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1.
J Clin Invest ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30507613

RESUMO

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained ß cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

2.
Cell Rep ; 22(10): 2667-2676, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514095

RESUMO

Many patients with type 1 diabetes (T1D) have residual ß cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual ß cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant ß cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and ß cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-ß cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.

3.
Proc Natl Acad Sci U S A ; 109(19): 7356-61, 2012 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-22529374

RESUMO

During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1(-)Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and ß-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing ß-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of ß-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and ß-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1ß(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and ß-cells. An accompanying increase in Nkx6-1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed ß-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate ß-cell formation.


Assuntos
Embrião de Mamíferos/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Western Blotting , Linhagem da Célula , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Fator 1-beta Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pâncreas/citologia , Pâncreas/embriologia , Receptores Notch/genética , Receptores Notch/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética
4.
Diabetes ; 60(3): 827-37, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21266327

RESUMO

OBJECTIVE: We examined the role of Rictor/mammalian target of rapamycin complex 2 (mTORC2), a key component of the phosphotidylinositol-3-kinase (PI3K)/mTORC2/AKT signaling pathway, in regulating both ß-cell mass and function. RESEARCH DESIGN AND METHODS: Mice with ß-cell-specific deletions of Rictor or Pten were studied to determine the effects of deleting either or both genes on ß-cell mass and glucose homeostasis. RESULTS: Rictor null mice exhibited mild hyperglycemia and glucose intolerance caused by a reduction in ß-cell mass, ß-cell proliferation, pancreatic insulin content, and glucose-stimulated insulin secretion. Islets from these mice exhibited decreased AKT-S473 phosphorylation and increased abundance of FoxO1 and p27 proteins. Conversely, Pten null (ßPtenKO) mice exhibited an increase in ß-cell mass caused by increased cellular proliferation and size. Although ß-cell mass was normal in mice lacking both Rictor and Pten (ßDKO), their ß-cells were larger than those in the ßPtenKO mice. Even though the ß-cell proliferation rate in the ßDKO mice was lower than in the ßPtenKO mice, there was a 12-fold increase the phosphorylation of AKT-T308. CONCLUSIONS: PI3K/AKT signaling through mTORC2/pAKT-S473 plays a key role in maintaining normal ß-cell mass. The phosphorylation of AKT-S473, by negatively regulating that of AKT-T308, is essential for maintaining a balance between ß-cell proliferation and cell size in response to proliferative stimuli.


Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Tamanho Celular , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Transdução de Sinais/fisiologia , Alelos , Análise de Variância , Animais , Apoptose/fisiologia , Western Blotting , Proteínas de Transporte/genética , Imunofluorescência , Genótipo , Glucose/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Diabetes ; 59(10): 2530-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20627934

RESUMO

OBJECTIVE: Several transcription factors are essential to pancreatic islet ß-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with ß-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the ß-cell. RESEARCH DESIGN AND METHODS: The distribution of MafA and MafB in the ß-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(ΔPanc)). RESULTS: MafB was produced in a larger fraction of ß-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(ΔPanc) islets, suggesting that MafA is required to sustain expression in adults. CONCLUSIONS: Our results provide insight into the sequential manner by which MafA and MafB regulate islet ß-cell formation and maturation.


Assuntos
Células Secretoras de Insulina/fisiologia , Fatores de Transcrição Maf Maior/genética , Fator de Transcrição MafB/genética , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Glucagon/biossíntese , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Insulina/biossíntese , Fatores de Transcrição Maf Maior/deficiência , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas/genética , RNA/genética , RNA/isolamento & purificação , RNA Mensageiro/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
6.
Cell Metab ; 5(4): 313-20, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17403375

RESUMO

When dietary carbohydrate is unavailable, glucose required to support metabolism in vital tissues is generated via gluconeogenesis in the liver. Expression of phosphoenolpyruvate carboxykinase (PEPCK), commonly considered the control point for liver gluconeogenesis, is normally regulated by circulating hormones to match systemic glucose demand. However, this regulation fails in diabetes. Because other molecular and metabolic factors can also influence gluconeogenesis, the explicit role of PEPCK protein content in the control of gluconeogenesis was unclear. In this study, metabolic control of liver gluconeogenesis was quantified in groups of mice with varying PEPCK protein content. Surprisingly, livers with a 90% reduction in PEPCK content showed only a approximately 40% reduction in gluconeogenic flux, indicating a lower than expected capacity for PEPCK protein content to control gluconeogenesis. However, PEPCK flux correlated tightly with TCA cycle activity, suggesting that under some conditions in mice, PEPCK expression must coordinate with hepatic energy metabolism to control gluconeogenesis.


Assuntos
Gluconeogênese/genética , Fígado/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/fisiologia , Fosfoenolpiruvato Carboxilase/fisiologia , Animais , Radioisótopos de Carbono/farmacocinética , Citosol/enzimologia , Deutério/farmacocinética , Metabolismo Energético/genética , Regulação Enzimológica da Expressão Gênica , Glucose/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Fosfoenolpiruvato Carboxilase/genética , Fosfoenolpiruvato Carboxilase/metabolismo , Traçadores Radioativos
7.
J Biol Chem ; 282(18): 13906-16, 2007 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-17353190

RESUMO

To better understand how glucokinase (GK) missense mutations associated with human glycemic diseases perturb glucose homeostasis, we generated and characterized mice with either an activating (A456V) or inactivating (K414E) mutation in the gk gene. Animals with these mutations exhibited alterations in their blood glucose concentration that were inversely related to the relative activity index of GK. Moreover, the threshold for glucose-stimulated insulin secretion from islets with either the activating or inactivating mutation were left- or right-shifted, respectively. However, we were surprised to find that mice with the activating mutation had markedly reduced amounts of hepatic GK activity. Further studies of bacterially expressed mutant enzymes revealed that GK(A456V) is as stable as the wild type enzyme, whereas GK(K414E) is thermolabile. However, the ability of GK regulatory protein to inhibit GK(A456V) was found to be less than that of the wild type enzyme, a finding consistent with impaired hepatic nuclear localization. Taken together, this study indicates that it is necessary to have knowledge of both thermolability and the interactions of mutant GK enzymes with GK regulatory protein when attempting to predict in vivo glycemic phenotypes based on the measurement of enzyme kinetics.


Assuntos
Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Glucoquinase/metabolismo , Transtornos do Metabolismo de Glucose/enzimologia , Fígado/enzimologia , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/genética , Ativação Enzimática/genética , Estabilidade Enzimática/genética , Glucoquinase/química , Glucoquinase/genética , Transtornos do Metabolismo de Glucose/genética , Transtornos do Metabolismo de Glucose/patologia , Temperatura Alta , Insulina/metabolismo , Fígado/patologia , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Fenótipo , Ligação Proteica/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
8.
Dev Cell ; 11(4): 583-9, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16962829

RESUMO

The rapamycin-insensitive mTOR complex 2 (mTORC2) has been suggested to play an important role in growth factor-dependent signaling. To explore this possibility further in a mammalian model system, we disrupted the expression of rictor, a specific component of mTORC2, in mice by using a multiallelic gene targeting strategy. Embryos that lack rictor develop normally until E9.5, and then exhibit growth arrest and die by E11.5. Although placental defects occur in null embryos, an epiblast-specific knockout of rictor only delayed lethality by a few days, thereby suggesting other important roles for this complex in the embryo proper. Analyses of rictor null embryos and fibroblasts indicate that mTORC2 is a primary kinase for Ser473 of Akt/PKB. Rictor null fibroblasts exhibit low proliferation rates, impaired Akt/PKB activity, and diminished metabolic activity. Taken together, these findings indicate that both rictor and mTORC2 are essential for the development of both embryonic and extraembryonic tissues.


Assuntos
Alelos , Proteínas de Transporte/metabolismo , Desenvolvimento Fetal/genética , Viabilidade Fetal/genética , Proteínas Quinases/metabolismo , Actinas/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Marcação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Proteínas Quinases/análise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina , Serina-Treonina Quinases TOR
9.
Mol Cell Biol ; 25(10): 4189-99, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15870288

RESUMO

The gastrointestinal hormone peptide YY is a potent inhibitor of food intake and is expressed early during differentiation of intestinal and pancreatic endocrine cells. In order to better understand the role of peptide YY in energy homeostasis and development, we created mice with a targeted deletion of the peptide YY gene. All intestinal and pancreatic endocrine cells developed normally in the absence of peptide YY with the exception of pancreatic polypeptide (PP) cells, indicating that peptide YY expression was not required for terminal differentiation. We used recombination-based cell lineage trace to determine if peptide YY cells were progenitors for gastrointestinal endocrine cells. Peptide YY(+) cells gave rise to all L-type enteroendocrine cells and to islet partial differential and PP cells. In the pancreas, approximately 40% of pancreatic alpha and rare beta cells arose from peptide YY(+) cells, suggesting that most beta cells and surprisingly the majority of alpha cells are not descendants of peptide YY(+)/glucagon-positive/insulin-positive cells that appear during early pancreagenesis. Despite the anorectic effects of exogenous peptide YY(3-36) following intraperitoneal administration, mice lacking peptide YY showed normal growth, food intake, energy expenditure, and responsiveness to peptide YY(3-36). These observations suggest that targeted disruption of the peptide YY gene does not perturb terminal endocrine cell differentiation or the control of food intake and energy homeostasis.


Assuntos
Diferenciação Celular , Fenômenos Fisiológicos do Sistema Digestório , Sistema Endócrino/fisiologia , Metabolismo Energético , Homeostase , Peptídeo YY/fisiologia , Animais , Linhagem da Célula , Sistema Digestório/citologia , Ingestão de Alimentos , Sistema Endócrino/citologia , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Transgênicos , Peptídeo YY/deficiência , Peptídeo YY/genética , Transgenes/genética , Ganho de Peso
10.
Proc Natl Acad Sci U S A ; 102(17): 6207-12, 2005 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-15833818

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a crucial role in adipocyte differentiation, glucose metabolism, and other physiological processes. To further explore the role of PPARgamma in adipose tissues, we used a Cre/loxP strategy to generate adipose-specific PPARgamma knockout mice. These animals exhibited marked abnormalities in the formation and function of both brown and white adipose tissues. When fed a high-fat diet, adipose-specific PPARgamma knockout mice displayed diminished weight gain despite hyperphagia, had diminished serum concentrations of both leptin and adiponectin, and did not develop glucose intolerance or insulin resistance. Characterization of in vivo glucose dynamics pointed to improved hepatic glucose metabolism as the basis for preventing high-fat diet-induced insulin resistance. Our findings further illustrate the essential role for PPARgamma in the development of adipose tissues and suggest that a compensatory induction of hepatic PPARgamma may stimulate an increase in glucose disposal by the liver.


Assuntos
Gorduras na Dieta , Resistência à Insulina/fisiologia , Obesidade/prevenção & controle , PPAR gama/deficiência , PPAR gama/genética , Animais , Glicemia/metabolismo , Cruzamentos Genéticos , Ingestão de Energia , Metabolismo Energético , Deleção de Genes , Teste de Tolerância a Glucose , Homeostase , Hiperinsulinismo/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , Atividade Motora , Obesidade/genética , Obesidade/patologia , Triglicerídeos/sangue
11.
J Biol Chem ; 279(47): 48941-9, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15347677

RESUMO

Liver-specific phosphoenolpyruvate carboxykinase (PEPCK) null mice, when fasted, maintain normal whole body glucose kinetics but develop dramatic hepatic steatosis. To identify the abnormalities of hepatic energy generation that lead to steatosis during fasting, we studied metabolic fluxes in livers lacking hepatic cytosolic PEPCK by NMR using 2H and 13C tracers. After a 4-h fast, glucose production from glycogenolysis and conversion of glycerol to glucose remains normal, whereas gluconeogenesis from tricarboxylic acid (TCA) cycle intermediates was nearly absent. Upon an extended 24-h fast, livers that lack PEPCK exhibit both 2-fold lower glucose production and oxygen consumption, compared with the controls, with all glucose production being derived only from glycerol. The mitochondrial reduction-oxidation (red-ox) state, as indicated by the NADH/NAD+ ratio, is 5-fold higher, and hepatic TCA cycle intermediate concentrations are dramatically increased in the PEPCK null livers. Consistent with this, flux through the TCA cycle and pyruvate cycling pathways is 10- and 40-fold lower, respectively. Disruption of hepatic cataplerosis due to loss of PEPCK leads to the accumulation of TCA cycle intermediates and a nearly complete blockage of gluconeogenesis from amino acids and lactate (an energy demanding process) but intact gluconeogenesis from glycerol (which contributes to net NADH production). Inhibition of the TCA cycle and fatty acid oxidation due to increased TCA cycle intermediate concentrations and reduced mitochondrial red-ox state lead to the development of steatosis.


Assuntos
Ciclo do Ácido Cítrico/fisiologia , Citosol/enzimologia , Fígado/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Animais , Fenômenos Bioquímicos , Bioquímica , Privação de Alimentos , Glucose/metabolismo , Hidrogênio/química , Cinética , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Modelos Biológicos , NAD/metabolismo , Oxirredução , Consumo de Oxigênio , Perfusão , Fosfoenolpiruvato Carboxiquinase (GTP)/fisiologia , Fosforilação , Fatores de Tempo
12.
Genesis ; 39(4): 256-62, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15286998

RESUMO

Recombinase-mediated cassette exchange (RMCE), when applied to mouse embryonic stem (ES) cells, promises to increase the ease with which genetic alterations can be introduced into targeted genomic loci in the mouse. However, existing selection strategies for identifying ES cells in which replacement DNA cassettes from a carrier plasmid have been exchanged correctly into a defined locus are suboptimal. Here, we report the generation in mouse ES cells of a loxed cassette acceptor (LCA) allele within the glucokinase (gk) gene locus. Using the gkLCA as a test allele, we developed a staggered positive-negative selection strategy that facilitates efficient identification of ES cell clones in which a DNA replacement cassette from a carrier plasmid has been exchanged correctly into the gkLCA allele. This selection strategy, by facilitating more efficient production of ES cell clones with various replacement DNA cassettes, should accelerate targeted repetitive introduction of gene modifications into the mouse.


Assuntos
Embrião de Mamíferos/citologia , Marcação de Genes/métodos , Mutagênese Insercional/métodos , Células-Tronco/citologia , Alelos , Animais , Primers do DNA , Componentes do Gene , Glucoquinase/genética , Glucoquinase/metabolismo , Camundongos , Plasmídeos/genética , Recombinases/metabolismo
13.
J Biol Chem ; 277(40): 37176-83, 2002 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-12149271

RESUMO

The ATP-sensitive potassium channel is a key molecular complex for glucose-stimulated insulin secretion in pancreatic beta cells. In humans, mutations in either of the two subunits for this channel, the sulfonylurea type 1 receptor (Sur1) or Kir6.2, cause persistent hyperinsulinemic hypoglycemia of infancy. We have generated and characterized Sur1 null mice. Interestingly, these animals remain euglycemic for a large portion of their life despite constant depolarization of membrane, elevated cytoplasmic free Ca(2+) concentrations, and intact sensitivity of the exocytotic machinery to Ca(2+). A comparison of glucose- and meal-stimulated insulin secretion showed that, although Sur1 null mice do not secrete insulin in response to glucose, they secrete nearly normal amounts of insulin in response to feeding. Because Sur1 null mice lack an insulin secretory response to GLP-1, even though their islets exhibit a normal rise in cAMP by GLP-1, we tested their response to cholinergic stimulation. We found that perfused Sur1 null pancreata secreted insulin in response to the cholinergic agonist carbachol in a glucose-dependent manner. Together, these findings suggest that cholinergic stimulation is one of the mechanisms that compensate for the severely impaired response to glucose and GLP-1 brought on by the absence of Sur1, thereby allowing euglycemia to be maintained.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Glicemia/metabolismo , Ingestão de Alimentos , Insulina/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/fisiologia , Receptores de Droga/fisiologia , Animais , Carbacol/farmacologia , Clonagem Molecular , Ingestão de Alimentos/fisiologia , Exocitose , Genótipo , Técnica Clamp de Glucose , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Perfusão , Canais de Potássio/deficiência , Canais de Potássio/genética , Receptores de Droga/deficiência , Receptores de Droga/genética , Proteínas Recombinantes/metabolismo , Receptores Sulfonilureia
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