RESUMEN
BACKGROUND AND AIMS: Destroying visceral sensory nerves impacts pancreatic islet function, glucose metabolism, and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. METHODS: We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of ß-cells with vagal sensory neurons, we recorded Ca2+ responses in individual nodose neurons in vivo while selectively stimulating ß-cells with chemogenetic and pharmacologic approaches. RESULTS: We found that pancreatic islets are innervated by vagal sensory axons expressing Phox2b, substance P, calcitonin-gene related peptide, and the serotonin receptor 5-HT3R. Centrally, vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. Nodose neurons responded in vivo to chemogenetic stimulation of ß-cells and to pancreas infusion with serotonin, but were not sensitive to insulin. Responses to chemogenetic and pharmacologic stimulation of ß-cells were blocked by a 5-HT3R antagonist and were enhanced by increasing serotonin levels in ß-cells. We further confirmed directly in living pancreas slices that sensory terminals in the islet were sensitive to serotonin. CONCLUSIONS: Our study establishes that pancreatic ß-cells communicate with vagal sensory neurons, likely using serotonin signaling as a transduction mechanism. Serotonin is coreleased with insulin and may therefore convey information about the secretory state of ß-cells via vagal afferent nerves.
Asunto(s)
Vías Aferentes/fisiología , Comunicación Celular , Células Secretoras de Insulina/fisiología , Ganglio Nudoso/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Femenino , Insulina/metabolismo , Microscopía Intravital , Masculino , Ratones , Ratones Transgénicos , Microscopía Confocal , Modelos Animales , Ganglio Nudoso/citología , Serotonina/metabolismo , Transducción de Señal/fisiologíaRESUMEN
AIMS/HYPOTHESIS: Tissue-resident macrophages sense the microenvironment and respond by producing signals that act locally to maintain a stable tissue state. It is now known that pancreatic islets contain their own unique resident macrophages, which have been shown to promote proliferation of the insulin-secreting beta cell. However, it is unclear how beta cells communicate with islet-resident macrophages. Here we hypothesised that islet macrophages sense changes in islet activity by detecting signals derived from beta cells. METHODS: To investigate how islet-resident macrophages respond to cues from the microenvironment, we generated mice expressing a genetically encoded Ca2+ indicator in myeloid cells. We produced living pancreatic slices from these mice and used them to monitor macrophage responses to stimulation of acinar, neural and endocrine cells. RESULTS: Islet-resident macrophages expressed functional purinergic receptors, making them exquisite sensors of interstitial ATP levels. Indeed, islet-resident macrophages responded selectively to ATP released locally from beta cells that were physiologically activated with high levels of glucose. Because ATP is co-released with insulin and is exclusively secreted by beta cells, the activation of purinergic receptors on resident macrophages facilitates their awareness of beta cell secretory activity. CONCLUSIONS/INTERPRETATION: Our results indicate that islet macrophages detect ATP as a proxy signal for the activation state of beta cells. Sensing beta cell activity may allow macrophages to adjust the secretion of factors to promote a stable islet composition and size.
Asunto(s)
Adenosina Trifosfato/metabolismo , Macrófagos/metabolismo , Páncreas/citología , Páncreas/metabolismo , Animales , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/citología , RatonesRESUMEN
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.
Asunto(s)
Islotes Pancreáticos/fisiología , Animales , Humanos , Islotes Pancreáticos/irrigación sanguínea , Islotes Pancreáticos/citología , Islotes Pancreáticos/inervación , Comunicación Paracrina , Transducción de SeñalRESUMEN
The autonomic nervous system is thought to modulate blood glucose homeostasis by regulating endocrine cell activity in the pancreatic islets of Langerhans. The role of islet innervation, however, has remained elusive because the direct effects of autonomic nervous input on islet cell physiology cannot be studied in the pancreas. Here, we used an in vivo model to study the role of islet nervous input in glucose homeostasis. We transplanted islets into the anterior chamber of the eye and found that islet grafts became densely innervated by the rich parasympathetic and sympathetic nervous supply of the iris. Parasympathetic innervation was imaged intravitally by using transgenic mice expressing GFP in cholinergic axons. To manipulate selectively the islet nervous input, we increased the ambient illumination to increase the parasympathetic input to the islet grafts via the pupillary light reflex. This reduced fasting glycemia and improved glucose tolerance. These effects could be blocked by topical application of the muscarinic antagonist atropine to the eye, indicating that local cholinergic innervation had a direct effect on islet function in vivo. By using this approach, we found that parasympathetic innervation influences islet function in C57BL/6 mice but not in 129X1 mice, which reflected differences in innervation densities and may explain major strain differences in glucose homeostasis. This study directly demonstrates that autonomic axons innervating the islet modulate glucose homeostasis.
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Sistema Nervioso Autónomo/fisiología , Ojo/inervación , Islotes Pancreáticos/fisiología , Modelos Biológicos , Animales , Proteínas Fluorescentes Verdes/metabolismo , Iris/inervación , Iris/fisiología , Trasplante de Islotes Pancreáticos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibras NerviosasRESUMEN
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.
Asunto(s)
Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Neurotransmisores/metabolismo , Comunicación Paracrina , Animales , Humanos , Secreción de Insulina , Islotes Pancreáticos/inervaciónRESUMEN
Intravital imaging emerged as an indispensible tool in biological research, and a variety of imaging techniques have been developed to noninvasively monitor tissues in vivo. However, most of the current techniques lack the resolution to study events at the single-cell level. Although intravital multiphoton microscopy has addressed this limitation, the need for repeated noninvasive access to the same tissue in longitudinal in vivo studies remains largely unmet. We now report on a previously unexplored approach to study immune responses after transplantation of pancreatic islets into the anterior chamber of the mouse eye. This approach enabled (i) longitudinal, noninvasive imaging of transplanted tissues in vivo; (ii) in vivo cytolabeling to assess cellular phenotype and viability in situ; (iii) local intervention by topical application or intraocular injection; and (iv) real-time tracking of infiltrating immune cells in the target tissue.
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Cámara Anterior/citología , Islotes Pancreáticos/citología , Microscopía Confocal/métodos , Linfocitos T/citología , Amidas/farmacología , Animales , Cámara Anterior/metabolismo , Cámara Anterior/cirugía , Antagonistas de los Receptores CCR5 , Quimiocinas/farmacología , Diabetes Mellitus Experimental/terapia , Ensayo de Inmunoadsorción Enzimática , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Islotes Pancreáticos/metabolismo , Trasplante de Islotes Pancreáticos/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Microscopía por Video/métodos , Compuestos de Amonio Cuaternario/farmacología , Receptores CCR5/metabolismo , Análisis de la Célula Individual/métodos , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de TiempoRESUMEN
Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human beta cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca(2+) concentration, [Ca(2+)](i), and hormone release in vitro, we show that human beta cells express ionotropic ATP receptors of the P2X(3) type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X(3) receptors in the beta-cell plasma membrane, resulting in increased [Ca(2+)](i) and enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the beta cell's secretory machinery. This may explain how the human pancreatic beta cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.
Asunto(s)
Adenosina Trifosfato/metabolismo , Comunicación Autocrina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Receptores Purinérgicos P2/metabolismo , Calcio/metabolismo , Humanos , Secreción de Insulina , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X3 , Transducción de SeñalRESUMEN
The pancreatic islet depends on blood supply to efficiently sense plasma glucose levels and deliver insulin and glucagon into the circulation. Long believed to be passive conduits of nutrients and hormones, islet capillaries were recently found to be densely covered with contractile pericytes with the capacity to locally control blood flow. Here, we determined the contribution of pericyte regulation of islet blood flow to plasma insulin and glucagon levels and glycemia. Selective optogenetic activation of pericytes in intraocular islet grafts contracted capillaries and diminished blood flow. In awake mice, acute light-induced stimulation of islet pericytes decreased insulin and increased glucagon plasma levels, producing hyperglycemic effects. Interestingly, pericytes are the targets of sympathetic nerves in the islet, suggesting that sympathetic control of hormone secretion may occur in part by modulating pericyte activity and blood flow. Indeed, in vivo activation of pericytes with the sympathetic agonist phenylephrine decreased blood flow in mouse islet grafts, lowered plasma insulin levels, and increased glycemia. We further show that islet pericytes and blood vessels in living human pancreas slices responded to sympathetic input. Our findings indicate that pericytes mediate vascular responses in the islet that are required for adequate hormone secretion and glucose homeostasis. Vascular and neuronal alterations that are commonly seen in the islets of people with diabetes may impair regulation of islet blood flow and thus precipitate islet dysfunction.
Asunto(s)
Glucagón , Islotes Pancreáticos , Animales , Glucemia , Glucosa/farmacología , Homeostasis , Humanos , Insulina , Islotes Pancreáticos/irrigación sanguínea , Ratones , PericitosRESUMEN
Neuromodulation is a promising new therapeutic avenue to treat chronic diseases. A paper that appeared recently in Nature Biotechnology (Guyot et al., 2019) now provides a roadmap for how to establish electrostimulation of nerves to delay or even prevent type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1 , Terapia por Estimulación Eléctrica , HumanosRESUMEN
Secretion of glucagon from the pancreatic α-cells is conventionally seen as the first and most important defense against hypoglycemia. Recent findings, however, show that α-cell signals stimulate insulin secretion from the neighboring ß-cell. This article focuses on these seemingly counterintuitive local actions of α-cells and describes how they impact islet biology and glucose metabolism. It is mostly based on studies published in the last decade on the physiology of α-cells in human islets and incorporates results from rodents where appropriate. As this and the accompanying articles show, the emerging picture of α-cell function is one of increased complexity that needs to be considered when developing new therapies aimed at promoting islet function in the context of diabetes.
Asunto(s)
Diabetes Mellitus/metabolismo , Células Secretoras de Glucagón/metabolismo , Glucagón/metabolismo , Comunicación Paracrina/fisiología , Animales , Humanos , Insulina/metabolismo , Secreción de Insulina/fisiologíaRESUMEN
Endocrine cells of the pancreatic islet interact with their microenvironment to maintain tissue homeostasis. Communication with local macrophages is particularly important in this context, but the homeostatic functions of human islet macrophages are not known. In this study, we show that the human islet contains macrophages in perivascular regions that are the main local source of the anti-inflammatory cytokine interleukin-10 (IL-10) and the metalloproteinase MMP9. Macrophage production and secretion of these homeostatic factors are controlled by endogenous purinergic signals. In obese and diabetic states, macrophage expression of purinergic receptors MMP9 and IL-10 is reduced. We propose that in those states, exacerbated ß-cell activity due to increased insulin demand and increased cell death produce high levels of ATP that downregulate purinergic receptor expression. Loss of ATP sensing in macrophages may reduce their secretory capacity.
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Islotes Pancreáticos/citología , Macrófagos/fisiología , Purinas/metabolismo , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Calcio/metabolismo , Citocinas , Citosol/química , Citosol/fisiología , Diabetes Mellitus/metabolismo , Regulación hacia Abajo , Regulación de la Expresión Génica , Humanos , Islotes Pancreáticos/diagnóstico por imagen , Ratones , Receptores Purinérgicos/metabolismo , Transducción de Señal , TranscriptomaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.
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Islotes Pancreáticos/ultraestructura , Comunicación Paracrina , Estado Prediabético/patología , Seudópodos/ultraestructura , Células Secretoras de Somatostatina/ultraestructura , Animales , Glucemia/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/ultraestructura , Microscopía Intravital , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones , Ratones Transgénicos , Microscopía Electrónica , Imagen Óptica , Optogenética , Estado Prediabético/metabolismo , Seudópodos/metabolismo , Células Secretoras de Somatostatina/citología , Células Secretoras de Somatostatina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Pancreatic beta cells synthesize and secrete the neurotransmitter γ-aminobutyric acid (GABA) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel (VRAC), functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from type 1 and type 2 diabetic patients, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.
Asunto(s)
Citosol/metabolismo , Células Secretoras de Insulina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Homeostasis , Humanos , Fracciones Subcelulares/metabolismoRESUMEN
Substantial amounts of nonendocrine cells are implanted as part of human islet grafts, and a possible influence of nonendocrine cells on clinical islet transplantation outcome has been postulated. There are currently no product release criteria specific for nonendocrine cells due to lack of available methods. The aims of this study were to develop a method for the evaluation of pancreatic ductal cells (PDCs) for clinical islet transplantation and to characterize them regarding phenotype, viability, and function. We assessed 161 human islet preparations using laser scanning cytometry (LSC/iCys) for phenotypic analysis of nonendocrine cells and flow cytometry (FACS) for PDC viability. PDC and beta-cells obtained from different density fractions during the islet cell purification were compared in terms of viability. Furthermore, we examined PDC ability to produce proinflammatory cytokines/chemokines, vascular endothelial growth factor (VEGF) and tissue factor (TF) relevant to islet graft outcome. Phenotypic analysis by LSC/iCys indicated that single staining for CK19 or CA19-9 was not enough for identifying PDCs, and that double staining for amylase and CK19 or CA19-9 allowed for quantitative evaluation of acinar cells and PDC content in human islet preparation. PDC showed a significantly higher viability than beta-cells (PDC vs beta-cell: 75.5+/-13.9 and 62.7+/-18.7%; P<0.0001). Although beta-cell viability was independent of its density, that of PDCs was higher as the density from which they were recovered increased. There was no correlation between PDCs and beta-cell viability (R(2)=0.0078). PDCs sorted from high-density fractions produced significantly higher amounts of proinflammatory mediators and VEGF, but not TF. We conclude that PDCs isolated from different fractions had different viability and functions. The precise characterization and assessment of these cells in addition to beta-cells in human islet cell products may be of assistance in understanding their contribution to islet engraftment and in developing strategies to enhance islet graft function.
Asunto(s)
Antígeno CA-19-9 , Células Secretoras de Insulina/citología , Trasplante de Islotes Pancreáticos , Queratina-19 , Conductos Pancreáticos/citología , Animales , Diabetes Mellitus Experimental , Humanos , Células Secretoras de Insulina/clasificación , Islotes Pancreáticos/citología , Citometría de Barrido por Láser , Ratones , Ratones Desnudos , FenotipoRESUMEN
Efficient insulin secretion requires a well-functioning pancreatic islet microvasculature. The dense network of islet capillaries includes the islet pericyte, a cell that has barely been studied. Here we show that islet pericytes help control local blood flow by adjusting islet capillary diameter. Islet pericytes cover 40% of the microvasculature, are contractile, and are innervated by sympathetic axons. Sympathetic adrenergic input increases pericyte activity and reduces capillary diameter and local blood flow. By contrast, activating beta cells by increasing glucose concentration inhibits pericytes, dilates islet capillaries, and increases local blood flow. These effects on pericytes are mediated by endogenous adenosine, which is likely derived from ATP co-released with insulin. Pericyte coverage of islet capillaries drops drastically in type 2 diabetes, suggesting that, under diabetic conditions, islets lose this mechanism to control their own blood supply. This may lead to inadequate insulin release into the circulation, further deteriorating glycemic control.
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Capilares , Glucosa/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/irrigación sanguínea , Pericitos , Adenosina/metabolismo , Adolescente , Adulto , Animales , Capilares/citología , Capilares/inervación , Capilares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Pericitos/citología , Pericitos/metabolismo , Flujo Sanguíneo RegionalRESUMEN
Every animal species has a signature blood glucose level or glycemic set point. These set points are different, and the normal glycemic levels (normoglycemia) of one species would be life threatening for other species. Mouse normoglycemia can be considered diabetic for humans. The biological determinants of the glycemic set point remain unclear. Here we show that the pancreatic islet imposes its glycemic set point on the organism, making it the bona fide glucostat in the body. Moreover, and in contrast to rodent islets, glucagon input from the alpha cell to the insulin-secreting beta cell is necessary to fine-tune the distinctive human set point. These findings affect transplantation and regenerative approaches to treat diabetes because restoring normoglycemia may require more than replacing only the beta cells. Furthermore, therapeutic strategies using glucagon receptor antagonists as hypoglycemic agents need to be reassessed, as they may reset the overall glucostat in the organism.
Asunto(s)
Células Secretoras de Glucagón/metabolismo , Glucagón/metabolismo , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Animales , Diabetes Mellitus Experimental , Humanos , Hipoglucemiantes/farmacología , Trasplante de Islotes Pancreáticos , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Comunicación Paracrina , Receptores de Glucagón/antagonistas & inhibidoresRESUMEN
We report the design and fabrication of a robust fluidic platform built out of inert plastic materials and micromachined features that promote optimized convective fluid transport. The platform is tested for perfusion interrogation of rodent and human pancreatic islets, dynamic secretion of hormones, concomitant live-cell imaging, and optogenetic stimulation of genetically engineered islets. A coupled quantitative fluid dynamics computational model of glucose stimulated insulin secretion and fluid dynamics was first utilized to design device geometries that are optimal for complete perfusion of three-dimensional islets, effective collection of secreted insulin, and minimization of system volumes and associated delays. Fluidic devices were then fabricated through rapid prototyping techniques, such as micromilling and laser engraving, as two interlocking parts from materials that are non-absorbent and inert. Finally, the assembly was tested for performance using both rodent and human islets with multiple assays conducted in parallel, such as dynamic perfusion, staining and optogenetics on standard microscopes, as well as for integration with commercial perfusion machines. The optimized design of convective fluid flows, use of bio-inert and non-absorbent materials, reversible assembly, manual access for loading and unloading of islets, and straightforward integration with commercial imaging and fluid handling systems proved to be critical for perfusion assay, and particularly suited for time-resolved optogenetics studies.
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Técnicas Citológicas , Islotes Pancreáticos , Técnicas Analíticas Microfluídicas , Modelos Biológicos , Animales , Células Cultivadas , Técnicas Citológicas/instrumentación , Técnicas Citológicas/métodos , Diseño de Equipo , Humanos , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Ratones , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Microscopía FluorescenteRESUMEN
Blood flow regulation in pancreatic islets is critical for function but poorly understood. Here, we establish an in vivo imaging platform in a non-human primate where islets transplanted autologously into the anterior chamber of the eye are monitored non-invasively and longitudinally at single-cell resolution. Engrafted islets were vascularized and innervated and maintained the cytoarchitecture of in situ islets in the pancreas. Blood flow velocity in the engrafted islets was not affected by increasing blood glucose levels and/or the GLP-1R agonist liraglutide. However, islet blood flow was dynamic in nature and fluctuated in various capillaries. This was associated with vasoconstriction events resembling a sphincter-like action, most likely regulated by adrenergic signaling. These observations suggest a mechanism in primate islets that diverts blood flow to cell regions with higher metabolic demand. The described imaging technology applied in non-human primate islets may contribute to a better understanding of human islet pathophysiology.
Asunto(s)
Velocidad del Flujo Sanguíneo , Islotes Pancreáticos/irrigación sanguínea , Animales , Glucemia/metabolismo , Capilares/fisiología , Células Cultivadas , Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Liraglutida/farmacología , Macaca fascicularis , Masculino , Flujo Sanguíneo Regional , VasoconstricciónRESUMEN
Incretin mimetics are frequently used in the treatment of type 2 diabetes because they potentiate ß cell response to glucose. Clinical evidence showing short-term benefits of such therapeutics (e.g., liraglutide) is abundant; however, there have been several recent reports of unexpected complications in association with incretin mimetic therapy. Importantly, clinical evidence on the potential effects of such agents on the ß cell and islet function during long-term, multiyear use remains lacking. We now show that prolonged daily liraglutide treatment of >200 days in humanized mice, transplanted with human pancreatic islets in the anterior chamber of the eye, is associated with compromised release of human insulin and deranged overall glucose homeostasis. These findings raise concern about the chronic potentiation of ß cell function through incretin mimetic therapy in diabetes.