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Che-Pei Kung Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA

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Maureen E Murphy Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA

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In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53’s role in metabolism may also be consequential to tumor suppression. Here, we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single-nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic.

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M. REISS
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R. E. HEMPHILL
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B. M. MURPHY
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J. M. HALKERSTON
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F. E. BADRICK
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Tracer methods with radioactive iodine have been employed in recent years to assess human thyroid function. Some authors measured the uptake of I131 by the thyroid, [Hamilton & Soley, 1940; Hertz, Roberts & Salter, 1942; Rawson, Evans, Means, Peacock, Lerman & Cortell, 1944; and others]: other authors measured the excretion [Hamilton & Soley, 1939; Keating, Power, Berkson & Haines, 1947; Skanse, 1948; and others]. Extensive investigations have been carried out with the help of radioactive iodine on the iodine metabolism in the thyroid function of animals (recently reviewed by Rawson & McArthur [1947]; Chaikoff & Taurog [1948] and Hevesy [1948]). The results of these experiments have so far been utilized only in a very restricted way for diagnostic purposes on human patients.

Although various tracer doses, with and without carrier, have been used, up to the present no standardized routine method for the investigation of patients has been developed.

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Daniel J Tobiansky Department of Psychology, The University of British Columbia
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada

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George V Kachkovski Department of Psychology, The University of British Columbia

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Reilly T Enos Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA

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Kim L Schmidt Department of Psychology, The University of British Columbia

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E Angela Murphy Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA

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Kiran K Soma Department of Psychology, The University of British Columbia
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
Department of Zoology, The University of British Columbia, Vancouver, British Columbia, Canada

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Sucrose consumption is associated with type 2 diabetes, cardiovascular disease, and cognitive deficits. Sucrose intake during pregnancy might have particularly prominent effects on metabolic, endocrine, and neural physiology. It remains unclear how consumption of sucrose affects parous females, especially in brain circuits that mediate food consumption and reward processing. Here, we examine whether a human-relevant level of sucrose before, during, and after pregnancy (17–18 weeks total) influences metabolic and neuroendocrine physiology in female rats. Females were fed either a control diet or a macronutrient-matched, isocaloric sucrose diet (25% of kcal from sucrose). Metabolically, sucrose impairs glucose tolerance, increases liver lipids, and increases a marker of adipose inflammation, but has no effect on body weight or overall visceral adiposity. Sucrose also decreases corticosterone levels in serum but not in the brain. Sucrose increases progesterone levels in serum and in the brain and increases the brain:serum ratio of progesterone in the mesocorticolimbic system and hypothalamus. These data suggest a dysregulation of systemic and local steroid signalling. Moreover, sucrose decreases tyrosine hydroxylase (TH), a catecholamine-synthetic enzyme, in the medial prefrontal cortex. Finally, sucrose consumption alters the expression pattern of FOSB, a marker of phasic dopamine signalling, in the nucleus accumbens. Overall, chronic consumption of sucrose at a human-relevant level alters metabolism, steroid levels, and brain dopamine signalling in a female rat model.

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SJ Conroy
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YH Abdel-Wahab
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EM Caraher
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PM Byrne
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E Murphy
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J Nolan
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PR Flatt
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P Newsholme
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There are conflicting reports on the effect of serum from patients with insulin-dependent diabetes mellitus (IDDM) or normal human serum on beta-cell function and insulin secretion. Here, we report that the sera of newly diagnosed IDDM patients potently suppresses insulin secretion from a clonal rat pancreatic beta-cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of the beta-cells was not significantly different between cells cultured in 10% (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h. Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v) IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10% v/v) normal human sera. After depletion of the complement components C1q and C3, the inhibition of insulin secretion induced by IDDM patient sera was significantly reversed (no significant difference was observed between cells cultured in complement-depleted IDDM patient sera and cells cultured in normal human sera or complement-depleted normal human sera). The concentration of glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the sera of six out of nine newly diagnosed IDDM patients in this study, whereas insulin auto-antibodies (IAA) were detected in the sera of three of the nine patients and islet-cell antibodies (ICA) in the sera of five of them. In addition, the concentration of soluble terminal complement complexes (SC5-9) was greater in some of the beta-cell culture media samples after 24 h incubation when the incubation medium was supplemented with IDDM patient sera than when supplementation was with normal human sera. We propose that the mechanism of sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement- and cytokine-stimulated intracellular events that attenuate the metabolite-induced secretory process.

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Daniel J Tobiansky Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada

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George V Kachkovski Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada

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Reilly T Enos Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA

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Kim L Schmidt Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada

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E Angela Murphy Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA

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Stan B Floresco Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada

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Kiran K Soma Department of Psychology, The University of British Columbia, Vancouver, British Columbia, Canada
Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
Department of Zoology, The University of British Columbia, Vancouver, British Columbia, Canada

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Maternal diets can have dramatic effects on the physiology, metabolism, and behaviour of offspring that persist into adulthood. However, the effects of maternal sucrose consumption on offspring remain unclear. Here, female rats were fed either a sucrose diet with a human-relevant level of sucrose (25% of kcal) or a macronutrient-matched, isocaloric control diet before, during, and after pregnancy. After weaning, all offspring were fed a standard low-sucrose rodent chow. We measured indicators of metabolism (weight, adipose, glucose tolerance, and liver lipids) during development and adulthood (16–24 weeks). We also measured food preference and motivation for sugar rewards in adulthood. Finally, in brain regions regulating these behaviours, we measured steroids and transcripts for steroidogenic enzymes, steroid receptors, and dopamine receptors. In male offspring, maternal sucrose intake decreased body mass and visceral adipose tissue, increased preference for high-sucrose and high-fat diets, increased motivation for sugar rewards, and decreased mRNA levels of Cyp17a1 (an androgenic enzyme) in the nucleus accumbens. In female offspring, maternal sucrose intake increased basal corticosterone levels. These data demonstrate the enduring, diverse, and sex-specific effects of maternal sucrose consumption on offspring phenotype.

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