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1.
Cell Metab ; 31(2): 215-216, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32023444

RESUMO

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.

2.
Diabetes ; 69(4): 550-558, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31882565

RESUMO

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.

3.
Sci Rep ; 9(1): 19622, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873081

RESUMO

Fast, precise and sustained neurotransmission requires graded Ca2+ signals at the presynaptic terminal. Neurotransmitter release depends on a complex interplay of Ca2+ fluxes and Ca2+ buffering in the presynaptic terminal that is not fully understood. Here, we show that the angiotensin-receptor-associated protein (ATRAP) localizes to synaptic terminals throughout the central nervous system. In the retinal photoreceptor synapse and the cerebellar mossy fiber-granule cell synapse, we find that ATRAP is involved in the generation of depolarization-evoked synaptic Ca2+ transients. Compared to wild type, Ca2+ imaging in acutely isolated preparations of the retina and the cerebellum from ATRAP knockout mice reveals a significant reduction of the sarcoendoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity. Thus, in addition to its conventional role in angiotensin signaling, ATRAP also modulates presynaptic Ca2+ signaling within the central nervous system.

5.
Diabetologia ; 62(7): 1237-1250, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087105

RESUMO

AIMS/HYPOTHESIS: Autoimmune attack against the insulin-producing beta cells in the pancreatic islets results in type 1 diabetes. However, despite considerable research, details of the type 1 diabetes immunopathology in situ are not fully understood mainly because of difficult access to the pancreatic islets in vivo. METHODS: Here, we used direct non-invasive confocal imaging of islets transplanted in the anterior chamber of the eye (ACE) to investigate the anti-islet autoimmunity in NOD mice before, during and after diabetes onset. ACE-transplanted islets allowed longitudinal studies of the autoimmune attack against islets and revealed the infiltration kinetics and in situ motility dynamics of fluorescence-labelled autoreactive T cells during diabetes development. Ex vivo immunostaining was also used to compare immune cell infiltrations into islet grafts in the eye and kidney as well as in pancreatic islets of the same diabetic NOD mice. RESULTS: We found similar immune infiltration in native pancreatic and ACE-transplanted islets, which established the ACE-transplanted islets as reliable reporters of the autoimmune response. Longitudinal studies in ACE-transplanted islets identified in vivo hallmarks of islet inflammation that concurred with early immune infiltration of the islets and preceded their collapse and hyperglycaemia onset. A model incorporating data on ACE-transplanted islet degranulation and swelling allowed early prediction of the autoimmune attack in the pancreas and prompted treatments to intercept type 1 diabetes. CONCLUSIONS/INTERPRETATION: The current findings highlight the value of ACE-transplanted islets in studying early type 1 diabetes pathogenesis in vivo and underscore the need for timely intervention to halt disease progression.

6.
J Vis Exp ; (140)2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30346412

RESUMO

The purpose of the method being presented is to show, for the first time, the transplant of newborn thymi into the anterior eye chamber of isogenic adult mice for in vivo longitudinal real-time monitoring of thymocytes´ dynamics within a vascularized thymus segment. Following the transplantation, laser scanning microscopy (LSM) through the cornea allows in vivo noninvasive repeated imaging at cellular resolution level. Importantly, the approach adds to previous intravital T-cell maturation imaging models the possibility for continuous progenitor cell recruitment and mature T-cell egress recordings in the same animal. Additional advantages of the system are the transparency of the grafted area, permitting macroscopic rapid monitoring of the implanted tissue, and the accessibility to the implant allowing for localized in addition to systemic treatments. The main limitation being the volume of the tissue that fits in the reduced space of the eye chamber which demands for lobe trimming. Organ integrity is maximized by dissecting thymus lobes in patterns previously shown to be functional for mature T-cell production. The technique is potentially suited to interrogate a milieu of medically relevant questions related to thymus function that include autoimmunity, immunodeficiency and central tolerance; processes which remain mechanistically poorly defined. The fine dissection of mechanisms guiding thymocyte migration, differentiation and selection should lead to novel therapeutic strategies targeting developing T cells.


Assuntos
Microscopia Confocal/métodos , Timócitos/química , Animais , Diferenciação Celular , Camundongos
7.
Cell Metab ; 27(3): 549-558.e4, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514065

RESUMO

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.


Assuntos
Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Diabetes Mellitus Experimental , Humanos , Hipoglicemiantes/farmacologia , Transplante das Ilhotas Pancreáticas , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Comunicação Parácrina , Receptores de Glucagon/antagonistas & inibidores
8.
Cell Metab ; 27(3): 630-644.e4, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514070

RESUMO

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.


Assuntos
Capilares , Glucose/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/irrigação sanguínea , Pericitos , Adenosina/metabolismo , Adolescente , Adulto , Animais , Capilares/citologia , Capilares/inervação , Capilares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Pericitos/citologia , Pericitos/metabolismo , Fluxo Sanguíneo Regional
9.
Diabetologia ; 61(1): 182-192, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28884198

RESUMO

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.


Assuntos
Trifosfato de Adenosina/metabolismo , Macrófagos/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Animais , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Camundongos
10.
J Vis Exp ; (127)2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28930993

RESUMO

Insulin secretion plays a central role in glucose homeostasis under normal physiological conditions as well as in disease. Current approaches to study insulin granule exocytosis either use electrophysiology or microscopy coupled to the expression of fluorescent reporters. However most of these techniques have been optimized for clonal cell lines or require dissociating pancreatic islets. In contrast, the method presented here allows for real time visualization of insulin granule exocytosis in intact pancreatic islets. In this protocol, we first describe the viral infection of isolated pancreatic islets with adenovirus that encodes a pH-sensitive green fluorescent protein (GFP), pHluorin, coupled to neuropeptide Y (NPY). Second, we describe the confocal imaging of islets five days after viral infection and how to monitor the insulin granule secretion. Briefly, the infected islets are placed on a coverslip on an imaging chamber and imaged under an upright laser-scanning confocal microscope while being continuously perfused with extracellular solution containing various stimuli. Confocal images spanning 50 µm of the islet are acquired as time-lapse recordings using a fast-resonant scanner. The fusion of insulin granules with the plasma membrane can be followed over time. This procedure also allows for testing a battery of stimuli in a single experiment, is compatible with both mouse and human islets, and can be combined with various dyes for functional imaging (e.g., membrane potential or cytosolic calcium dyes).


Assuntos
Grânulos Citoplasmáticos/metabolismo , Exocitose/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Microscopia Confocal/métodos , Neuropeptídeo Y/metabolismo , Animais , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Camundongos
11.
FASEB J ; 31(11): 4734-4744, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28687610

RESUMO

In pancreatic ß cells, muscarinic cholinergic receptor M3 (M3R) stimulates glucose-induced secretion of insulin. Regulator of G-protein signaling (RGS) proteins are critical modulators of GPCR activity, yet their role in ß cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G-protein subunit Gß5, such that the knockout of the Gnb5 gene results in degradation of all R7 subunits. We found that Gnb5 knockout in mice or in the insulin-secreting MIN6 cell line almost completely eliminates insulinotropic activity of M3R. Moreover, overexpression of Gß5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5-/- MIN6 cells showed that cAMP, diacylglycerol, or Ca2+ levels were not significantly affected. There was no reduction in the amplitude of free Ca2+ responses in islets from the Gnb5-/- mice, but the frequency of Ca2+ oscillations induced by cholinergic agonist was lowered by more than 30%. Ablation of Gnb5 impaired M3R-stimulated phosphorylation of ERK1/2. Stimulation of the ERK pathway in Gnb5-/- cells by epidermal growth factor restored M3R-stimulated insulin release to near normal levels. Identification of the novel role of Gß5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic ß-cell function.-Wang, Q., Pronin, A. N., Levay, K., Almaca, J., Fornoni, A., Caicedo, A., Slepak, V. Z. Regulator of G-protein signaling Gß5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.


Assuntos
Sinalização do Cálcio/fisiologia , Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas RGS/metabolismo , Receptor Muscarínico M3/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , AMP Cíclico/genética , AMP Cíclico/metabolismo , Subunidades beta da Proteína de Ligação ao GTP/genética , Secreção de Insulina , Células Secretoras de Insulina/citologia , Camundongos , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/fisiologia , Proteínas RGS/genética , Receptor Muscarínico M3/genética
12.
Lab Chip ; 17(5): 772-781, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28157238

RESUMO

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.


Assuntos
Técnicas Citológicas , Ilhotas Pancreáticas , Técnicas Analíticas Microfluídicas , Modelos Biológicos , Animais , Células Cultivadas , Técnicas Citológicas/instrumentação , Técnicas Citológicas/métodos , Desenho de Equipamento , Humanos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Microscopia de Fluorescência
13.
Nat Commun ; 8: 14295, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28145434

RESUMO

ß-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the ß-arrestin-2 gene, barr2, in ß-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in ß-arrestin-2 (barr2) deficient ß-cells. In human ß-cells, barr2 knockdown abolished glucose-induced insulin secretion. We also show that the presence of barr2 is essential for proper CAMKII function in ß-cells. Importantly, overexpression of barr2 in ß-cells greatly ameliorates the metabolic deficits displayed by mice consuming a high-fat diet. Thus, our data identify barr2 as an important regulator of ß-cell function, which may serve as a new target to improve ß-cell function.


Assuntos
Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Transdução de Sinais/genética , beta-Arrestina 2/genética , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Dieta Hiperlipídica , Expressão Gênica , Humanos , Insulina/metabolismo , Secreção de Insulina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , beta-Arrestina 2/metabolismo
14.
Cell Rep ; 17(12): 3281-3291, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-28009296

RESUMO

In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity.


Assuntos
Diabetes Mellitus/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Animais , AMP Cíclico/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucose/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Camundongos , Serotonina/biossíntese , Transdução de Sinais
15.
Adv Exp Med Biol ; 938: 11-24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27586419

RESUMO

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 Sinais
16.
Cell Metab ; 23(3): 541-6, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26876561

RESUMO

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.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/fisiologia , Liraglutida/farmacologia , Animais , Glicemia , Diabetes Mellitus Experimental/sangue , Avaliação Pré-Clínica de Medicamentos , Olho/patologia , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Transplante das Ilhotas Pancreáticas , Camundongos
17.
Diabetologia ; 58(12): 2810-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26376795

RESUMO

AIMS/HYPOTHESIS: Insulin secretion is widely studied because it plays a central role in glucose homeostasis and diabetes. Processes from insulin granule fusion in beta cells to in vivo insulin secretion have been elucidated, but data at the cellular level do not fully account for several aspects of the macroscopic secretory pattern. Here we investigated how individual secretory events are coordinated spatially and temporally within intact human islets. METHODS: We used the fluorescent probe neuropeptide Y (NPY)-pHluorin to visualise insulin granule secretion in isolated intact human islets. RESULTS: We found that individual beta cells respond to increases in glucose concentration by releasing insulin granules in very discrete bursts with periods consistent with in vivo pulsatile insulin secretion. In successive secretory bursts during prolonged exposure to high glucose levels, secretory events progressively localised to preferential release sites, coinciding with the transition to second phase insulin secretion. Granule secretion was very synchronised in neighbouring beta cells, forming discrete regional clusters of activity. CONCLUSIONS/INTERPRETATION: These results reveal how individual secretory events are coordinated to produce pulsatile insulin secretion from human islets.


Assuntos
Exocitose/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Adulto , Células Cultivadas , Grânulos Citoplasmáticos/metabolismo , Feminino , Glucose/farmacologia , Proteínas de Fluorescência Verde , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/anatomia & histologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neuropeptídeo Y/metabolismo
18.
Proc Natl Acad Sci U S A ; 111(49): 17612-7, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25404292

RESUMO

Pancreatic islets secrete hormones that play a key role in regulating blood glucose levels (glycemia). Age-dependent impairment of islet function and concomitant dysregulation of glycemia are major health threats in aged populations. However, the major causes of the age-dependent decline of islet function are still disputed. Here we demonstrate that aging of pancreatic islets in mice and humans is notably associated with inflammation and fibrosis of islet blood vessels but does not affect glucose sensing and the insulin secretory capacity of islet beta cells. Accordingly, when transplanted into the anterior chamber of the eye of young mice with diabetes, islets from old mice are revascularized with healthy blood vessels, show strong islet cell proliferation, and fully restore control of glycemia. Our results indicate that beta cell function does not decline with age and suggest that islet function is threatened by an age-dependent impairment of islet vascular function. Strategies to mitigate age-dependent dysregulation in glycemia should therefore target systemic and/or local inflammation and fibrosis of the aged islet vasculature.


Assuntos
Envelhecimento , Glicemia/metabolismo , Capilares/fisiologia , Ilhotas Pancreáticas/fisiologia , Adolescente , Adulto , Idoso , Animais , Proliferação de Células , Fibrose , Glucose/metabolismo , Homeostase , Humanos , Inflamação , Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Perfusão , Fatores de Tempo , Adulto Jovem
19.
Best Pract Res Clin Endocrinol Metab ; 28(5): 745-56, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25256769

RESUMO

The autonomic nervous system affects glucose metabolism partly through its connection to the pancreatic islet. Since its discovery by Paul Langerhans, the precise innervation patterns of the islet has remained elusive, mainly because of technical limitations. Using 3-dimensional reconstructions of axonal terminal fields, recent studies have determined the innervation patterns of mouse and human islets. In contrast to the mouse islet, endocrine cells within the human islet are sparsely contacted by autonomic axons. Instead, the invading sympathetic axons preferentially innervate smooth muscle cells of blood vessels. This innervation pattern suggests that, rather than acting directly on endocrine cells, sympathetic nerves may control hormone secretion by modulating blood flow in human islets. In addition to autonomic efferent axons, islets also receive sensory innervation. These axons transmit sensory information to the brain but also have the ability to locally release neuroactive substances that have been suggested to promote diabetes pathogenesis. We discuss recent findings on islet innervation, the connections of the islet with the brain, and the role islet innervation plays during the progression of diabetes.


Assuntos
Sistema Nervoso Autônomo/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus/metabolismo , Ilhotas Pancreáticas/metabolismo , Neurônios/fisiologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Diabetes Mellitus/fisiopatologia , Metabolismo Energético/fisiologia , Humanos , Ilhotas Pancreáticas/fisiopatologia , Camundongos
20.
Endocrinology ; 155(8): 3160-71, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24885572

RESUMO

Dio3 is the most distal gene of the imprinted Dlk1-Dio3 gene locus and is expressed according to parental origin. Dio3 encodes the type 3 deiodinase (D3), a thioredoxin-fold like containing selenoenzyme that inactivates thyroid hormone and dampens thyroid hormone signaling. Here we used heterozygous animals with disruption of the Dio3 gene to study the allelic expression pattern of Dio3 in pancreatic ß-cells and the metabolic phenotype resulting from its inactivation. Adult heterozygous mice with disruption of the Dio3 gene with maternal inheritance of the inactive Dio3 allele exhibited a total loss of D3 activity in isolated pancreatic islets, approximately 30% reduction in total pancreatic islet area, a marked decrease in insulin2 mRNA and in vivo glucose intolerance. In contrast, inheritance of the inactive Dio3 allele from the father did not affect D3 activity in isolated pancreatic islets and did not result in a pancreatic phenotype. Furthermore, exposure of pancreatic explants, D3-expressing MIN6-C3 cells or isolated pancreatic islets to 100 nM T3 for 24 hours reduced insulin2 mRNA by approximately 50% and the peak of glucose-induced insulin secretion. An unbiased analysis of T3-treated pancreatic islets revealed the down-regulation of 21 gene sets (false discovery rate q value < 25%) involved in nucleolar function and transcription of rRNA, ribonucleotide binding, mRNA translation, and membrane organization. We conclude that the Dio3 gene is preferentially expressed from the maternal allele in pancreatic islets and that the inactivation of this allele is sufficient to disrupt glucose homeostasis by reducing the pancreatic islet area, insulin2 gene expression, and glucose-stimulated insulin secretion.


Assuntos
Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Iodeto Peroxidase/genética , Alelos , Animais , Regulação da Expressão Gênica , Homeostase , Padrões de Herança , Insulina/metabolismo , Secreção de Insulina , Iodeto Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Glândula Tireoide/fisiologia , Tri-Iodotironina/fisiologia
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