Socratics. After exploring sense-making’s Greek roots, I examine sense-making’s philosophical undercurrents found in Hegel’s Phenomenology of Spirit (1807), where he also returns to the simplicity of the Greeks for his concept of sense. With Chapter Two I explore sense-making methodology and find, in light of the Greek and Hegelian dialectic, a dialogical bridge connecting sense-making’s theory with pragmatic uses. This bridge between Dervin’s situation and use occupies a distinct position in sense-making theory. Moreover, building upon Brenda Dervin’s model of sense-making, I use her metaphors of gap and bridge analogy to discuss the dialectic and dialogic components of sense making. The purpose of Chapter Three is pragmatic – to gain insight into the online information-seeking needs, experiences, and motivation of first-degree relatives (FDRs) of breast cancer survivors through the lens of sense-making. This research analyses four questions: 1) information-seeking behavior among FDRs of cancer survivors compared to survivors and to undiagnosed, non-related online cancer information seekers in the general population, 2) types of and places where information is sought, 3) barriers or gaps and satisfaction rates FDRs face in their cancer information quest, and 4) types and degrees of cancer information and resources FDRs want and use in their information search for themselves and other family members. An online survey instrument designed to investigate these questions was developed and pilot tested. Via an email communication, the Susan Love Breast Cancer Research Foundation distributed 322,000 invitations to its membership to complete the survey, and from March 24th to April 5th 10,692 women agreed to take the survey with 8,804 volunteers actually completing survey responses. Of the 8,804 surveys, 95% of FDRs have searched for cancer information online, and 84% of FDRs use the Internet as a sense-making tool for additional information they have received from doctors or nurses. FDRs report needing much more information than either survivors or family/friends in ten out of fifteen categories related to breast and ovarian cancer. When searching for cancer information online, FDRs also rank highest in several of sense-making’s emotional levels: uncertainty, confusion, frustration, doubt, and disappointment than do either survivors or friends and family. The sense-making process has existed in theory and praxis since the early Greeks. In applying sense–making’s theory to a contemporary problem, the survey reveals unaddressed situations and gaps of FDRs’ information search process. FDRs are a highly motivated group of online information seekers whose needs are largely unaddressed as a result of gaps in available online information targeted to address their specific needs. Since FDRs represent a quarter of the population, further research addressing their specific online information needs and experiences is necessary.

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources

Actitudes hacia la Enfermedad del Alzheimer según el género y la edad de adultos colombianos

La enfermedad de Alzheimer (EA) es la demencia más frecuente y su prevalencia continúa en aumento tanto en Colombia como en el mundo. Esta investigación tuvo como objetivo explorar si las actitudes hacia la EA varían según la edad y género de 450 personas adultas colombianas. Se realizó un estudio exploratorio de corte transversal en el que se aplicó un cuestionario autodiligenciado. Se encontró que efectivamente hay algunas diferencias según la edad y el género en el componente cognoscitivo (creencias y conocimiento) y conductual (intención conductual y conducta) de las actitudes; y diferencias según el género en el componente afectivo. Se concluye que los conocimientos sobre la EA son escasos, que la tristeza es la emoción predominante hacia la EA y que es un tema de interés en el que predomina la idea de que afecta especialmente la memoria. Se discutieron los resultados reconociendo que esta es una aproximación inicial a las actitudes hacia la EA.

Investigation of IGF2/ApaI and H19/RsaI polymorphisms in patients with cutaneous melanoma

Objective: The etiology of cutaneous melanoma is complex, involving both heterogeneous genetic and environmental components. The aim of our study was to verify if single polymorphic sites within IGF2 and H19 genes and their consequent haplotypes influence risk and/or prognosis of familial melanoma. Design: Twenty one patients with clinical criteria of hereditary melanoma (early onset, presence of multiple primary melanoma, and/or one or more affected first- or second-degree relatives) and previously screened for CDKN2A mutations were genotyped by IGF2/ApaI and H19/RsaI PCR-RFLPs. Data were compared between patients and a control group (100 healthy young individuals) using Chi-square and Fisher`s exact tests. We also investigated if these polymorphic sites could be microRNAs potential targets, using RegRNA software. Results: Although the IGF2 and HI9 genotypes/haplotypes were not significantly associated with melanoma, two of the most severe cases (very early onset or multiple melanomas) showed to be heterozygous for both genes. We found an overlap between IGF2/ApaI and miR-615-5p, and between H19/RsaI and miR-574-3p. Conclusions: Some studies have shown H19, and IGF2 genes (or related genes or protein, for example, IGF2R and IMP-3) differential expression in melanoma. However, no study has attempted to examine markers across this cluster in relation to melanoma until now. Since the base change may impair the pairing of microRNA and its binding site, our results suggest a new window for future studies of IGF2 and H19 genetic variability and posttranscriptional regulation. Due to the importance and based on the present results, we suggest that the genotype/haplotype analysis of IGF2 and H19 polymorphisms should be better investigated in large populations with cutaneous melanoma, attempting to tie the association with progression of the disease. (C) 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.

PACHYCHOROID: an inherited condition?

PURPOSE: Thick choroid (pachychoroid) is associated with central serous chorioretinopathy (CSC), but whether pachychoroid is inherited is unknown. METHODS: In a prospective observational study, first- or second-degree relatives (16 individuals) of 5 patients with CSC had refraction and visual acuity measurement, fundus examination, nonmydriatic photography, and autofluorescence photography. Eyes were graded using the following criteria: 0: normal fundus and autofluorescence photography, 1: focal retinal pigment epithelium hyperfluorescence and/or hypofluorescence and/or retinal pigment epithelial detachment, 2: CSC or diffuse retinal epitheliopathy. Choroid thickness was measured by enhanced depth imaging mode on optical coherence tomography. RESULTS: Considering 395 μm as the threshold limit for normal subfoveal choroidal thickness, 50% of the eyes from relatives had a thick choroid. Nine eyes of Grade 0 (28%) with an isolated pachychoroid would thus have been considered normal, if choroidal thickness was not included as a screening sign predisposing for CSC. CONCLUSION: Our observation suggests that pachychoroid could be an inherited condition with potentially a dominant transmission mode. Its inclusion in the phenotype of CSC for genetic studies should be considered.

Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P = 0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs.

FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.

The P48T germline mutation and polymorphism in the CDKN2A gene of patients with melanoma

CDKN2A has been implicated as a melanoma susceptibility gene in some kindreds with a family history of this disease. Mutations in CDKN2A may produce an imbalance between functional p16ink4a and cyclin D causing abnormal cell growth. We searched for germline mutations in this gene in 22 patients with clinical criteria of hereditary cancer (early onset, presence of multiple primary melanoma or 1 or more first- or second-degree relatives affected) by secondary structural content prediction, a mutation scanning method that relies on the propensity for single-strand DNA to take on a three-dimensional structure that is highly sequence dependent, and sequencing the samples with alterations in the electrophoretic mobility. The prevalence of CDKN2A mutation in our study was 4.5% (1/22) and there was a correlation between family history and probability of mutation detection. We found the P48T mutation in 1 patient with 2 melanoma-affected relatives. The patient descends from Italian families and this mutation has been reported previously only in Italian families in two independent studies. This leads us to suggest the presence of a mutational "hotspot" within this gene or a founder mutation. We also detected a high prevalence (59.1%) of polymorphisms, mainly alleles 500 C/G (7/31.8%) or 540 C/T (6/27.3%), in the 3' untranslated region of exon 3. This result reinforces the idea that these rare polymorphic alleles have been significantly associated with the risk of developing melanoma.

Alcohol dehydrogenase 3 genotype as a risk factor for upper aerodigestive tract cancers

Objective: To assess alcohol dehydrogenase 3 (ADH3) polymorphism at position Ile349Val as indicator of risk factor for upper aerodigestive tract (UADT) cancer to verify its association with UADT cancer in nonalcoholic or nonsmoking individuals.Design: Cross-sectional study.Setting: Primary care or referral center.Patients: the study group consisted of 141 consecutive patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx admitted for surgical treatment. The comparison group consisted of 94 inpatients without cancer from the A. C. Camargo or other São Paulo (Brazil) hospital and 40 healthy individuals.Intervention: All participants were interviewed and data were collected using a structured questionnaire. After written informed consent was obtained, 20 mL of blood was collected in heparinized tubes.Main Outcome Measures: Odds ratio for ADH3 genotypes using logistic regression models.Results: After adjustment for sex, age, tobacco use, and history of cancer in first-degree family relatives, a significantly higher odds ratio for UADT cancer was observed among individuals with AA genotype and low cumulative alcohol consumption (:5 100 kg of ethanol) (odds ratio=3.8 [95% confidence interval, 1.5-9.7]). A 4-fold increase in odds ratio for UADT cancer among individuals with AA genotype and low tobacco consumption (:525 pack-years) was also found in the adjusted model.Conclusions: These results suggest that genotype AA may be a risk factor for UADT cancer, especially in individuals with low alcohol or tobacco consumption. However, further epidemiological case-control or cohort studies, preferably prospective, are needed to establish the exact role of ADH3 polymorphism and its association with the development of UADT cancers.

Relative contributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity(P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity(P = .37). beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity tall, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity(P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity land glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians. Copyright (C) 2000 by W.B. Saunders Company.