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White River Junction, VT, United States

Fernandez-Real J.M.,University of Girona | Fernandez-Real J.M.,CIBER ISCIII | Mcclain D.,University of Utah | Mcclain D.,Veterans Administration Research Service | Review M.M.,Bambino Gesu Childrens Hospital and Research Institute
Diabetes Care

OBJECTIVE The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing b-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucosemetabolism in the senescentmuscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate b-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. © 2015 by the American Diabetes Association. Source

Huang S.C.,University of California at San Diego | Lee J.K.,University of California at San Diego | Smith E.J.,University of California at San Diego | Doctolero R.T.,University of California at San Diego | And 6 more authors.

Background: Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN, a gene inactivated in the germline of some hamartomatous polyposis syndrome patients. Methods: Ten hamartomatous polyposis syndrome patients were genotyped for germline mutations. Epithelial and nonepithelial polyp DNA were assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. In addition, 99 MSI-high sporadic CRCs and 50 each of hMLH1-/- and hMSH3-/- cell clones were examined for PTEN frameshifts. Results: Twenty-five (58%) of 43 hamartomatous polyposis syndrome polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3 deficiency. MSI domains lost hMSH3 expression, and PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wild type exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however, MSI-high sporadic CRC showed 11 (11%) of 99 frameshifts within PTEN, with 4 tumors having complete loss of PTEN expression. Subcloning hMLH1-/- and hMSH3-/- cells revealed somatic PTEN frameshifts in 4% and 12% of clones, respectively. Conclusions: Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN +/- patients lose PTEN expression, but loss is not a universal early feature of all hamartomatous polyposis syndrome. However, PTEN frameshifts can occur in hMSH3-deficient cells, suggesting that hMSH3 deficiency could drive hamartomatous polyposis syndrome tumorigenesis. © 2010 American Cancer Society. Source

Simcox J.A.,University of Utah | Mitchell T.C.,University of Utah | Gao Y.,University of Utah | Just S.F.,University of Utah | And 9 more authors.

The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. © 2015 by the American Diabetes Association. Source

Fellows A.,Veterans Administration Research Service | Mierke D.F.,Dartmouth College | Nichols R.C.,Veterans Administration Research Service

The macrophage is essential to the innate immune response, but also contributes to human disease by aggravating inflammation. Under severe inflammation, macrophages and other immune cells over-produce immune mediators, including vascular endothelial growth factor (VEGF). The VEGF protein stimulates macrophage activation and induces macrophage migration. A natural inhibitor of VEGF, the soluble VEGF receptor (sFlt-1) is also produced by macrophages and sFlt-1 has been used clinically to block VEGF. In macrophages, we have shown that the mRNA regulatory protein AUF1/hnRNP D represses VEGF gene expression by inhibiting translation of AURE-regulated VEGF mRNA. Peptides (AUF1-RGG peptides) that are modeled on the arginine-glycine-glycine (RGG) motif in AUF1 also block VEGF expression. This report shows that the AUF1-RGG peptides reduce two other AURE-regulated genes, TNF and GLUT1. Three alternative splice variants of sFlt-1 contain AURE in their 3'UTR, and in an apparent paradox, AUF1-RGG peptides stimulate expression of these three sFlt-1 Variants. The AUF1-RGG peptides likely act by distinct mechanisms with complimentary effects to repress VEGF gene expression and over-express the endogenous VEGF blocking agent, sFlt-1. The AUF1-RGG peptides are novel reagents that reduce VEGF and other inflammatory mediators, and may be useful tools to suppress severe inflammation. © 2013 . Source

Nichols R.C.,Veterans Administration Research Service | Wang X.W.,Microbiology and Immunology | Hamilton B.J.,Microbiology and Immunology | Collins J.E.,Microbiology and Immunology | And 2 more authors.
Molecular Biotechnology

The study of post-transcriptional regulation is constrained by the technical limitations associated with both transient and stable transfection of chimeric reporter plasmids examining the activity of 30-UTR cis-acting elements. We report the adaptation of a commercially available system that enables consistent stable integration of chimeric reporter cDNA into a single genomic site in which transcription is induced by tetracycline. Using this system, we demonstrate the tight control afforded by this system and its suitability in mapping the regulatory function of defined cis-acting elements in the human TNF 30-UTR, as well as the distinct effects of serum starvation on transiently transfected and stably integrated chimeric reporter genes. © 2011 Springer Science+Business Media, LLC. Source

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