Mélanie Béland

Association of diabetes with anxiety: A systematic review and meta-analysis

OBJECTIVES Anxiety has been shown to be associated with poor outcomes in people with diabetes. However, there has been little research which has specifically examined whether diabetes mellitus is associated with an increased likelihood of co-morbid anxiety. The aim of this systematic review and meta-analysis was to determine whether people with diabetes are more likely to have anxiety disorders or elevated anxiety symptoms than people who do not have diabetes. METHODS A systematic review was performed by three independent reviewers who searched for articles that examined the association between anxiety and diabetes in adults 16 or older. Those studies that met eligibility criteria were put forward for meta-analysis using a random-effects model. RESULTS A total of twelve studies with data for 12,626 people with diabetes were eligible for inclusion in the systematic review and meta-analysis. Significant and positive associations were found for diabetes with both anxiety disorders, 1.20 (1.10-1.31), and elevated anxiety symptoms, 1.48 (1.02-1.93). The pooled OR for all studies that assessed anxiety was 1.25 (1.10-1.39). CONCLUSIONS Results from this meta-analysis provide support that diabetes is associated with an increased likelihood of having anxiety disorders and elevated anxiety symptoms.

Cdx1 Autoregulation Is Governed by a Novel Cdx1-LEF1 Transcription Complex

ABSTRACT The Cdx1 gene product is essential for normal anterior-posterior vertebral patterning. Expression of Cdx1 is regulated by several pathways implicated in anterior-posterior patterning events, including retinoid and Wnt signaling. We have previously shown that retinoic acid plays a key role in early stages of Cdx1 expression at embryonic day 7.5 (E7.5), while both Wnt3a signaling and an autoregulatory loop, dependent on Cdx1 itself, are involved in later stages of expression (E8.5 to E9.5). This autoregulation is reflected by the ability of Cdx1 to affect expression from proximal Cdx1 promoter sequences in tissue culture. However, this region is devoid of a demonstrable Cdx response element(s). We have now found that Cdx1 and LEF1, a nuclear effector of Wnt signaling, synergize to induce expression from the Cdx1 promoter through previously documented LEF/T-cell factor response elements. We also found a direct physical interaction between the homeodomain of Cdx1 and the B box of LEF1, suggesting a basis for this synergy. Consistent with these observations, analysis of Cdx1 Wnt3avt compound mutants demonstrated that Wnt and Cdx1 converged on Cdx1 expression and vertebral patterning in vivo. Further data suggest that Cdx-high-mobility group box interactions might be involved in a number of additional pathways.

Exploring the Association of Psychological Status with Self-Rated Diabetes Control: Results from the Montreal Evaluation of Diabetes Treatment Study

AIMS There is an increasing interest in single-item self-rated indicators of perceived health and control status in people with chronic illnesses such as diabetes. However, self-rated measures can be associated with indicators of psychological status. The aim of this paper is to explore the association of anxiety, depression, and diabetes distress with self-rated diabetes control. METHODS Telephone interviews were conducted with 1,787 people with type 2 diabetes taking oral hypoglycemic medication. Diabetes control, health behaviors, and outcomes, anxiety, depression, and diabetes distress were assessed by standardized questionnaires. Self-reported diabetes control was modeled using logistic regression. RESULTS The best fit logistic regression model for self-rated poor diabetes control was a model that incorporated diabetes distress. When adjusted for age, sex, and all other health behaviors and outcomes, poor diabetes control was most associated with diabetes distress, physical inactivity, being overweight, and poor eating habits. CONCLUSIONS Results from this study indicate that poor self-rated diabetes control shares the strongest associations with diabetes-specific distress along with perceptions of diabetes-specific healthcare behaviors and outcomes.

Chicken Ovalbumin Upstream Promoter-Transcription Factor Members Repress Retinoic Acid-induced Cdx1 Expression

It is well established that Hox genes are key players in specifying positional identity along the anterior-posterior axis and are targets of diverse transcription factors implicated in axial patterning. Members of the CDX family (CDX1, -2, and -4) are among such effectors of Hox expression as pertains to vertebral patterning in the mouse. Cdx members are themselves targets of signaling molecules that are also implicated in axial patterning, including retinoic acid (RA) and certain members of Wnt and fibroblast growth factor families. In this regard, we have previously shown that, in the mouse, Cdx1 is directly regulated by RA at the late primitive streak stage (embryonic day (E) 7.5) through a RA response element in the proximal Cdx1 promoter. At E8.5, Cdx1 expression remains essentially limited to the posterior embryo. RA, however, is excluded from the caudal embryo at this later stage, but is found in a more anterior domain encompassing the prospective trunk region. These observations suggest the existence of a repressor mechanism that prevents expression of Cdx1 in these anterior domains of retinoid signaling at E8.5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element. Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded. Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo.

Male-biased aganglionic megacolon in the TashT mouse line due to perturbation of silencer elements in a large gene desert of chromosome 10.

Neural crest cells (NCC) are a transient migratory cell population that generates diverse cell types such as neurons and glia of the enteric nervous system (ENS). Via an insertional mutation screen for loci affecting NCC development in mice, we identified one line—named TashT—that displays a partially penetrant aganglionic megacolon phenotype in a strong male-biased manner. Interestingly, this phenotype is highly reminiscent of human Hirschsprung’s disease, a neurocristopathy with a still unexplained male sex bias. In contrast to the megacolon phenotype, colonic aganglionosis is almost fully penetrant in homozygous TashT animals. The sex bias in megacolon expressivity can be explained by the fact that the male ENS ends, on average, around a “tipping point” of minimal colonic ganglionosis while the female ENS ends, on average, just beyond it. Detailed analysis of embryonic intestines revealed that aganglionosis in homozygous TashT animals is due to slower migration of enteric NCC. The TashT insertional mutation is localized in a gene desert containing multiple highly conserved elements that exhibit repressive activity in reporter assays. RNAseq analyses and 3C assays revealed that the TashT insertion results, at least in part, in NCC-specific relief of repression of the uncharacterized gene Fam162b; an outcome independently confirmed via transient transgenesis. The transcriptional signature of enteric NCC from homozygous TashT embryos is also characterized by the deregulation of genes encoding members of the most important signaling pathways for ENS formation—Gdnf/Ret and Edn3/Ednrb—and, intriguingly, the downregulation of specific subsets of X-linked genes. In conclusion, this study not only allowed the identification of Fam162b coding and regulatory sequences as novel candidate loci for Hirschsprung’s disease but also provides important new insights into its male sex bias.

Self-rated diabetes control in a Canadian population with type 2 diabetes: associations with health behaviours and outcomes.

AIMS Diabetes control is a multifaceted process involving successful adherence to a self-care regimen as indicated by improved health outcomes. The aim of this study was to ascertain the construct validity of self-reported diabetes control in a population-based survey. METHODS This study assessed 1848 participants with type 2 diabetes who took part in the Montreal Diabetes Health and Wellbeing Study in Quebec, Canada. Participants were administered the diabetes complications index as well as sociodemographic and health questions. RESULTS Fair/poor diabetes control was associated with being less likely to check blood glucose weekly, being less likely to drink alcohol, being more likely to report being physically inactive, reporting fair/poor eating habits, being obese and having 1 or more diabetes complications. When all variables were included in a regression model the two variables most strongly associated with poor fair/poor diabetes control were reporting fair/poor eating habits (odds ratio 1.36, 95% CI 1.00-1.85) and having 2 or more diabetes complications (odds ratio 1.60, 95% CI 1.06-2.40). CONCLUSIONS Results from this study indicate that self-rated diabetes control has associations with diabetes-specific self-care behaviours and outcomes, and is a general indicator of self-care and diabetes-related complications in a population-based survey.

An Ebox element in the proximal Gata4 promoter is required for Gata4 expression in vivo.

GATA4 is an essential transcription factor required for the development and function of multiple tissues, including a major role in gonadogenesis. Despite its crucial role, the molecular mechanisms that regulate Gata4 expression in vivo remain poorly understood. We recently found that the Gata4 gene is expressed as multiple transcripts with distinct 5′ origins. These co-expressed alternative transcripts are generated by different non-coding first exons with transcripts E1a and E1b being the most prominent. Moreover, we previously showed that an Ebox element, located in Gata4 5′ flanking sequences upstream of exon 1a, is important for the promoter activity of these sequences in cell lines. To confirm the importance of this element in vivo, we generated and characterized Gata4 Ebox knockout mice. Quantitative PCR analyses realized on gonads, heart and liver at three developmental stages (embryonic, pre-pubertal and adult) revealed that the Ebox mutation leads to a robust and specific decrease (up to 89%) of Gata4 E1a transcript expression in all tissues and stages examined. However, a detailed characterization of the gonads revealed normal morphology and GATA4 protein levels in these mutants. Our qPCR data further indicate that this outcome is most likely due to the presence of Gata4 E1b mRNA, whose expression levels were not decreased by the Ebox mutation. In conclusion, our work clearly confirms the importance of the proximal Ebox element and suggests that adequate GATA4 protein expression is likely protected by a compensation mechanism between Gata4 E1a and E1b transcripts operating at the translational level.

Lineage Specification from Prostate Progenitor Cells Requires Gata3-Dependent Mitotic Spindle Orientation

Summary During prostate development, basal and luminal cell lineages are generated through symmetric and asymmetric divisions of bipotent basal cells. However, the extent to which spindle orientation controls division symmetry or cell fate, and the upstream factors regulating this process, are still elusive. We report that GATA3 is expressed in both prostate basal progenitor and luminal cells and that loss of GATA3 leads to a mislocalization of PRKCZ, resulting in mitotic spindle randomization during progenitor cell division. Inherently proliferative intermediate progenitor cells accumulate, leading to an expansion of the luminal compartment. These defects ultimately result in a loss of tissue polarity and defective branching morphogenesis. We further show that disrupting the interaction between PRKCZ and PARD6B is sufficient to recapitulate the spindle and cell lineage phenotypes. Collectively, these results identify a critical role for GATA3 in prostate lineage specification, and further highlight the importance of regulating spindle orientation for hierarchical cell lineage organization.

Cdx1 Interacts Physically with a Subset of Hox Proteins

Cdx and Hox gene families encode homeodomain-containing transcription factors involved in anterior-posterior vertebral patterning. Although Cdx proteins are direct transcriptional regulators of Hox gene expression, both Hox and Cdx proteins are known to interact with other homeodomain transcription factors, leading us to speculate that Cdx and Hox proteins may also interact physically. In testing this, we found that that Cdx1 is indeed capable of associating with a subset of Hox proteins. This interaction is localized to the homeodomain region of both classes of proteins, is reliant on specific arginine residues in helix I of the Hox homeodomain, and is further modulated by N-terminal Hox sequences. More promiscuous interactions were seen with Hox proteins expressed in vivo, suggestive of bridging factors or post-translational modifications. Finally, we demonstrate that this interaction modulates Cdx-Hox transcriptional activity on a Hox-responsive element. This study is the first example of Cdx-Hox protein interactions and suggests that such complexes may modulate Hox and/or Cdx function.

Abstract A54: CnABP, a novel modulator of the Calcineurin‐NFAT signaling pathway, is overexpressed in Wilms' tumors and promotes cell migration

Wilms9 tumor (WT) is a classical cancer type that arises from abnormal differentiation of kidney progenitor cells, and occurs at a frequency of 1 in 10,000 live births, accounting for approx. 90% of childhood kidney cancer. Abnormally high levels of Pax2 (paired‐box protein 2), a key regulator of kidney development, have been observed in both WT and renal cell carcinoma, which correlate with proliferation and increased invasiveness. Therefore the misexpression of Pax2 and its target genes may play an important role in tumor initiation and/or progression. To test this, we screened for target genes of Pax2 by cDNA microarray in the embryonic kidney. We identified CnABP (Calcineurin A Binding Protein), a novel gene under Pax2 regulation. In situ hybridization indicates that CnABP coexpresses with Pax2 in the condensing mesenchyme, the abnormal differentiation of which gives rise to WT. Furthermore, expression analysis by quantitative PCR indicates that CnABP is overexpressed in more than 70% of Wilms9 tumors. Interestingly, in the proportion of tumors with upregulated PAX2 expression, more than 80% also overexpress CnABP. We characterized CnABP as a membrane‐anchored protein that primarily promotes cell proliferation and migration. Mediators of these activities were investigated by Yeast‐two‐hybrid and immunoprecipitation, which identified an interaction between CnABP and Calcineurin A, the catalytic subunit of a calcium‐responsive serine/threonine phosphatase Calcineurin. We showed that CnABP modulates phosphatase activities of Calcineurin, which consequently inhibits calcium/Calcineurin‐dependent NFAT nuclear translocation. We further demonstrated that the inhibition of NFAT nuclear localization results in reduced NFAT‐specific transcriptional activity. Components of the Calcineurin complex have been reported as differentially expressed genes distinguishing recurrent from non‐recurrent Wilms9 tumors. This is in line with the evidence we presented, as CnABP is upregulated in Wilms9 tumors and is shown to promote proliferation and migration. Citation Information: Cancer Res 2009;69(23 Suppl):A54.