RESUMO
When exposed to nutrient excess and insulin resistance, pancreatic ß-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming ß-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic ß-cells (Igf2ßKO) in mice. We show that autocrine actions of IGF2 are not critical for ß-cell development, or for the early post-natal wave of ß-cell remodelling. Additionally, adult Igf2ßKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2ßKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2ßKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2ßKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of ß-cell IGF2 during early development determine their adaptive capacity in adult life.
Assuntos
Plasticidade Celular/fisiologia , Fator de Crescimento Insulin-Like II/fisiologia , Células Secretoras de Insulina/citologia , Animais , Feminino , Glucose/metabolismo , Homeostase , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , GravidezRESUMO
The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.
Assuntos
Fator de Crescimento Insulin-Like II/genética , Mesoderma/crescimento & desenvolvimento , Pâncreas/crescimento & desenvolvimento , Comunicação Parácrina/genética , Células Acinares/metabolismo , Células Acinares/patologia , Aminoácidos/genética , Animais , Linhagem da Célula/genética , Cromo , Metilação de DNA/genética , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Ácidos Nicotínicos/genética , Pâncreas/citologia , Pâncreas/metabolismo , Gravidez , RNA Longo não Codificante/genéticaRESUMO
AIMS/HYPOTHESIS: Ageing is a major risk factor for development of metabolic diseases such as type 2 diabetes. Identification of the mechanisms underlying this association could help to elucidate the relationship between age-associated progressive loss of metabolic health and development of type 2 diabetes. We aimed to determine molecular signatures during ageing in the endocrine pancreas. METHODS: Global gene transcription was measured in pancreatic islets isolated from young and old rats by Ilumina BeadChip arrays. Promoter DNA methylation was measured by Sequenom MassArray in 46 genes that showed differential expression with age, and correlations with expression were established. Alterations in morphological and cellular processes with age were determined by immunohistochemical methods. RESULTS: Age-related changes in gene expression were found at 623 loci (>1.5-fold, false discovery rate [FDR] <5%), with a significant (FDR < 0.05) enrichment in genes previously implicated in islet-cell function (Enpp1, Abcc8), type 2 diabetes (Tspan8, Kcnq1), inflammatory processes (Cxcl9, Il33) and extracellular matrix organisation (Col3a1, Dpt). Age-associated transcriptional differences negatively correlated with promoter DNA methylation at several loci related to inflammation, glucose homeostasis, cell proliferation and cell-matrix interactions (Il33, Cxcl9, Gpr119, Fbp2, Col3a1, Dpt, Spp1). CONCLUSIONS/INTERPRETATION: Our findings suggest that a significant proportion of pancreatic islets develop a low-grade 'chronic' inflammatory status with ageing and this may trigger altered functional plasticity. Furthermore, we identified changes in expression of genes previously linked to type 2 diabetes and associated changes in DNA methylation that could explain their age-associated dysregulation. These findings provide new insights into key (epi)genetic signatures of the ageing process in islets.
Assuntos
Envelhecimento/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Inflamação/genética , Ilhotas Pancreáticas/metabolismo , Envelhecimento/genética , Animais , Quimiocina CXCL9/genética , Colágeno Tipo III/genética , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/genética , Inflamação/metabolismo , Canal de Potássio KCNQ1/genética , Masculino , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Ratos , Receptores de Sulfonilureias/genética , Tetraspaninas/genéticaRESUMO
The development of the endocrine pancreas is controlled by a hierarchical network of transcriptional regulators. It is increasingly evident that this requires a tightly interconnected epigenetic "programme" to drive endocrine cell differentiation and maintain islet function. Epigenetic regulators such as DNA and histone-modifying enzymes are now known to contribute to determination of pancreatic cell lineage, maintenance of cellular differentiation states, and normal functioning of adult pancreatic endocrine cells. Persistent effects of an early suboptimal environment, known to increase risk of type 2 diabetes in later life, can alter the epigenetic control of transcriptional master regulators, such as Hnf4a and Pdx1. Recent genome-wide analyses also suggest that an altered epigenetic landscape is associated with the ß cell failure observed in type 2 diabetes and aging. At the cellular level, epigenetic mechanisms may provide a mechanistic link between energy metabolism and stable patterns of gene expression. Key energy metabolites influence the activity of epigenetic regulators, which in turn alter transcription to maintain cellular homeostasis. The challenge is now to understand the detailed molecular mechanisms that underlie these diverse roles of epigenetics, and the extent to which they contribute to the pathogenesis of type 2 diabetes. In-depth understanding of the developmental and environmental epigenetic programming of the endocrine pancreas has the potential to lead to novel therapeutic approaches in diabetes.