RESUMO
Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level. Graphical abstract.
Assuntos
Glicemia/metabolismo , Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Animais , Proteínas Reguladoras de Apoptose , Glicemia/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Proteínas de Drosophila , Metabolismo Energético/fisiologia , Retroalimentação Fisiológica/fisiologia , Controle Glicêmico , Homeostase , Humanos , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/fisiopatologia , Obesidade/fisiopatologia , Sistema Nervoso Parassimpático/fisiopatologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Intraportal islet transplantation has been clinically applied for treatment of unstable type 1 diabetes. However, in the liver, systematic assessment of the dispersed islet grafts and the graft-hepatic integration remains difficult, even in animal models. This is due to the lack of global and in-depth analyses of the transplanted islets and their microenvironment. Here, we apply three-dimensional (3-D) mouse liver histology to investigate the islet graft microstructure, vasculature, and innervation. Streptozotocin-induced diabetic mice were used in syngeneic intraportal islet transplantation to achieve euglycemia. Optically cleared livers were prepared to enable 3-D morphological and quantitative analyses of the engrafted islets. 3-D image data reveal the clot- and plaque-like islet grafts in the liver: the former are derived from islet emboli and associated with ischemia, whereas the latter (minority) resemble the plaques on the walls of portal vessels (e.g., at the bifurcation) with mild, if any, perigraft tissue damage. Three weeks after transplantation, both types of grafts are revascularized, yet significantly more lymphatics are associated with the plaque- than clot-like grafts. Regarding the islet reinnervation, both types of grafts connect to the periportal nerve plexus and develop peri- and intragraft innervation. Specifically, the sympathetic axons and varicosities contact the α-cells, highlighting the graft-host neural integration. We present the heterogeneity of the intraportally transplanted islets and the graft-host neurovascular integration in mice. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue and cellular analyses of human islet grafts in the liver.NEW & NOTEWORTHY Modern 3-D histology identifies the clot- and plaque-like islet grafts in the mouse liver, which otherwise cannot be distinguished with the standard microtome-based histology. The two types of grafts are similar in blood microvessel density and sympathetic reinnervation. Their differences, however, are their locations, severity of associated liver injury, and access to lymphatic vessels. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue/cellular analyses of human islet grafts in the liver.
Assuntos
Diabetes Mellitus Experimental/terapia , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Fígado/patologia , Animais , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/patologia , Sobrevivência de Enxerto/fisiologia , Técnicas Histológicas , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/patologia , Transplante das Ilhotas Pancreáticas/métodos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Veia Porta , Regeneração/fisiologiaRESUMO
Increasing evidence suggests that, although pancreatic islets can function autonomously to detect and respond to changes in the circulating glucose level, the brain cooperates with the islet to maintain glycaemic control. Here, we review the role of the central and autonomic nervous systems in the control of the endocrine pancreas, including mechanisms whereby the brain senses circulating blood glucose levels. We also examine whether dysfunction in these systems might contribute to complications of type 1 diabetes and the pathogenesis of type 2 diabetes. Graphical abstract.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Glicemia/metabolismo , Sistema Nervoso Central/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/inervação , Animais , Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Células Receptoras SensoriaisRESUMO
The pancreas consists of both the exocrine (acini and ducts) and endocrine (islets) compartments to participate in and regulate the body's digestive and metabolic activities. These activities are subjected to neural modulation, but characterization of the human pancreatic afferent and efferent nerves remains difficult because of the lack of three-dimensional (3-D) image data. Here we prepare transparent human donor pancreases for 3-D histology to reveal the pancreatic microstructure, vasculature, and innervation in a global and integrated fashion. The pancreatic neural network consists of the substance P (SP)-positive sensory (afferent) nerves, the vesicular acetylcholine transporter (VAChT)-positive parasympathetic (efferent) nerves, and the tyrosine hydroxylase (TH)-positive sympathetic (efferent) nerves. The SP+ afferent nerves were found residing along the basal domain of the interlobular ducts. The VAChT+ and TH+ efferent nerves were identified at the peri-acinar and perivascular spaces, which follow the blood vessels to the islets. In the intrapancreatic ganglia, the SP+ (scattered minority, ~7%) and VAChT+ neurons co-localize, suggesting a local afferent-efferent interaction. Compared with the mouse pancreas, the human pancreas differs in 1) the lack of SP+ afferent nerves in the islet, 2) the lower ganglionic density, and 3) the obvious presence of VAChT+ and TH+ nerves around the intralobular adipocytes. The latter implicates the neural influence on the pancreatic steatosis. Overall, our 3-D image data reveal the human pancreatic afferent and efferent innervation patterns and provide the anatomical foundation for future high-definition analyses of neural remodeling in human pancreatic diseases.NEW & NOTEWORTHY Modern three-dimensional (3-D) histology with multiplex optical signals identifies the afferent and efferent innervation patterns of human pancreas, which otherwise cannot be defined with standard histology. Our 3-D image data reveal the unexpected association of sensory and parasympathetic nerves/neurons in the intrapancreatic ganglia and identify the sympathetic and parasympathetic nerve contacts with the infiltrated adipocytes. The multiplex approach offers a new way to characterize the human pancreas in remodeling (e.g., fatty infiltration and duct lesion progression).
Assuntos
Ilhotas Pancreáticas/citologia , Neurônios Aferentes/citologia , Neurônios Eferentes/citologia , Pâncreas Exócrino/citologia , Células Acinares/citologia , Tecido Adiposo/citologia , Tecido Adiposo/inervação , Adulto , Animais , Feminino , Humanos , Imageamento Tridimensional , Ilhotas Pancreáticas/inervação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Técnicas de Rastreamento Neuroanatômico , Neurônios Aferentes/metabolismo , Neurônios Eferentes/metabolismo , Pâncreas Exócrino/inervação , Substância P/genética , Substância P/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
Neurovascular alignment is a common anatomical feature of organs, but the mechanisms leading to this arrangement are incompletely understood. Here, we show that vascular endothelial growth factor (VEGF) signaling profoundly affects both vascularization and innervation of the pancreatic islet. In mature islets, nerves are closely associated with capillaries, but the islet vascularization process during embryonic organogenesis significantly precedes islet innervation. Although a simple neuronal meshwork interconnects the developing islet clusters as they begin to form at E14.5, the substantial ingrowth of nerve fibers into islets occurs postnatally, when islet vascularization is already complete. Using genetic mouse models, we demonstrate that VEGF regulates islet innervation indirectly through its effects on intra-islet endothelial cells. Our data indicate that formation of a VEGF-directed, intra-islet vascular plexus is required for development of islet innervation, and that VEGF-induced islet hypervascularization leads to increased nerve fiber ingrowth. Transcriptome analysis of hypervascularized islets revealed an increased expression of extracellular matrix components and axon guidance molecules, with these transcripts being enriched in the islet-derived endothelial cell population. We propose a mechanism for coordinated neurovascular development within pancreatic islets, in which endocrine cell-derived VEGF directs the patterning of intra-islet capillaries during embryogenesis, forming a scaffold for the postnatal ingrowth of essential autonomic nerve fibers.
Assuntos
Vasos Sanguíneos/fisiologia , Comunicação Celular/genética , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/inervação , Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Vasos Sanguíneos/embriologia , Células Cultivadas , Embrião de Mamíferos , Endotélio Vascular/embriologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Feminino , Ilhotas Pancreáticas/embriologia , Camundongos , Camundongos Transgênicos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The progressive loss of pancreatic ß-cell mass that occurs in both type 1 and type 2 diabetes is a primary factor driving efforts to identify strategies for effectively increasing, enhancing or restoring ß-cell mass. While factors that seem to influence ß-cell proliferation in specific contexts have been described, reliable stimulation of human ß-cell proliferation has remained a challenge. Importantly, ß-cells exist in the context of a complex, integrated pancreatic islet microenvironment where they interact with other endocrine cells, vascular endothelial cells, extracellular matrix, neuronal projections and islet macrophages. This review highlights different components of the pancreatic microenvironment, and reviews what is known about how signaling that occurs between ß-cells and these other components influences ß-cell proliferation. Future efforts to further define the role of the pancreatic islet microenvironment on ß-cell proliferation may lead to the development of successful approaches to increase or restore ß-cell mass in diabetes.
Assuntos
Comunicação Celular , Proliferação de Células , Microambiente Celular , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Modelos Biológicos , Animais , Apoptose , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/imunologia , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/patologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Células Secretoras de Polipeptídeo Pancreático/citologia , Células Secretoras de Polipeptídeo Pancreático/imunologia , Células Secretoras de Polipeptídeo Pancreático/metabolismo , Células Secretoras de Polipeptídeo Pancreático/patologia , Células Secretoras de Somatostatina/citologia , Células Secretoras de Somatostatina/imunologia , Células Secretoras de Somatostatina/metabolismo , Células Secretoras de Somatostatina/patologia , Especificidade da EspécieRESUMO
BACKGROUND: Obesity and insulin resistance lead to islet hyperplasia. However, how the islet remodeling influences the pancreatic environment and the associated neurovascular networks is largely unknown. The lack of information is primarily due to the difficulty of global visualization of the hyperplasic islet (>200 µm) and the neurovascular environment with high definition. METHODS: We modulated the pancreatic optical property to achieve 3-dimensional (3-D) whole-islet histology and to integrate transmitted light microscopy (which provides the ground-truth tissue information) with confocal fluorescence imaging. The new optical and imaging conditions were used to globally examine the hyperplastic islets of the young (2 months) obese db/db and ob/ob mice, which otherwise cannot be easily portrayed by the standard microtome-based histology. The voxel-based islet micrographs were digitally processed for stereo projection and qualitative and quantitative analyses of the islet tissue networks. RESULTS: Paired staining and imaging of the pancreatic islets, ducts and neurovascular networks reveal the unexpected formation of the 'neuro-insular-ductal complex' in the young obese mice. The complex consists of the peri- and/or intra-islet ducts and prominent peri-ductal sympathetic nerves; the latter contributes to a marked increase in islet sympathetic innervation. In vascular characterization, we identify a decreased perivascular density of the ob/ob islet pericytes, which adapt to ensheathing the dilated microvessels with hypertrophic processes. CONCLUSIONS: Modulation of pancreatic optical property enables 3-D panoramic examination of islets in the young hyperphagic mice to reveal the formation of the islet-duct complex and neurovascular remodeling. On the basis of the morphological proximity of the remodeled tissue networks, we propose a reactive islet microenvironment consisting of the endocrine cells, ductal epithelium and neurovascular tissues in response to the metabolic challenge that is experienced early in life.
Assuntos
Hiperfagia/patologia , Imageamento Tridimensional , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/inervação , Obesidade/patologia , Sistema Nervoso Simpático/patologia , Animais , Resistência à Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Obesos , Plasticidade Neuronal , Obesidade/metabolismoRESUMO
Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell-cell communication is a fundamental property of this micro-organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication.
Assuntos
Comunicação Celular/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Modelos Biológicos , Animais , Junções Comunicantes/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Comunicação Parácrina/fisiologiaRESUMO
Type 1 diabetes (T1D) patients who receive pancreatic islet transplant experience significant improvement in their quality-of-life. This comes primarily through improved control of blood sugar levels, restored awareness of hypoglycemia, and prevention of serious and potentially life-threatening diabetes-associated complications, such as kidney failure, heart and vascular disease, stroke, nerve damage, and blindness. Therefore, beta cell replacement through transplantation of isolated islets is an important option in the treatment of T1D. However, lasting success of this promising therapy depends on durable survival and efficacy of the transplanted islets, which are directly influenced by the islet isolation procedures. Thus, isolating pancreatic islets with consistent and reliable quality is critical in the clinical application of islet transplantation.Quality of isolated islets is important in pre-clinical studies as well, as efforts to advance and improve clinical outcomes of islet transplant therapy have relied heavily on animal models ranging from rodents, to pigs, to nonhuman primates. As a result, pancreatic islets have been isolated from these and other species and used in a variety of in vitro or in vivo applications for this and other research purposes. Protocols for islet isolation have been somewhat similar across species, especially, in mammals. However, given the increasing evidence about the distinct structural and functional features of human and mouse islets, using similar methods of islet isolation may contribute to inconsistencies in the islet quality, immunogenicity, and experimental outcomes. This may also contribute to the discrepancies commonly observed between pre-clinical findings and clinical outcomes. Therefore, it is prudent to consider the particular features of pancreatic islets from different species when optimizing islet isolation protocols.In this chapter, we explore the structural and functional features of pancreatic islets from mice, pigs, nonhuman primates, and humans because of their prevalent use in nonclinical, preclinical, and clinical applications.
Assuntos
Ilhotas Pancreáticas/fisiologia , Animais , Humanos , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/inervação , Comunicação Parácrina , Transdução de SinaisRESUMO
Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Regulação para Baixo , Gânglios Simpáticos/fisiopatologia , Glucagon/metabolismo , Hiperglicemia/etiologia , Ilhotas Pancreáticas/metabolismo , Transmissão Sináptica , Animais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estimulação Elétrica , Gânglios Simpáticos/efeitos dos fármacos , Gânglios Simpáticos/metabolismo , Estimulantes Ganglionares/farmacologia , Glucagon/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/inervação , Masculino , Proteínas Mutantes/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Agonistas Nicotínicos/farmacologia , Norepinefrina/sangue , Norepinefrina/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Degeneração Walleriana/complicaçõesRESUMO
The neural apparatus and the endocrine part of the pancreas was studied in Wistar rats aged 3-4 and 19 months (n = 24) using the immunohistochemical reactions for synaptophysin (Syn), tyrosine hydroxylase (TH) and protein gene product 9.5 (PGP 9.5). Since Syn and PGP 9.5 are highly selective in detection of pancreatic islet (PI) endocrinocytes, it was possible to examine their topography and density in all parts of the pancreas. It was found that in rats aged 19 months, the total number of PI was decreased as compared to that in young animals. The study of PI size distribution has shown that the number of large islets decreased with age. Young animals showed rich innervation of the pancreas which was represented by three nerve plexuses: the first was a broadly-looped one, formed by small nerve trunks and bundles of unmyelinated and myelinated nerve fibers, the second consisted of thin bundles of postganglionic axons and microganglia, and the third (main terminal plexus) was formed by axons with varicosities and synapses of "en passant" type. In aged rats, marked degenerative changes in the neurons of intramural ganglia, nerve trunks and bundles were noted together with the reduction or complete absence of Syn- and TH-positive efferent parasympathetic and sympathetic terminals around blood vessels, excretory ducts, denervation of the exocrine and endocrine parts of the pancreas. Innervation disturbances in some lobules were accompanied by small inflammatory perivascular infiltrates.
Assuntos
Envelhecimento/patologia , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/patologia , Envelhecimento/metabolismo , Animais , Gânglios Autônomos/metabolismo , Gânglios Autônomos/ultraestrutura , Imuno-Histoquímica , Ilhotas Pancreáticas/metabolismo , Fibras Nervosas/metabolismo , Fibras Nervosas/ultraestrutura , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/ultraestrutura , Ratos Wistar , Sinaptofisina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In this symposium review we discuss the role of neurotransmitters as paracrine signals that regulate pancreatic islet function. A large number of neurotransmitters and their receptors has been identified in the islet, but relatively little is known about their involvement in islet biology. Interestingly, neurotransmitters initially thought to be present in autonomic axons innervating the islet are also present in endocrine cells of the human islet. These neurotransmitters can thus be released as paracrine signals to help control hormone release. Here we propose that the role of neurotransmitters may extend beyond controlling endocrine cell function to work as signals modulating vascular flow and immune responses within the islet.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Neurotransmissores/metabolismo , Comunicação Parácrina , Animais , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/inervaçãoRESUMO
Children exposed to a maternal Western-style diet in utero have an increased risk of developing type 2 diabetes. Understanding the mechanisms and an investigation of possible interventions are critical to reversing this phenomenon. We examined the impact of maternal Western-style diet consumption on the development of islet vascularization and innervation, both of which are critical to normal islet function, in fetal and juvenile offspring. Furthermore, we assessed whether improved dietary intake or resveratrol supplementation could ameliorate the harmful consequences of Western-style diet consumption during pregnancy. Adult female Japanese macaques were maintained on a control or Western-style diet for 4-7 yr. One cohort of dams was switched back onto a control diet, whereas another cohort received resveratrol supplementation throughout gestation. Pregnancies were terminated in the early third trimester by C-section, or offspring were born naturally and sent to necropsy at 1 yr of age. Western-style diet consumption resulted in impaired fetal islet capillary density and sympathetic islet innervation. Furthermore, this reduction in vascularization persisted in the juvenile offspring. This effect is independent of changes in the expression of key angiogenic markers. Diet reversal normalized islet vascularization to control offspring levels, whereas resveratrol supplementation caused a significant increase in capillary density above controls. These data provide a novel mechanism by which maternal Western-style diet consumption leads to increased susceptibility to type 2 diabetes in the offspring. Importantly, an improved maternal diet may mitigate these harmful effects. However, until the long-term consequences of increased vascularization can be determined, resveratrol use during pregnancy is not advised.
Assuntos
Capilares/crescimento & desenvolvimento , Dieta , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/inervação , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Sistema Nervoso Simpático/crescimento & desenvolvimento , Animais , Feminino , Macaca mulatta , Masculino , Neovascularização Fisiológica/fisiologia , Gravidez , PrenhezRESUMO
Microscopic examination of transplanted islets in an ectopic environment provides information to evaluate islet engraftment, including revascularization and reinnervation. However, because of the dispersed nature of blood vessels and nerves, global visualization of the graft neurovascular network has been difficult. In this research we revealed the neurovascular network by preparing transparent mouse islet grafts under the kidney capsule with optical clearing to investigate the sympathetic reinnervation via three-dimensional confocal microscopy. Normoglycemic and streptozotocin-induced diabetic mice were used in syngeneic islet transplantation, with both groups maintaining euglycemia after transplantation. Triple staining of insulin/glucagon, blood vessels, and tyrosine hydroxylase (sympathetic marker) was used to reveal the graft microstructure, vasculature, and sympathetic innervation. Three weeks after transplantation, we observed perigraft sympathetic innervation similar to the peri-islet sympathetic innervation in the pancreas. Six weeks after transplantation, prominent intragraft, perivascular sympathetic innervation was achieved, resembling the pancreatic intraislet, perivascular sympathetic innervation in situ. Meanwhile, in diabetic recipients, a higher graft sympathetic nerve density was found compared with grafts in normoglycemic recipients, indicating the graft neural plasticity in response to the physiological difference of the recipients and the resolving power of this imaging approach. Overall, this new graft imaging method provides a useful tool to identify the islet neurovascular complex in an ectopic environment to study islet engraftment.
Assuntos
Transplante das Ilhotas Pancreáticas/fisiologia , Ilhotas Pancreáticas/inervação , Rim/inervação , Plasticidade Neuronal/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Rim/metabolismo , CamundongosRESUMO
Meal-fed (MF) rats with access to food for only 4 consecutive hours during the light cycle learn to eat large meals to maintain energy balance. MF animals develop behavioral and endocrine changes that permit glucose tolerance despite increased meal size. We hypothesized that enhanced activity of the enteroinsular axis mediates glucose homeostasis during MF. Cohorts of rats were allocated to MF or ad libitum (AL) regimens for 2-4 wk. Insulin secretion and glucose tolerance were determined after oral carbohydrate and intraperitoneal (ip) and intravenous (iv) glucose. MF rats ate less than AL in the first week but maintained a comparable weight trajectory thereafter. MF rats had decreased glucose excursions after a liquid mixed meal (AUC: MF 75 ± 7, AL 461 ± 28 mmol·l⻹·min, P < 0.001), with left-shifted insulin secretion (AUC(0-15): MF 31.0 ± 4.9, AL 9.6 ± 4.4 pM·min, P < 0.02), which peaked before a significant rise in blood glucose. Both groups had comparable fasting glucagon levels, but postprandial responses were lower with MF. However, neither intestinal expression of proGIP and proglucagon mRNA nor plasma incretin levels differed between MF and AL groups. There were no differences in the insulin response to ip or iv glucose between MF and AL rats. These findings demonstrate that MF improves oral glucose tolerance and is associated with significant changes in postprandial islet hormone secretion. Because MF enhanced ß-cell function during oral but not parenteral carbohydrate administration, and was not accounted for by changes in circulating incretins, these results support a neural mechanism of adaptive insulin secretion.
Assuntos
Alostase , Comportamento Alimentar , Intolerância à Glucose/tratamento farmacológico , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Refeições , Sistemas Neurossecretores/fisiopatologia , Animais , Comportamento Animal , Polipeptídeo Inibidor Gástrico/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Glucagon/sangue , Glucagon/genética , Glucagon/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Hiperglicemia/prevenção & controle , Íleo/metabolismo , Incretinas/sangue , Incretinas/metabolismo , Insulina/sangue , Secreção de Insulina , Mucosa Intestinal/metabolismo , Ilhotas Pancreáticas/inervação , Jejuno/metabolismo , Masculino , Especificidade de Órgãos , Período Pós-Prandial , Proglucagon/genética , Proglucagon/metabolismo , Ratos Long-EvansRESUMO
Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective ß3-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for ß3-adrenoceptors.
Assuntos
Hiperlipidemias/fisiopatologia , Insulina/metabolismo , Ilhotas Pancreáticas/irrigação sanguínea , Receptores Adrenérgicos beta 3/metabolismo , Fluxo Sanguíneo Regional , Regulação para Cima , Nervo Vago/fisiopatologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Emulsões/efeitos adversos , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Insulina/sangue , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pâncreas/irrigação sanguínea , Pâncreas/efeitos dos fármacos , Pâncreas/inervação , Pâncreas/metabolismo , Perfusão , Fosfolipídeos/efeitos adversos , Propanolaminas/farmacologia , Ratos Endogâmicos WF , Receptores Adrenérgicos beta 3/química , Fluxo Sanguíneo Regional/efeitos dos fármacos , Óleo de Soja/efeitos adversos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos , Vagotomia Troncular , Nervo Vago/efeitos dos fármacos , Nervo Vago/cirurgiaRESUMO
Dysregulation of hepatic glucose uptake (HGU) and inability of insulin to suppress hepatic glucose production (HGP) contribute to hyperglycaemia in patients with type 2 diabetes (T2D). Growing evidence suggests that insulin can inhibit HGP not only through a direct effect on the liver but also through a mechanism involving the brain. Yet, the notion that insulin action in the brain plays a physiological role in the control of HGP continues to be controversial. Although studies in dogs suggest that the direct hepatic effect of insulin is sufficient to explain day-to-day control of HGP, a surprising outcome has been revealed by recent studies in mice, investigating whether the direct hepatic action of insulin is necessary for normal HGP: when the hepatic insulin signalling pathway was genetically disrupted, HGP was maintained normally even in the absence of direct input from insulin. Here, we present evidence that points to a potentially important role of the brain in the physiological control of both HGU and HGP in response to input from insulin as well as other hormones and nutrients.
Assuntos
Encéfalo/metabolismo , Retroalimentação Fisiológica , Gluconeogênese , Glicólise , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Modelos Biológicos , Animais , Glucose/metabolismo , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/agonistas , Proteínas Substratos do Receptor de Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/inervação , Fígado/inervação , Neurônios/metabolismo , Transdução de SinaisRESUMO
Pulsatile secretion is an inherent property of hormone-releasing pancreatic islet cells. This secretory pattern is physiologically important and compromised in diabetes. Neurotransmitters released from islet cells may shape the pulses in auto/paracrine feedback loops. Within islets, glucose-stimulated ß-cells couple via gap junctions to generate synchronized insulin pulses. In contrast, α- and δ-cells lack gap junctions, and glucagon release from islets stimulated by lack of glucose is non-pulsatile. Increasing glucose concentrations gradually inhibit glucagon secretion by α-cell-intrinsic mechanism/s. Further glucose elevation will stimulate pulsatile insulin release and co-secretion of neurotransmitters. Excitatory ATP may synchronize ß-cells with δ-cells to generate coinciding pulses of insulin and somatostatin. Inhibitory neurotransmitters from ß- and δ-cells can then generate antiphase pulses of glucagon release. Neurotransmitters released from intrapancreatic ganglia are required to synchronize ß-cells between islets to coordinate insulin pulsatility from the entire pancreas, whereas paracrine intra-islet effects still suffice to explain coordinated pulsatile release of glucagon and somatostatin. The present review discusses how neurotransmitters contribute to the pulsatility at different levels of integration.
Assuntos
Monoaminas Biogênicas/fisiologia , Retroalimentação Fisiológica , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/metabolismo , Modelos Biológicos , Neurônios/metabolismo , Transmissão Sináptica , Animais , Regulação do Apetite , Comunicação Autócrina , Sinalização do Cálcio , Glucagon/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Cinética , Somatostatina/metabolismoRESUMO
It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases.
Assuntos
Encéfalo/metabolismo , Retroalimentação Fisiológica , Glucoquinase/metabolismo , Glucose/metabolismo , Ilhotas Pancreáticas/metabolismo , Modelos Neurológicos , Neurônios/metabolismo , Animais , Encéfalo/citologia , Diabetes Mellitus/metabolismo , Metabolismo Energético , Glucoquinase/genética , Humanos , Hipoglicemia/metabolismo , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/inervação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Obesidade/metabolismo , Especificidade de ÓrgãosRESUMO
Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and ß-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair ß-cell mass expansion during the weaning period and ß-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.