RESUMO
The exact physiological role for the monoamine serotonin (5-HT) in modulation of insulin secretion is yet to be fully understood. Although the presence of this monoamine in islets of Langerhans is well established, it is only with recent advances that the complex signalling network in islets involving 5-HT is being unravelled. With more than fourteen different 5-HT receptors expressed in human islets and receptor-independent mechanisms in insulin-producing ß-cells, our understanding of 5-HT's regulation of insulin secretion is increasing. It is now widely accepted that failure of the pancreatic ß-cell to release sufficient amounts of insulin is the main cause of type 2 diabetes (T2D), an ongoing global epidemic. In this context, 5-HT signalling may be of importance. In fact, 5-HT may serve an essential role in regulating the release of insulin and glucagon, the two main hormones that control glucose and lipid homoeostasis. In this review, we will discuss past and current understanding of 5-HT's role in the endocrine pancreas.
Assuntos
Insulina/metabolismo , Serotonina/metabolismo , Animais , Glucose/metabolismo , Humanos , Células Secretoras de Insulina/fisiologiaRESUMO
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição SOXD/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Cromatina/metabolismo , Exocitose , Feminino , Regulação da Expressão Gênica , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Florizina/química , RNA Interferente Pequeno/metabolismo , Ratos , Ácido Valproico/químicaRESUMO
We have characterized a 185-kb contig surrounding a transgene on distal mouse chromosome 11, the insertion of which has caused a recessive phenotype with skeletal malformations. By cDNA selection and sequencing we have found six genes (Lasp1, Rpl23, Mllt6, Pip5k2b, Psmb3, Zfp144), one truncated gene (Mel13), and one pseudogene (Rps15-ps) within this region. The murine Mllt6 gene is new, it was identified by its high homology (90% identity) with the human homologue MLLT6. Psmb3 and Pip5k2b had not yet been assigned to mouse chromosomes. A comparison with the corresponding region on human chromosome 17q12 revealed several small-scale rearrangements during evolutionary divergence within this cluster of densely packed genes.
Assuntos
Cromossomos de Mamíferos/genética , Colágeno Tipo I , Mutação , Proteínas Adaptadoras de Transdução de Sinal , Animais , Sequência de Bases , Colágeno/genética , Cadeia alfa 1 do Colágeno Tipo I , Proteínas do Citoesqueleto , Elementos de DNA Transponíveis , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Evolução Molecular , Rearranjo Gênico , Ligação Genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas Ferro-Enxofre , Proteínas com Domínio LIM , Óperon Lac , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais , Dados de Sequência Molecular , Família Multigênica , Mutagênese Insercional , Proteínas de Neoplasias/genética , Mapeamento Físico do Cromossomo , Proteínas/genética , Pseudogenes , Proteínas Ribossômicas/genética , Especificidade da EspécieRESUMO
The mouse gene coding for ribosomal protein L23 (Rpl23) has been fully sequenced, including 580 bp of the 5' upstream region. The 5-kb gene comprises 5 exons and contains an unusually long (3,153 bp) third intron. The gene was mapped to the distal region of mouse chromosome 11, homologous to human chromosome 17q21-->q22.
