RESUMO
Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse family of ionic channels that includes ATP-dependent potassium (KATP) channels in the potassium rectifier channel subfamily. These channels were initially described in heart muscle and then in other tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle tissues. In pancreatic beta cells, KATP channels are primarily responsible for maintaining the membrane potential and for depolarization-mediated insulin release, and their decreased density and activity may be related to insulin resistance. KATP channels' relationship with insulin resistance is beginning to be explored in extra-pancreatic beta tissues like the skeletal muscle, where KATP channels are involved in insulin-dependent glucose recapture and their activation may lead to insulin resistance. In adipose tissues, KATP channels containing Kir6.2 protein subunits could be related to the increase in free fatty acids and insulin resistance; therefore, pathological processes that promote prolonged adipocyte KATP channel inhibition might lead to obesity due to insulin resistance. In the central nervous system, KATP channel activation can regulate peripheric glycemia and lead to brain insulin resistance, an early peripheral alteration that can lead to the development of pathologies such as obesity and Type 2 Diabetes Mellitus (T2DM). In this review, we aim to discuss the characteristics of KATP channels, their relationship with clinical disorders, and their mechanisms and potential associations with peripheral and central insulin resistance.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Canais de Potássio , Insulina , Insulina Regular Humana , Hormônios Pancreáticos , Canais KATP , Obesidade , Potássio , Trifosfato de AdenosinaRESUMO
Pancreatic islets are mini-organs composed of hundreds or thousands of É, ß and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones for the regulation of blood glucose. In pancreatic islets, hormone secretion is tightly regulated by both internal and external mechanisms, including electrical communication and paracrine signaling between islet cells. Given its complexity, the experimental study of pancreatic islets has been complemented with computational modeling as a tool to gain a better understanding about how all the mechanisms involved at different levels of organization interact. In this review, we describe how multicellular models of pancreatic cells have evolved from the early models of electrically coupled ß-cells to models in which experimentally derived architectures and both electrical and paracrine signals have been considered.
Assuntos
Células Secretoras de Insulina , Ilhotas Pancreáticas , Ilhotas Pancreáticas/fisiologia , Células Secretoras de Insulina/fisiologia , Insulina , Glucagon , Hormônios PancreáticosRESUMO
AIMS: The objective of this study was to assess the mechanisms underlying pancreatic islet adaptation in diabetic mothers and their pups. Additionally, the influence of pancreatic adaptations on maternal reproductive performance was also investigated. MAIN METHODS: Wistar rats were injected with streptozotocin for diabetes induction. At adulthood (3â¯months), all animals underwent an oral glucose tolerance test (OGTT) for glucose assessment as an inclusion criterion. Following, the animals were mated. At day 18 of pregnancy, the mothers were killed for blood collect ion to determine fasting insulin and glucagon concentrations. The pancreas was removed and processed for the immunohistochemical analysis of insulin, glucagon, somatostatin, Ki-67 and PDX-1, superoxide dismutase 1 (SOD-1), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA). The pregnant uterus was also collected for the evaluation of embryofetal loss. KEY FINDINGS: The diabetic rats showed increased glucose, serum glucagon and insulin concentrations, and embryofetal loss rates. They also showed a reduction in pancreatic islets area and percentage of cells stained for insulin, increased the percentage of non-ß cells (alpha e delta cells) stained for Ki-67, glucagon, and somatostatin. Moreover, the cells stained for somatostatin were spread across the islets and showed stronger staining for MDA and weaker staining for GSH-Px. SIGNIFICANCE: Diabetes leads to adaptive responses from the endocrine pancreas in pregnancy that especially involves non-ß cells, modifying the mantle-core structure. Nonetheless, these adaptations are not enough for glucose homeostasis and affect the maternal environment, which in turn impairs fetal development.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Gravidez em Diabéticas/fisiopatologia , Animais , Antioxidantes/metabolismo , Enzimas/metabolismo , Feminino , Teste de Tolerância a Glucose , Insulina/sangue , Masculino , Estresse Oxidativo , Hormônios Pancreáticos/metabolismo , Gravidez , Ratos WistarRESUMO
The experiment was carried out in a completely randomized design (CRD) with 625 broiler chicks (Ross 308) for 5 repetitions (25 birds per each replicated) on the 5 treatments diet. Treatments included two different types of cereal grains (wheat, and barley) with or without an enzyme supplementation along with a corn-based diet as control group. The experimental diets were formulated to have similar contents of crude protein, metabolizable energy, total non-starch polysaccharides (NSP) and were fed in two periods of starter and grower. Experimental traits were consisted growth performance, ileal flora numeration, villus morphology in 3 parts of the intestine, digesta viscosity and pancreatic enzyme activity, and determining the gene expression level of glucose transporter (SGLT1) and mucin producer (MUC2) in the jejunum. Results indicated that inclusion of wheat and barley to corn-soy based diet with or without exo-enzymes blend on growth performance traits were significant (p 0.01). Feed intake and average daily gain in wheat diet was lower, conversely FCR was higher than other groups (p 0.01). Maximum microbial count were observed in wheat and barley diets and minimum were observed in enzyme supplemented diets respectively (p 0.01). Control group and enzyme supplemented diets had minimum counting of gram negative, coliform and clostridium, but maximum counting of lactobacilli and bifidobacter were observed in enzyme supplemented diets (p 0.01). Viscosity and activities of pancreatic a-amylase and lipase were significantly increased in chicks fed wheat and barley when compared to the control group fed on corn (p 0.01). Feeding wheat and barley diets reduced villus height in different parts of the small intestine when compared to those fed on a corn diet (p 0.01).(AU)
Assuntos
Animais , Aves Domésticas/crescimento & desenvolvimento , Aves Domésticas/metabolismo , Aves Domésticas/fisiologia , Glucose , Hormônios Pancreáticos/efeitos adversos , Hormônios Pancreáticos/análise , PolissacarídeosRESUMO
The experiment was carried out in a completely randomized design (CRD) with 625 broiler chicks (Ross 308) for 5 repetitions (25 birds per each replicated) on the 5 treatments diet. Treatments included two different types of cereal grains (wheat, and barley) with or without an enzyme supplementation along with a corn-based diet as control group. The experimental diets were formulated to have similar contents of crude protein, metabolizable energy, total non-starch polysaccharides (NSP) and were fed in two periods of starter and grower. Experimental traits were consisted growth performance, ileal flora numeration, villus morphology in 3 parts of the intestine, digesta viscosity and pancreatic enzyme activity, and determining the gene expression level of glucose transporter (SGLT1) and mucin producer (MUC2) in the jejunum. Results indicated that inclusion of wheat and barley to corn-soy based diet with or without exo-enzymes blend on growth performance traits were significant (p 0.01). Feed intake and average daily gain in wheat diet was lower, conversely FCR was higher than other groups (p 0.01). Maximum microbial count were observed in wheat and barley diets and minimum were observed in enzyme supplemented diets respectively (p 0.01). Control group and enzyme supplemented diets had minimum counting of gram negative, coliform and clostridium, but maximum counting of lactobacilli and bifidobacter were observed in enzyme supplemented diets (p 0.01). Viscosity and activities of pancreatic a-amylase and lipase were significantly increased in chicks fed wheat and barley when compared to the control group fed on corn (p 0.01). Feeding wheat and barley diets reduced villus height in different parts of the small intestine when compared to those fed on a corn diet (p 0.01).
Assuntos
Animais , Aves Domésticas/crescimento & desenvolvimento , Aves Domésticas/fisiologia , Aves Domésticas/metabolismo , Glucose , Hormônios Pancreáticos/análise , Hormônios Pancreáticos/efeitos adversos , PolissacarídeosRESUMO
The aim of the study was to investigate the role of diabetic intrauterine environment on circulating insulin, glucagon, and somatostatin levels in pregnant rats, fetuses, and offspring. Diabetes was induced in female Wistar rats by streptozotocin at birth or as adult and the animals were assigned into: control (C); mildly diabetic (MD); and severely diabetic (SD). The rats were mated and distributed into 2 subgroups: euthanasia at day 21 of pregnancy and at day 10 postpartum. Both MD and SD dams showed impaired oral glucose tolerance. SD dams had lower body weight and insulin levels compared to C and MD dams. SD fetuses presented hyperglycemia and reduction of insulin and glucagon levels compared to C and MD fetuses. SD newborns had diminished total pancreatic insulin and plasma somatostatin compared to the other groups. MD dams and fetuses had lower glucagon and somatostatin levels compared to C dams. MD offspring had maintained lower somatostatin levels to neonatal period. Diabetes causes alterations in circulating levels of pancreatic hormones in the mother and offspring.
Assuntos
Biomarcadores/sangue , Diabetes Mellitus Experimental/fisiopatologia , Glucagon/sangue , Insulina/sangue , Hormônios Pancreáticos/sangue , Somatostatina/sangue , Animais , Animais Recém-Nascidos , Feminino , Gravidez , Ratos , Ratos WistarRESUMO
Hepatic oval cells (OC) are considered to be facultative liver stem cells and, because they may undergo differentiation into a variety of cell lineages, they might have the potential to be used in cellular therapy. Signals delivered by extracellular matrix (ECM) proteins take part in cellular differentiation in cooperation with signals from growth factors; indeed, some ECM proteins, such as laminin (LAM) and fibronectin (FN), have been shown to contribute to beta-cell differentiation and islet development, respectively. Since no previous studies have investigated the effect of ECM proteins on the expression of islet cell markers by cultured OC, the purpose of the present study was to evaluate whether FN and LAM modulate the expression of genes related to the endocrine pancreas in these liver cells. OC proliferation was induced in Wistar rats by prolonged treatment with 2-acetoaminofluorene/allyl alcohol and confirmed by reverse transcription/polymerase chain reaction and hepatic immunocytochemical and histopathological analyses. OC isolation was performed by Ficoll gradient and magnetic-activated cell sorting. OC were cultured for 1 and 2 months under several conditions with specific growth factors, over a FN or LAM substrate or in high glucose, nicotinamide and fetal calf serum. OC cultured on FN substrate expressed Pdx-1, Pax-6, insulin 2 and glucagon. LAM also induced the expression of Pdx-1, insulin 1 and insulin 2, glucagon, somatostatin and GLUT-2. Our results suggest that these ECM proteins can be used in protocols of OC transdifferentiation aimed at reducing the period necessary for complete transdifferentiation.
Assuntos
Fibronectinas/farmacologia , Células Secretoras de Insulina/metabolismo , Laminina/farmacologia , Fígado/efeitos dos fármacos , Hormônios Pancreáticos/metabolismo , Células-Tronco/efeitos dos fármacos , 2-Acetilaminofluoreno/toxicidade , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Separação Celular , Células Cultivadas , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucagon/genética , Glucagon/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Insulina/genética , Insulina/metabolismo , Fígado/citologia , Fígado/metabolismo , Masculino , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Hormônios Pancreáticos/genética , Propanóis/toxicidade , Ratos , Ratos Wistar , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Organismos Livres de Patógenos Específicos , Células-Tronco/citologia , Células-Tronco/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
Carcinoid tumors of the ampulla of Vater (ACs) differ from duodenal carcinoid tumors (DCs). A search for AC and DC was made between 1980 and 2000. The clinicopathologic features and follow-up were assessed. Immunohistochemistry for panneuroendocrine markers, hormone products, proliferating cell nuclear antigen (PCNA), Ki- 67, p21(cip1), and p27(kip1) were performed. A blind proliferative index counting 500 cells was made. Differences were contrasted using the Fisher exact and 2-sided Student t test. Five ACs and 8 DCs were identified in 9 women and 4 men with median ages of 59 and 64 years and mean tumor diameters of 1.6 and 1.85 cm, respectively. All patients with AC presented jaundice, and most patients with DC were asymptomatic (P = .047). Metastases were present in 4 ACs and 1 DC (P =.03). Tumor cells expressed synaptophysin and chromogranin in 60% of ACs and in 100% and 87% of DCs. Gastrin was expressed in 75% of DCs and 20% of ACs (P < .05). The mean value for PCNA index was 4.0% in ACs and 3.2% in DCs, and mean values for Ki-67 were 12.2% and 10.2%, respectively (P = NS). Expression of p21(cip1) and p27(kip1) was observed in 40% of ACs and 37.5% and 12.5% of DCs. Three of 5 patients with AC died of the disease within an average of 11 months, and none of the patients with DC had died at 103 months of follow-up. The more aggressive behavior of ACs is not associated with higher proliferative indices or with different expression of cell cycle inhibitors.
Assuntos
Ampola Hepatopancreática , Tumor Carcinoide/diagnóstico , Neoplasias do Ducto Colédoco/diagnóstico , Neoplasias Duodenais/diagnóstico , Tumor Carcinoide/metabolismo , Tumor Carcinoide/patologia , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Divisão Celular , Núcleo Celular/metabolismo , Neoplasias do Ducto Colédoco/metabolismo , Neoplasias do Ducto Colédoco/patologia , Diagnóstico Diferencial , Neoplasias Duodenais/metabolismo , Neoplasias Duodenais/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Cinética , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Hormônios Pancreáticos/imunologia , Hormônios Pancreáticos/metabolismo , Antígeno Nuclear de Célula em Proliferação/imunologia , Antígeno Nuclear de Célula em Proliferação/metabolismoRESUMO
We have investigated the type and frequency of hormone coexpression in the endocrine pancreas of amphibians both under basal conditions and after sustained glucose loading. Adult male specimens of the wild toad Bufo arenarum were injected with a 50% (w/v) glucose solution (2 g/100 g) for 2 days, while control animals received an equal volume of the vehicle. Serum glucose levels were measured at the time of sacrifice and the pancreatic free lobe was processed for light microscopy. A double-labeling immunofluorescence study was performed for the detection of insulin (I), glucagon (G), somatostatin (S), and pancreatic polypeptide (PP). Heterospecific antisera against the following hormone combinations were used for their detection and immunocytochemical localization: I+G, I+PP, G+PP, S+G, and S+PP; visualization of the reacted IgG's was effected by fluorescein- and rhodamine-conjugated species-specific antibodies as fluorophores. Intracellular hormone coexpression was found to occur in the combinations G+PP, S+G, and S+PP. Moreover, glucose administration caused, together with a marked hyperglycemia (123 +/- 17 vs 23 +/- 1 mg/dl; P < 0.05), a decrease in the fraction of cells containing both G and PP together (from 106.3 +/- 8.1 to 26 +/- 4 cell/mm2) along with a reciprocal rise in the number of cells possessing G alone (from 128.7-152.3 to 235.9-274 cell/mm2). The fewer number of cells coexpressing either of the other two hormone combinations, however, were unaffected by glucose injection. With respect to the simultaneous measurement of I+G and I+PP, no cells were detected with both hormones of either pair, and the I-containing cells were more frequent in each instance in the control toads (264.8 +/- 22.3 to 269.2 +/- 27 cell/mm2). For both combinations, however, this value diminished significantly in the glucose-treated animals (108 +/- 2 cell/mm2 for I+G and 112.1 +/- 7. 8 cell/mm2 for I+PP). While the G-containing cells became more numerous (rising to 235.9 +/- 12.4, 274 +/- 26, and 250.4 +/- 23.7 cell/mm2 for I-G, G-PP, and G-S combinations, respectively), the PP- and S-containing cells remained unaffected. We conclude that the copresence of different hormones within the same cell is a relatively common finding in the non-I-secreting elements of the adult toad pancreas and that the proportions of specific cell types are affected by glucose administration. We thus propose that intracellular hormonal coexpression in this fashion may well represent a rapid and efficient regulatory mechanism for compensating for the metabolic stress imposed by glucose loading.