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1.
J Endocrinol Invest ; 41(6): 691-701, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29168078

RESUMO

PURPOSE: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals. METHODS: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography. RESULTS: After surgery, body weight development was equal among groups (P g = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35). CONCLUSIONS: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Gastrectomia/métodos , Gastrinas/farmacologia , Células Secretoras de Insulina/patologia , Animais , Terapia Combinada , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Hormônios/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Pantoprazol , Ratos
2.
Sci Rep ; 5: 10740, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26030284

RESUMO

The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.


Assuntos
Difusão Dinâmica da Luz , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Animais , Ilhotas Pancreáticas/crescimento & desenvolvimento , Ilhotas Pancreáticas/ultraestrutura , Camundongos , Tamanho do Órgão , Hormônios Pancreáticos/metabolismo , Ratos
3.
Cell Death Dis ; 4: e523, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23470530

RESUMO

We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to ß cells ex vivo. Here we evaluate the role of Ngn3(+) cells in ß cell expansion in situ. PDL not only induced doubling of the ß cell volume but also increased the total number of islets. ß cells proliferated without extended delay (the so-called 'refractory' period), their proliferation potential was highest in small islets, and 86% of the ß cell expansion was attributable to proliferation of pre-existing ß cells. At sufficiently high Ngn3 expression level, upto 14% of all ß cells and 40% of small islet ß cells derived from non-ß cells. Moreover, ß cell proliferation was blunted by a selective ablation of Ngn3(+) cells but not by conditional knockout of Ngn3 in pre-existing ß cells supporting a key role for Ngn3(+) insulin(-) cells in ß cell proliferation and expansion. We conclude that Ngn3(+) cell-dependent proliferation of pre-existing and newly-formed ß cells as well as reprogramming of non-ß cells contribute to in vivo ß cell expansion in the injured pancreas of adult mice.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Secretoras de Insulina/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proliferação de Células , Tamanho Celular , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/genética , Pâncreas/lesões , Pâncreas/patologia , Regeneração
4.
Diabetologia ; 55(12): 3331-40, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22926403

RESUMO

AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment. RESULTS: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.


Assuntos
Diabetes Mellitus Experimental/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , NF-kappa B/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Imunofluorescência , Homeostase , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Proteína de Ligação a Fosfatidiletanolamina/farmacologia , Fosforilação
5.
Diabetologia ; 51(12): 2148-54, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18777169

RESUMO

While many recently published reviews have covered non-invasive nuclear imaging techniques, the aim of this review is to focus on current developments in optical imaging technologies for investigating the pancreas. Several of these modalities are being developed into non-invasive, real-time monitoring routines for pancreatic diseases. However, they also provide pre-clinical ex vivo and/or intravital tools for three-dimensional quantitative assessments of cellular and molecular events, with levels of specificity and resolution difficult to achieve with other currently available modalities.


Assuntos
Diagnóstico por Imagem/métodos , Pancreatopatias/diagnóstico , Animais , Genes Reporter/genética , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Pancreatopatias/genética , Pancreatopatias/metabolismo
7.
Genes Dev ; 12(12): 1763-8, 1998 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-9637677

RESUMO

To study the late beta-cell-specific function of the homeodomain protein IPF1/PDX1 we have generated mice in which the Ipf1/Pdx1 gene has been disrupted specifically in beta cells. These mice develop diabetes with age, and we show that IPF1/PDX1 is required for maintaining the beta cell identity by positively regulating insulin and islet amyloid polypeptide expression and by repressing glucagon expression. We also provide evidence that IPF1/PDX1 regulates the expression of Glut2 in a dosage-dependent manner suggesting that lowered IPF1/PDX1 activity may contribute to the development of type II diabetes by causing impaired expression of both Glut2 and insulin.


Assuntos
Diabetes Mellitus Tipo 2/genética , Genes/genética , Ilhotas Pancreáticas/metabolismo , Transativadores/genética , Transativadores/fisiologia , Amiloide/análise , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Glucagon/análise , Intolerância à Glucose , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 2 , Heterozigoto , Proteínas de Homeodomínio/análise , Imuno-Histoquímica , Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Mutantes , Proteínas de Transporte de Monossacarídeos/análise , Mutagênese Sítio-Dirigida , Fenótipo , Ativação Transcricional/genética
8.
Curr Biol ; 7(10): 801-4, 1997 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-9368764

RESUMO

The generation of the pancreas and small intestine from the embryonic gut depends on intercellular signalling between the endodermal and mesodermal cells of the gut. In particular, the differentiation of intestinal mesoderm into smooth muscle has been suggested to depend on signals from adjacent endodermal cells. One candidate mediator of endodermally derived signals in the embryonic hindgut is the secreted protein Sonic hedgehog (Shh). The Shh gene is expressed throughout the embryonic gut endoderm with the exception of the pancreatic bud endoderm, which instead expresses high levels of the homeodomain protein Ipf1/Pdx1 (insulin promoter factor 1/pancreatic and duodenal homeobox 1), an essential regulator of early pancreatic development. Here, we have examined whether the differential expression of Shh in the embryonic gut tube controls the differentiation of the surrounding mesoderm into specialised mesoderm derivatives of the small intestine and pancreas. To test this, we used the promoter of the Ipf1/Pdx1 gene to selectively express Shh in the developing pancreatic epithelium. In Ipf1/Pdx1-Shh transgenic mice, the pancreatic mesoderm developed into smooth muscle and interstitial cells of Cajal, characteristic of the intestine, rather than into pancreatic mesenchyme and spleen. Also, pancreatic explants exposed to Shh underwent a similar program of intestinal differentiation. These results provide evidence that the differential expression of endodermally derived Shh controls the fate of adjacent mesoderm at different regions of the gut tube.


Assuntos
Proteínas de Homeodomínio , Intestinos/embriologia , Pâncreas/embriologia , Proteínas/metabolismo , Animais , Diferenciação Celular , Duodeno/embriologia , Epitélio , Proteínas Hedgehog , Proteínas de Membrana/biossíntese , Mesoderma/citologia , Camundongos , Camundongos Transgênicos , Receptores Patched , Fenótipo , Biossíntese de Proteínas , Ratos , Receptores de Superfície Celular , Transativadores/genética , Transgenes
9.
Nature ; 385(6613): 257-60, 1997 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-9000074

RESUMO

The mammalian pancreas is a specialized derivative of the primitive gut endoderm and controls many homeostatic functions through the activity of its component exocrine acinar and endocrine islet cells. The LIM homeodomain protein ISL1 is expressed in all classes of islet cells in the adult and its expression in the embryo is initiated soon after the islet cells have left the cell cycle. ISL1 is also expressed in mesenchymal cells that surround the dorsal but not ventral evagination of the gut endoderm, which together comprise the pancreatic anlagen. To define the role of ISL1 in the development of the pancreas, we have now analysed acinar and islet cell differentiation in mice deficient in ISL1 function. Dorsal pancreatic mesenchyme does not form in ISL1-mutant embryos and there is an associated failure of exocrine cell differentiation in the dorsal but not the ventral pancreas. There is also a complete loss of differentiated islet cells. Exocrine, but not endocrine, cell differentiation in the dorsal pancreas can be rescued in vitro by provision of mesenchyme derived from wild-type embryos. These results indicate that ISL1, by virtue of its requirement for the formation of dorsal mesenchyme, is necessary for the development of the dorsal exocrine pancreas, and also that ISL1 function in pancreatic endodermal cells is required for the generation of all endocrine islet cells.


Assuntos
Proteínas de Homeodomínio/fisiologia , Ilhotas Pancreáticas/embriologia , Mesoderma/fisiologia , Proteínas do Tecido Nervoso , Pâncreas/embriologia , Animais , Diferenciação Celular/fisiologia , Técnicas de Cultura , Desenvolvimento Embrionário e Fetal/fisiologia , Marcação de Genes , Glucagon/metabolismo , Proteínas de Homeodomínio/genética , Proteínas com Homeodomínio LIM , Mesoderma/metabolismo , Camundongos , Pâncreas/metabolismo , Fatores de Transcrição
10.
Development ; 122(5): 1409-16, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8625829

RESUMO

We have previously shown that mice carrying a null mutation in the homeobox gene ipf1, now renamed to pdx1, selectively lack a pancreas. To elucidate the level at which PDX1 is required during the development of the pancreas, we have in this study analyzed the early stages of pancreas ontogeny in PDX-/- mice. These analyses have revealed that the early inductive events leading to the formation of the pancreatic buds and the appearance of the early insulin and glucagon cells occur in the PDX1-deficient embryos. However, the subsequent morphogenesis of the pancreatic epithelium and the progression of differentiation of the endocrine cells are arrested in the pdx1-/- embryos. In contrast, the pancreatic mesenchyme grows and develops, both morphologically and functionally, independently of the epithelium. We also show that the pancreatic epithelium in the pdx1 mutants is unable to respond to the mesenchymal-derived signal(s) which normally promote pancreatic morphogenesis. Together these data provide evidence that PDX-1 acts cell autonomously and that the lack of a pancreas in the pdx1-/- mice is due to a defect in the pancreatic epithelium.


Assuntos
Proteínas de Homeodomínio/metabolismo , Pâncreas/embriologia , Transativadores/metabolismo , Animais , Sequência de Bases , Comunicação Celular , Epitélio/embriologia , Glucagon/biossíntese , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Hibridização In Situ , Insulina/biossíntese , Ilhotas Pancreáticas/embriologia , Mesoderma/fisiologia , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Morfogênese , Transativadores/deficiência , Transativadores/genética
11.
Int J Dev Biol ; 39(5): 789-98, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8645563

RESUMO

Insulin promoter factor 1 (IPF1), is a homeodomain protein which, in the adult mouse pancreas, is selectively expressed in beta-cells, and which binds to, and transactivates, the insulin promoter via the P1 element. In mouse embryos, IPF1 expression is initiated when the foregut endoderm commits to a pancreatic fate, i.e. prior to both morphogenesis and hormone specific gene expression. At later stages of development the expression is restricted to the dorsal and ventral walls of the primitive foregut at the positions where the pancreases will form. Mice homozygous for a targeted mutation in the Ipf1 gene selectively lack the pancreas. The mutant pups develop to term and are born alive, but die after a few days. The gastrointestinal tract with its associated organs show no obvious malformations. No pancreatic tissue and no ectopic expression of insulin or pancreatic amylase could be detected in this region in mutant neonates or embryos. These findings demonstrate that IPF1 is needed for the formation of the pancreas, and suggest that IPF1 acts to determine the fate of common pancreatic precursor cells and/or to regulate their propagation. The lack of a pancreas in the Ipf1-deficient mutants, the pattern of IPF1 expression and its ability to stimulate insulin gene transcription, strongly suggest that IPF1 functions both in the early specification of the primitive gut to a pancreatic fate and in the maturation of the pancreatic beta-cell.


Assuntos
Desenvolvimento Embrionário e Fetal , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/fisiologia , Ilhotas Pancreáticas/crescimento & desenvolvimento , Pâncreas/crescimento & desenvolvimento , Transativadores/fisiologia , Envelhecimento/fisiologia , Sequência de Aminoácidos , Animais , Proteínas de Homeodomínio/biossíntese , Imuno-Histoquímica , Insulina/biossíntese , Insulina/genética , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/embriologia , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Morfogênese , Pâncreas/citologia , Pâncreas/embriologia , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Homologia de Sequência de Aminoácidos , Transativadores/biossíntese , Ativação Transcricional
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