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The pancreatic β-cell responds to changes in the nutrient environment to maintain glucose homeostasis by adapting its function and mass. Nutrients can act directly on the β-cell and also indirectly through the brain via autonomic nerves innervating islets. Despite the importance of the brain-islet axis in insulin secretion, relatively little is known regarding its involvement in β-cell proliferation. We previously demonstrated that prolonged infusions of nutrients in rats provoke a dramatic increase in β-cell proliferation in part because of the direct action of nutrients. Here, we addressed the contribution of the autonomic nervous system. In isolated islets, muscarinic stimulation increased, whereas adrenergic stimulation decreased, glucose-induced β-cell proliferation. Blocking α-adrenergic receptors reversed the effect of epinephrine on glucose + nonesterified fatty acids (NEFA)-induced β-cell proliferation, whereas activation of α-adrenergic receptors was without effect. Infusion of glucose + NEFA toward the brain stimulated β-cell proliferation, and this effect was abrogated following celiac vagotomy. The increase in β-cell proliferation following peripheral infusions of glucose + NEFA was not inhibited by vagotomy or atropine treatment but was blocked by coinfusion of epinephrine. We conclude that β-cell proliferation is stimulated by parasympathetic and inhibited by sympathetic signals. Whereas glucose + NEFA in the brain stimulates β-cell proliferation through the vagus nerve, β-cell proliferation in response to systemic nutrient excess does not involve parasympathetic signals but may be associated with decreased sympathetic tone. [ABSTRACT FROM AUTHOR]

The present study attempted to identify individual and contextual factors associated with outcomes in a group of 63 latency-aged children disclosing sexual abuse (SA). Children reporting SA were found to display greater internalizing and externalizing behavioral difficulties as well as more sexualized behaviors relative to same-age non-abused peers. Mothers also reported these children as less socially competent than their peers. Family contextual factors appeared to be associated with behavioral difficulties and made a unique contribution to the prediction of externalizing and sexualized behaviors. Of the personal variables, avoidance coping was found to be linked to poorer outcomes. In examining possible factors linked to ‘resilient’ outcomes in a 6-month time-frame, family conflict and avoidance coping were found to be associated to clinical status in children reporting SA. [ABSTRACT FROM AUTHOR]

Examines the role of hepatic apolipoprotein (apo) E in low- and high-density lipoprotein (LDL and HDL) metabolism in HepG2 cells. Effects of reduced apoE level on LDL-protein association and degradation; Involvement of hepatic apoE in cholesteryl esters selective uptake pathways; Correlation of apoE level with HDL[sub 3] holoparticle uptake.

Evaluates the adjustment of sexually abused children according to the revised posttraumatic stress disorder (PTSD) model in Montreal, Quebec. Participation of abused children under the Child Protection Clinic of Ste-Justine Hospital; Measures of the PTSD type I and type II symptoms; Employment of the History of Victimization Scale for abuse-related cases.

Objective: The main objective of this study was to evaluate the mediator role of coping strategies and social support on the adaptation of children following CSA. Empirical studies indicate that short-term consequences of child sexual abuse (CSA) are multiple and varied (Kendall-Tackett, Williams, & Finkelhor, 1993; Wolfe & Birt, 1995). While abuse-related characteristics were first studied to explain the variability of CSA outcome, more recently, the influence of other variables such as coping strategies and social support have been considered. Method: Fifty sexually abused children aged between 7 and 12 participated in this study. The Child Behavior Checklist (Achenbach, 1991) and the Perceived Competence Scale for Children (Hatter, 1985) were used to measure victims' adjustment. Coping strategies were evaluated by the Self-Report Coping Scale (Causey & Dubow, 1992) and the children completed the Perceived Social Support (Halter, 1985). A French version of the History of Victimization (Wolfe, Gentile, & Bourdeau, 1987) was used to gather abuse-related characteristics from medical records. Results: Results indicate that sexually abused children exhibit internalizing and externalizing behavior problems following CSA. Coping strategies and social support exert direct effects on victims' adjustment instead of the mediator influences originally expected. Among abuse-related variables, only the perpetrator's identity is directly related to internalizing symptoms. Conclusions: The absence of mediational effects of coping and social support is discussed in light of the measures used and the cross-sectional nature of the study. Results highlight the importance of parental implication and the consideration of coping strategies in designing therapeutic interventions with this population. [ABSTRACT FROM AUTHOR]

The potential to treat diabetes by increasing beta-cell mass is driving a major effort to identify beta-cell mitogens. Demonstration of mitogen activity in human beta cells is frequently performed in ex vivo assays. However, reported disparities in the efficacy of beta-cell mitogens led us to investigate the sources of this variability. We studied 35 male (23) and female (12) human islet batches covering a range of donor ages and BMI. Islets were kept intact or dispersed into single cells and cultured in the presence of harmine, glucose, or heparin-binding epidermal growth factor-like growth factor (HB-EGF), and subsequently analyzed by immunohistochemistry or flow cytometry. Proliferating cells were identified by double labeling with EdU and Ki67 and glucagon, c-peptide or Nkx6.1, and cytokeratin-19 to respectively label alpha, beta, and ductal cells. Harmine and HB-EGF stimulated human beta-cell proliferation, but the effect of glucose was dependent on the assay and the donor. Harmine potently stimulated alpha-cell proliferation and both harmine and HB-EGF increased proliferation of insulin- and glucagon-negative cells, including cytokeratin 19-positive cells. Given the abundance of non-beta cells in human islet preparations, our results suggest that assessment of beta-cell mitogens requires complementary approaches and rigorous identification of cell identity using multiple markers. [ABSTRACT FROM AUTHOR]

The article presents an interview with American psychologist and author Harlene Anderson. Topics discussed include relation of Anderson and Harry Goolishian, Anderson's experience of working in a community mental health center which offers experience of learning family therapy and understanding the identity of people in social context, and her re-involvement with writing.

The article presents an interview with philosopher Harlene Anderson. She said that collaborative philosophy and practices reflect a view of ethics that have been historically, culturally, contextually and communally created. She also said that the postmodern offers a different way of thinking about the nature of meaning and knowledge to develop the transformation of that knowledge is a communal process.

This study examined maternal perceptions of their child's response to the medical evaluation for alleged sexual abuse. A total of 50 mothers were interviewed 6 months after a visit to a Child Protection Clinic for a medical evaluation of alleged sexual abuse. The mothers answered a questionnaire on their child's reactions to the medical visit. More than 60% of children were perceived as being reassured about physical integrity. The degree of psychological distress was independent of perpetrator's identity and severity of the abuse. Mothers considered that a hypothetical second visit would generate in their child a level of anxiety that increased with perceived intensity of fear of the examination and decreased with perceived kindness of the physician. These results suggest that the physician's behaviour during the medical evaluation for alleged sexual abuse has an influence on the child's degree of distress that is independent of type and severity of abuse. Copyright © 2001 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Investigates the uptake and fate of class B scavenger receptor (SR-B) ligands in HepG2 (human hepatoma) cells. Performance of saturation binding experiments; Revelation of moderate-affinity binding sites for all SR-B ligands; Involvement of catabolism CD36 ligands in the process in HepG2 cells.

FFAR1/GPR40 is a seven-transmembrane domain receptor (7TMR) expressed in pancreatic β cells and activated by FFAs. Pharmacological activation of GPR40 is a strategy under consideration to increase insulin secretion in type 2 diabetes. GPR40 is known to signal predominantly via the heterotrimeric G proteins Gq/11. However, 7TMRs can also activate functionally distinct G protein-independent signaling via β-arrestins. Further, G protein- and β-arrestin-based signaling can be differentially modulated by different ligands, thus eliciting ligand-specific responses ("biased agonism"). Whether GPR40 engages β- arrestin-dependent mechanisms and is subject to biased agonism is unknown. Using bioluminescence resonance energy transfer-based biosensors for real-time monitoring of cell signaling in living cells, we detected a ligand-induced GPR40-β- arrestin interaction, with the synthetic GPR40 agonist TAK-875 being more effective than palmitate or oleate in recruitingβ-arrestins 1 and 2. Conversely, TAK-875 acted as a partial agonist of Gq/11-dependent GPR40 signaling relative to both FFAs. Pharmacological blockade of Gq activity decreased FFA-induced insulin secretion. In contrast, knockdown or genetic ablation of β-arrestin 2 in an insulin-secreting cell line and mouse pancreatic islets, respectively, uniquely attenuated the insulinotropic activity of TAK-875, thus providing functional validation of the biosensor data. Collectively, these data reveal that in addition to coupling to Gq/11, GPR40 is functionally linked to a β-arrestin 2-mediated insulinotropic signaling axis. These observations expose previously unrecognized complexity for GPR40 signal transduction and may guide the development of biased agonists showing improved clinical profile in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Prolonged exposure of pancreatic beta-cells to simultaneously elevated levels of fatty acids and glucose (glucolipotoxicity) impairs insulin gene transcription. However, the intracellular signaling pathways mediating these effects are mostly unknown. This study aimed to ascertain the role of extracellular-regulated kinases (ERKs)1/2, protein kinase B (PKB), and Per-Arnt-Sim kinase (PASK) in palmitate inhibition of insulin gene expression in pancreatic beta-cells.Research Design and Methods: MIN6 cells and isolated rat islets were cultured in the presence of elevated glucose, with or without palmitate or ceramide. ERK1/2 phosphorylation, PKB phosphorylation, and PASK expression were examined by immunoblotting and real-time PCR. The role of these kinases in insulin gene expression was assessed using pharmacological and molecular approaches.Results: Exposure of MIN6 cells and islets to elevated glucose induced ERK1/2 and PKB phosphorylation, which was further enhanced by palmitate. Inhibition of ERK1/2, but not of PKB, partially prevented the inhibition of insulin gene expression in the presence of palmitate or ceramide. Glucose-induced expression of PASK mRNA and protein levels was reduced in the presence of palmitate. Overexpression of wild-type PASK increased insulin and pancreatic duodenal homeobox-1 gene expression in MIN6 cells and rat islets incubated with glucose and palmitate, whereas overexpression of a kinase-dead PASK mutant in rat islets decreased expression of insulin and pancreatic duodenal homeobox-1 and increased C/EBPbeta expression.Conclusions: Both the PASK and ERK1/2 signaling pathways mediate palmitate inhibition of insulin gene expression. These findings identify PASK as a novel mediator of glucolipotoxicity on the insulin gene in pancreatic beta-cells. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Prolonged exposure of pancreatic β-cells to simultaneously elevated levels of fatty acids and glucose (glucolipotoxicity) impairs insulin gene transcription. However, the intracellular signaling pathways mediating these effects are mostly unknown. This study aimed to ascertain the role of extracellular-regulated kinases (ERKs)1/2, protein kinase B (PKB), and Per-Arnt-Sim kinase (PASK) in palmitate inhibition of insulin gene expression in pancreatic β-cells. RESEARCH DESIGN AND METHODS--MIN6 cells and isolated rat islets were cultured in the presence of elevated glucose, with or without palmitate or ceramide. ERK1/2 phosphorylation, PKB phosphorylation, and PASK expression were examined by immunoblotting and real-time PCR. The role of these kinases in insulin gene expression was assessed using pharmacological and molecular approaches. RESULTS--Exposure of MIN6 cells and islets to elevated glucose induced ERK1/2 and PKB phosphorylation, which was further enhanced by palmitate. Inhibition of ERK1/2, but not of PKB, partially prevented the inhibition of insulin gene expression in the presence of palmitate or ceramide. Glucose-induced expression of PASK mRNA and protein levels was reduced in the presence of palmitate. Overexpression of wild-type PASK increased insulin and pancreatic duodenal homeobox-1 gene expression in MIN6 cells and rat islets incubated with glucose and palmitate, whereas overexpression of a kinase-dead PASK mutant in rat islets decreased expression of insulin and pancreatic duodenal homeobox-1 and increased C/EBPβ expression. CONCLUSIONS--Both the PASK and ERK1/2 signaling pathways mediate palmitate inhibition of insulin gene expression. These findings identify PASK as a novel mediator of glucolipotoxicity on the insulin gene in pancreatic β-cells. Diabetes 58: 2048-2058, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--The G-protein-coupled receptor GPR40 is expressed in pancreatic β-cells and is activated by long-chain fatty acids. Gene deletion studies have shown that GPR40 mediates, at least in part, fatty acid-amplification of glucose-induced insulin secretion (GSIS) but is not implicated in GSIS itself. However, the role of GPR40 in the long-term effects of fatty acids on insulin secretion remains controversial. This study aimed to test the hypothesis that GPR40 plays a role in insulin secretion after high-fat feeding. RESEARCH DESIGN AND METHODS--GPR40 knockout (KO) mice on a C57BL/6 background and their wild-type (WT) littermates were fed a high-fat diet (HFD) for 11 weeks. Glucose tolerance, insulin tolerance, and insulin secretion in response to glucose and Intralipid were assessed during the course of the diet period. RESULTS--GPR40 KO mice had fasting hyperglycemia. They became as obese, glucose intolerant, and insulin resistant as their WT littermates given HFD and developed a similar degree of liver steatosis. Their fasting blood glucose levels increased earlier than those of control mice during the course of the HFD. The remarkable increase in insulin secretory responses to intravenous glucose and Intralipid seen in WT mice after HFD was of much lower magnitude in GPR40 KO mice. CONCLUSIONS--GPR40 plays a role not only in fatty acid modulation of insulin secretion, but also in GSIS after high-fat feeding. These observations raise doubts on the validity of a therapeutic approach based on GPR40 antagonism for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids, in the presence of high glucose, impairs insulin gene expression via a transcriptional mechanism involving nuclear exclusion of pancreas-duodenum homeobox-1 (Pdx-1) and loss of MafA expression. Whether such a phenomenon also occurs in vivo is unknown. Our objective was therefore to ascertain whether chronic nutrient oversupply inhibits insulin gene expression in vivo. RESEARCH DESIGN AND METHODS--Wistar rats received alternating 4-h infusions of glucose and Intralipid for a total of 72 h. Control groups received alternating infusions of glucose and saline, saline and Intralipid, or saline only. Insulin and C-peptide secretion were measured under hyperglycemic clamps. Insulin secretion and gene expression were assessed in isolated islets, and β-cell mass was quantified by morphometric analysis. RESULTS--Neither C-peptide secretion nor insulin sensitivity was different among infusion regimens. Insulin content and insulin mRNA levels were lower in islets isolated from rats infused with glucose plus Intralipid. This was associated with reduced Pdx-1 binding to the endogenous insulin promoter, and an increased proportion of Pdx-1 localized in the cytoplasm versus the nucleus. In contrast, MafA mRNA and protein levels and β-cell mass and proliferation were unchanged. CONCLUSIONS--Cyclical and alternating infusions of glucose and Intralipid in normal rats inhibit insulin gene expression without affecting insulin secretion or β-cell mass. We conclude that fatty acid inhibition of insulin gene expression, in the presence of high glucose, is an early functional defect that may contribute to β-cell failure in type 2 diabetes. Diabetes 57: 424-431, 2008 [ABSTRACT FROM AUTHOR]

Long-chain fatty acids amplify insulin secretion from the pancreatic βcell. The G-protein--coupled receptor GPR40 is specifically expressed in β-cells and is activated by fatty acids; however, its role in acute regulation of insulin secretion in vivo remains unclear. To this aim, we generated GPR40 knockout (KO) mice and examined glucose homeostasis, insulin secretion in response to glucose and Intralipid in vivo, and insulin secretion in vitro after short-and long-term exposure to fatty acids. Our results show that GPR40 KO mice have essentially normal glucose tolerance and insulin secretion in response to glucose. Insulin secretion in response to Intralipid was reduced by ∼50%. In isolated islets, insulin secretion in response to glucose and other secretagogues was unaltered, but fatty acid potentiation of insulin release was markedly reduced. The Gα[sub q/11] inhibitor YM-254890 dose-dependently reduced palmitate potentiation of glucose-induced insulin secretion. Islets from GPR40 KO mice were as sensitive to fatty acid inhibition of insulin secretion upon prolonged exposure as islets from wild-type animals. We conclude that GPR40 contributes approximately half of the full acute insulin secretary response to fatty acids in mice but does not play a role in the mechanisms by which fatty acids chronically impair insulin secretion. Diabetes 56:1087-1094, 2007 [ABSTRACT FROM AUTHOR]

Puberty is a time of hormonal changes associated with insulin resistance (IR). Although insulin sensitivity is restored at the end of puberty in healthy youth, it does not resolve in obese adolescents leading to an increased risk of metabolic disease such as T2D. During pregnancy-induced IR, pancreatic β cells increase their functional mass to maintain glucose homeostasis. During puberty, however, the mechanism of β-cell compensation to IR and its role in glucose metabolism in adulthood have not been established. In this study we characterized pancreatic β-cell adaptation to pubertal IR in rats and evaluated the effect of metabolic stress during puberty on glucose homeostasis in adult animals. Methods: Wistar rats were fed a chow or high fat diet (HFD) during puberty. Fasted plasma insulin and glucose tolerance were determined from weaning to adulthood. β-cell proliferation was assessed by immunostaining of pancreatic cryosections for Ki67 and insulin or Nkx6.1. β-cell mass was measured by morphometric analysis of insulin staining. Isolated islets from Wistar rats were exposed during 72h to the serum of prepubertal, pubertal, or postpubertal animals and β-cell proliferation was evaluated by flow cytometry using insulin and EdU antibodies. Results: During puberty, glucose intolerance was associated with an increase in insulin levels, suggestive of IR. Accordingly, puberty was characterized by a pulse in β-cell proliferation and a rise in β-cell mass. Pubertal but not pre or post pubertal rat serum induced β-cell proliferation in isolated islets. HFD led to a decrease in β-cell proliferation during puberty with impaired glucose tolerance and defective insulin secretion in adult animals. Conclusion: During puberty in rats, β cells proliferate to compensate for IR. Metabolic stress during puberty impairs glucose homeostasis later in life. Future studies will identify the circulating factor(s) that trigger β-cell expansion during puberty. Disclosure: A. Castell: None. G. Fergusson: None. M. Ethier: None. C. Tremblay: None. J. Ghislain: None. V. Poitout: None. [ABSTRACT FROM AUTHOR]