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1.
Diabetologia ; 60(6): 1043-1050, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28343277

RESUMO

AIMS/HYPOTHESIS: Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the Tcf7l2 gene in pancreatic alpha cells. METHODS: Alpha cell-selective deletion of Tcf7l2 was achieved by crossing mice with floxed Tcf7l2 alleles to mice bearing a Cre recombinase transgene driven by the preproglucagon promoter (PPGCre), resulting in Tcf7l2AKO mice. Glucose homeostasis and hormone secretion in vivo and in vitro, and islet cell mass were measured using standard techniques. RESULTS: While glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased (AUC for glucose during the first 60 min period of hyperinsulinaemic-hypoglycaemic clamp test was increased by 1.98 ± 0.26-fold [p < 0.05; n = 6] in Tcf7l2AKO mice vs wild-type mice) and glucagon secretion tended to be lower (plasma glucagon: 0.40 ± 0.03-fold vs wild-type littermate controls [p < 0.01; n = 6]). Tcf7l2AKO mice displayed reduced fasted plasma glucose concentration. Glucagon release at low glucose was impaired in islets isolated from Tcf7l2AKO mice (0.37 ± 0.02-fold vs islets from wild-type littermate control mice [p < 0.01; n = 6). Alpha cell mass was also reduced (72.3 ± 20.3% [p < 0.05; n = 7) in Tcf7l2AKO mice compared with wild-type mice. CONCLUSIONS/INTERPRETATION: The present findings demonstrate an alpha cell-autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function.


Assuntos
Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Hipoglicemia/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Animais , Feminino , Glucose/metabolismo , Imuno-Histoquímica , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proglucagon/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
2.
PLoS Genet ; 9(1): e1003160, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23300479

RESUMO

Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.


Assuntos
Gônadas , Insulina , Receptor IGF Tipo 1 , Receptor de Insulina , Processos de Determinação Sexual/genética , Córtex Suprarrenal/crescimento & desenvolvimento , Córtex Suprarrenal/patologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Animais , Diferenciação Celular/genética , Linhagem da Célula , Proliferação de Células , Transtornos do Desenvolvimento Sexual/genética , Feminino , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Gônadas/patologia , Humanos , Insulina/genética , Insulina/metabolismo , Masculino , Camundongos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Cromossomos Sexuais , Transdução de Sinais , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
3.
Diabetologia ; 58(2): 304-12, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25413047

RESUMO

AIMS/HYPOTHESIS: Non-invasive imaging of beta cells is a much-needed development but is one that faces significant biological and technological hurdles. A relevant imaging method should at least allow for an evaluation over time of the mass of beta cells under physiological and pathological conditions, and for an assessment of novel therapies. We, therefore, investigated the ability of a new MRI probe to repeatedly measure the loss of beta cells in a rodent model. METHODS: We developed an innovative nanoparticle probe that targets the glucagon-like peptide 1 receptor, and can be used for both fluorescence imaging and MRI. Using fluorescence, we characterised the specificity and biodistribution of the probe. Using 1.5 T MRI, we longitudinally imaged the changes in insulin content in male and female mice of the RIP-DTr strain, which mimic the changes expected in type 1 and type 2 diabetes, respectively. RESULTS: We showed that this probe selectively labelled beta cells in situ, imaged in vivo native pancreatic islets and evaluated their loss after diphtheria toxin administration, in a model of graded beta cell deletion. Thus, using clinical MRI, the probe quantitatively differentiates, in the same mouse strain, between female animals featuring a 50% loss of beta cells and the males featuring an almost complete loss of beta cells. CONCLUSIONS/INTERPRETATION: The approach addresses several of the hurdles that have so far limited the non-invasive imaging of beta cells, including the potential to repeatedly monitor the very same animals using clinically available equipment, and to differentiate graded losses of beta cells.


Assuntos
Glucagon/metabolismo , Células Secretoras de Insulina/metabolismo , Imageamento por Ressonância Magnética , Fragmentos de Peptídeos/metabolismo , Receptores de Glucagon/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Sondas Moleculares , Distribuição Tecidual
4.
Trends Cell Biol ; 34(3): 180-197, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37626005

RESUMO

ß-Cell replacement by in situ reprogramming of non-ß-cells is a promising diabetes therapy. Following the observation that near-total ß-cell ablation in adult mice triggers the reprogramming of pancreatic α-, δ-, and γ-cells into insulin (INS)-producing cells, recent studies are delving deep into the mechanisms controlling adult α-cell identity. Systematic analyses of the α-cell transcriptome and epigenome have started to pinpoint features that could be crucial for maintaining α-cell identity. Using different transgenic and chemical approaches, significant advances have been made in reprogramming α-cells in vivo into INS-secreting cells in mice. The recent reprogramming of human α-cells in vitro is an important step forward that must now be complemented with a comprehensive molecular dissection of the mechanisms controlling α-cell identity.


Assuntos
Células Secretoras de Glucagon , Células Secretoras de Insulina , Humanos , Camundongos , Animais , Insulina , Glucagon
5.
Commun Biol ; 7(1): 833, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982170

RESUMO

Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function. Interestingly, this proliferative response occurred independently of inflammation, as demonstrated in ablated immunodeficient mice. Furthermore, exposure to high-fat diet stimulated beta-cell proliferation but negatively impacted beta-cell function. In contrast, an equivalent slower ablation model revealed a delayed but similar proliferative response, suggesting proliferation as a common regenerative response. However, high-fat diet failed to promote proliferation in this model, indicating a differential response to metabolic stressors. Overall, our findings shed light on the complex interplay between beta-cell loss, inflammation, and stress in modulating pancreatic islet regeneration. Understanding these mechanisms could pave the way for novel therapeutic strategies based on beta-cell proliferation.


Assuntos
Proliferação de Células , Dieta Hiperlipídica , Células Secretoras de Insulina , Regeneração , Animais , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Camundongos , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Inflamação/patologia
6.
Nat Cell Biol ; 5(4): 330-5, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12640462

RESUMO

Homeostasis of blood glucose is maintained by hormone secretion from the pancreatic islets of Langerhans. Glucose stimulates insulin secretion from beta-cells but suppresses the release of glucagon, a hormone that raises blood glucose, from alpha-cells. The mechanism by which nutrients stimulate insulin secretion has been studied extensively: ATP has been identified as the main messenger and the ATP-sensitive potassium channel as an essential transducer in this process. By contrast, much less is known about the mechanisms by which nutrients modulate glucagon secretion. Here we use conventional pancreas perfusion and a transcriptional targeting strategy to analyse cell-type-specific signal transduction and the relationship between islet alpha- and beta-cells. We find that pyruvate, a glycolytic intermediate and principal substrate of mitochondria, stimulates glucagon secretion. Our analyses indicate that, although alpha-cells, like beta-cells, possess the inherent capacity to respond to nutrients, secretion from alpha-cells is normally suppressed by the simultaneous activation of beta-cells. Zinc released from beta-cells may be implicated in this suppression. Our results define the fundamental mechanisms of differential responses to identical stimuli between cells in a microorgan.


Assuntos
Comunicação Celular/fisiologia , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Glicemia/fisiologia , Sinalização do Cálcio/fisiologia , Células Cultivadas , Glucose/metabolismo , Glucose/farmacologia , Glicólise/fisiologia , Homeostase/fisiologia , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Potenciais da Membrana/fisiologia , Ácido Pirúvico/metabolismo , Ácido Pirúvico/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Zinco/metabolismo , Zinco/farmacologia
7.
Diabetes ; 69(11): 2340-2351, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32769118

RESUMO

Pancreatic ß-cell proliferation has been gaining much attention as a therapeutic target for the prevention and treatment of diabetes. In order to evaluate potential ß-cell mitogens, accurate and reliable methods for the detection and quantification of the ß-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating ß-cells as mVenus+ cells by using RIP-Cre; R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in ß-cells. In response to ß-cell proliferation stimuli, such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of 5-ethynyl-2'-deoxyuridine-positive insulin+ cells per insulin+ cells and the number of mVenus+ cells per mCherry+ mVenus- cells + mCherry- mVenus+ cells were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating ß-cells in the islets and morphometric analysis of the islets after known mitogenic interventions such as S961, DIO, pregnancy, and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of ß-cell proliferation in response to mitogenic stimulation.


Assuntos
Proliferação de Células/fisiologia , Dieta Hiperlipídica/efeitos adversos , Células Secretoras de Insulina/fisiologia , Obesidade/induzido quimicamente , Peptídeos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez
8.
Sci Rep ; 9(1): 15562, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664108

RESUMO

The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic ß-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+ release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+ entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+ by the GPR40 agonist, fasiglifam. Furthermore, ß-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but also in vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic ß-cells.


Assuntos
Receptores de Inositol 1,4,5-Trifosfato/genética , Proteína ORAI1/genética , Receptores Acoplados a Proteínas G/genética , Molécula 1 de Interação Estromal/genética , Animais , Cálcio/metabolismo , Sinalização do Cálcio/genética , Retículo Endoplasmático/genética , Glucose/genética , Glucose/metabolismo , Humanos , Insulina/biossíntese , Insulina/genética , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout
9.
Curr Opin Organ Transplant ; 12(1): 40-48, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27792088

RESUMO

PURPOSE OF REVIEW: To summarize recent progress in understanding of the extrinsic and intrinsic signals directing pancreas development from early endoderm. RECENT FINDINGS: The pancreatic mesoderm was shown not only to play a permissive role in pancreas determination but also to control endocrine commitment and maturation through the interplay between Notch and fibroblast growth factor signaling. The requirement of Wnt (wingless-type)/ß-catenin signaling in the expansion of the acinar cell lineage, and the spatial-temporal specificity of PDX1 (pancreatic and duodenal homeobox) activity, which is needed for proper acinar development, were also demonstrated. A novel factor, IA1 (insulinoma-associated 1), was identified as an endocrine marker downstream of Ngn3 (neurogenin); MAFB (musculo-aponeurotic fibrosarcoma) was shown to be a marker of α-cell and ß-cell precursors, and ARX (aristaless-related homeobox), a marker of α-cell progenitors, was revealed to directly antagonize PAX4 (paired homeobox) in determining α-cell and ß-cell lineages. SUMMARY: Cell fate specification results from combined effects of extrinsic and intrinsic regulators and sensitivity of target cells to them, which vary depending on the precise stage of cell commitment or differentiation. Knowledge of the hierarchy of the different factors influencing pancreas development will aid in developing new cell therapies to treat diabetes.

10.
Cancer Res ; 63(16): 4836-41, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941803

RESUMO

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.


Assuntos
Insulinoma/etiologia , Ilhotas Pancreáticas/metabolismo , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/etiologia , Proteínas Proto-Oncogênicas , Animais , Glicemia/análise , Proteínas do Citoesqueleto/análise , Deleção de Genes , Insulina/sangue , Camundongos , Camundongos Knockout , Transativadores/análise , beta Catenina
11.
PLoS One ; 11(3): e0150880, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26959991

RESUMO

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing ß-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic ß-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of ß-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and ß-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered ß-cell function, presumably contributing to T2D pathogenesis.


Assuntos
Conexinas/metabolismo , Células Secretoras de Insulina/metabolismo , RNA Mensageiro/genética , Animais , Western Blotting , Membrana Celular/metabolismo , Conexinas/genética , Feminino , Imunofluorescência , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/química , Proteína delta-2 de Junções Comunicantes
12.
Mech Dev ; 121(1): 3-14, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14706695

RESUMO

Expression of nestin has been suggested to be a characteristic of pancreatic islet stem cells. To determine whether nestin is indeed expressed in such putative cells during embryonic development, or in the adult pancreas after injury, we performed a cell lineage analysis using two independent lines of transgenic mice encoding Cre recombinase under the control of rat nestin cis-regulatory sequences, each crossed with loxP-bearing R26R mice. F1 animals produced the reporter molecule beta-galactosidase only upon Cre-mediated recombination, thus solely in cells using (or having used) the transgenic nestin promoter. In early pancreatic primordia, beta-galactosidase was observed in mesenchymal and epithelial cells. At later developmental stages or in adults, vast clusters of acinar cells and few ductal cells were labeled, in addition to fibroblasts and vascular cells, but no endocrine cells were tagged by beta-galactosidase. This correlated with the transient expression, observed with an anti-nestin antibody, of endogenous nestin in about 5% of epithelial cells during development (whether in cord-forming arrangements or in nascent acini), and in vascular and mesenchymal structures. After partial pancreatectomy, there was a transient increase of the number of anti-nestin-labeled endothelial cells, but again, no endocrine cells bore beta-galactosidase. Together, these findings show that nestin is expressed in the pancreatic exocrine cell lineage, and suggest that consistent nestin expression is not a major feature of islet endocrine progenitor cells.


Assuntos
Proteínas de Filamentos Intermediários/genética , Proteínas do Tecido Nervoso/genética , Pâncreas/metabolismo , Amilases/metabolismo , Animais , Células Cultivadas , Epitélio/metabolismo , Genes Reporter , Proteínas de Filamentos Intermediários/biossíntese , Mesoderma/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/biossíntese , Nestina , Pâncreas/embriologia , Ratos
13.
Mol Metab ; 4(4): 277-86, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25830091

RESUMO

AIMS/HYPOTHESIS: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. METHODS: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. RESULTS: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. CONCLUSIONS/INTERPRETATION: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.

14.
Mol Endocrinol ; 27(5): 814-27, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23518924

RESUMO

Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs. Whereas ablation of insulin/IGF signaling appears dispensable for GCs and spermatogenesis, adult testes of mice lacking both Insr and Igf1r in SCs (SC-Insr;Igf1r) displayed a 75% reduction in testis size and daily sperm production as a result of a reduced proliferation rate of immature SCs during the late fetal and early neonatal testicular period. In addition, in vivo analyses revealed that FSH requires the insulin/IGF signaling pathway to mediate its proliferative effects on immature SCs. Collectively, these results emphasize the essential role played by growth factors of the insulin family in regulating the final number of SCs, testis size, and daily sperm output. They also indicate that the insulin/IGF signaling pathway is required for FSH-mediated SC proliferation.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Receptor de Insulina/metabolismo , Células de Sertoli/citologia , Células de Sertoli/metabolismo , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células , Forma Celular/efeitos dos fármacos , Feminino , Feto/citologia , Feto/embriologia , Perfilação da Expressão Gênica , Células Germinativas/citologia , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Humanos , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Túbulos Seminíferos/citologia , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/citologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Hormônios Tireóideos/farmacologia
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