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Eva Tudurí

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

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Ãngel Nadal

Universitat de Miguel Hernández d'Elx

Iván Quesada

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Timothy J. Kieffer

University of British Columbia

Laura Marroquí

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Rubén Nogueiras

Center for Research in Molecular Medicine and Chronic Diseases

Maria M. Glavas

University of British Columbia

Sergi Soriano

Universitat de Miguel Hernández d'Elx

Paloma Alonso‐Magdalena

Universitat de Miguel Hernández d'Elx

Heather C. Denroche

University of British Columbia

Jessica K. Fox

University of British Columbia

Cooperative Institutions

University of British Columbia

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Universitat de Miguel Hernández d'Elx

Centro de Investigación Biomédica en Red

Consejo Superior de Investigaciones Científicas

Universidad Autónoma de Madrid

Universidade de Santiago de Compostela

University of Toronto

Instituto de Investigación Sanitaria de Santiago

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GPR55 and the regulation of glucose homeostasis

The International Journal of Biochemistry & Cell Biology (2017)

Eva Tudurí Miguel López Carlos Diéguez Ãngel Nadal Rubén Nogueiras

Homeostasis

10.1016/j.biocel.2017.04.010

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Citations (11)

Morphological and functional adaptations of pancreatic alpha-cells during late pregnancy in the mouse

Metabolism (2019)

Cristina Quesada‐Candela Eva Tudurí Laura Marroquí Paloma Alonso‐Magdalena Iván Quesada

Alpha (finance)

10.1016/j.metabol.2019.153963

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Citations (25)

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes

JCI Insight (2020)

Tao Liang Tairan Qin Fei Kang Youhou Kang Li Xie

SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet β cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse β cells in vivo and human β cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules. Such effects on T2D Goto-Kakizaki rats improved glucose homeostasis that was superior to conventional treatment with sulfonylurea glybenclamide. SNAP23, although fusion competent in slower secretory cells, in the context of β cells acts as a weak partial fusion agonist or inhibitory SNARE. Here, SNAP23 depletion promotes SNAP25 to bind calcium channels more quickly and longer where granule fusion occurs to increase exocytosis efficiency. β Cell SNAP23 antagonism is a strategy to treat diabetes.

SNAP23

SNAP25

10.1172/jci.insight.129694

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Citations (16)

AAV8 Ins1-Cre can produce efficient β-cell recombination but requires consideration of off-target effects

Scientific Reports (2020)

Adam Ramzy Eva Tudurí Maria M. Glavas Robert K. Baker Majid Mojibian

Abstract In vivo genetic manipulation is used to study the impact of gene deletion or re-expression on β-cell function and organism physiology. Cre-LoxP is a system wherein LoxP sites flanking a gene are recognized by Cre recombinase. Cre transgenic mice are the most prevalent technology used to deliver Cre but many models have caveats of off-target recombination, impaired β-cell function, and high cost of animal production. Inducible estrogen receptor conjugated Cre models face leaky recombination and confounding effects of tamoxifen. As an alternative, we characterize an adeno associated virus (AAV) with a rat insulin 1 promoter driving Cre recombinase (AAV8 Ins1-Cre) that is economical and rapid to implement, and has limited caveats. Intraperitoneal AAV8 Ins1-Cre produced efficient β-cell recombination, alongside some hepatic, exocrine pancreas, α-cell, δ-cell, and hypothalamic recombination. Delivery of lower doses via the pancreatic duct retained good rates of β-cell recombination and limited rates of off-target recombination. Unlike inducible Cre in transgenic mice, AAV8 Ins1-Cre required no tamoxifen and premature recombination was avoided. We demonstrate the utility of this technology by inducing hyperglycemia in inducible insulin knockout mice ( Ins1 −/− ; Ins2 f/f ). AAV-mediated expression of Cre in β-cells provides an effective alternative to transgenic approaches for inducible knockout studies.

Cre recombinase

Cre-Lox recombination

Gene targeting

10.1038/s41598-020-67136-w

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Citations (15)

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

Frontiers in Physiology (2018)

Juan Martı́nez-Pinna Sergi Soriano Eva Tudurí Ãngel Nadal Fernando de Castro

Ca2+-activated ion channels shape membrane excitability in response to elevations in intracellular Ca2+. The most extensively studied Ca2+-sensitive ion channels are Ca2+-activated K+ channels, whereas the physiological importance of Ca2+-activated Cl- channels has been poorly studied. Here we show that a Ca2+-activated Cl- currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells. Electrophysiological recording of mouse sympathetic neurons in an in vitro preparation of the superior cervical ganglion (SCG) identifies neurons with two different firing patterns in response to long depolarizing current pulses (1 s). Neurons classified as phasic (Ph) made up 67% of the cell population whilst the remainders were tonic (T). When a high frequency train of spikes was induced by intracellular current injection, SCG sympathetic neurons reached an afterpotential mainly dependent on the ratio of activation of two Ca2+-dependent currents: the K+ [IK(Ca)] and CaCC. When the IK(Ca) was larger, an afterhyperpolarization was the predominant afterpotential but when the CaCC was larger, an afterdepolarization (ADP) was predominant. These afterpotentials can be observed after a single action potential (AP). Ph and T neurons had similar ADPs and hence, the CaCC does not seem to determine the firing pattern (Ph or T) of these neurons. However, inhibition of Ca2+-activated Cl- channels with anthracene-9'-carboxylic acid (9AC) selectively inhibits the ADP, reducing the firing frequency and the instantaneous frequency without affecting the characteristics of single- or first-spike firing of both Ph and T neurons. Furthermore, we found that the CaCC underlying the ADP was significantly larger in SCG neurons from males than from females. Furthermore, the CaCC ANO1/TMEM16A was more strongly expressed in male than in female SCGs. Blocking ADPs with 9AC did not modify synaptic transmission in either Ph or T neurons. We conclude that the CaCC responsible for ADPs increases repetitive firing in both Ph and T neurons, and it is more relevant in male mouse sympathetic ganglion neurons.

Afterhyperpolarization

Sympathetic ganglion

Reversal potential

Bursting

10.3389/fphys.2018.00508

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Citations (11)

Pancreatic islet cells: A model for calcium‐dependent peptide release

HFSP journal (2010)

Bernat Soria Eva Tudurí Alejandro González Abdelkrim Hmadcha Franz Martı́n

In mammals the concentration of blood glucose is kept close to 5 mmol∕l. Different cell types in the islet of Langerhans participate in the control of glucose homeostasis. β-cells, the most frequent type in pancreatic islets, are responsible for the synthesis, storage, and release of insulin. Insulin, released with increases in blood glucose promotes glucose uptake into the cells. In response to glucose changes, pancreatic α-, β-, and δ-cells regulate their electrical activity and Ca(2+) signals to release glucagon, insulin, and somatostatin, respectively. While all these signaling steps are stimulated in hypoglycemic conditions in α-cells, the activation of these events require higher glucose concentrations in β and also in δ-cells. The stimulus-secretion coupling process and intracellular Ca(2+) ([Ca(2+)](i)) dynamics that allow β-cells to secrete is well-accepted. Conversely, the mechanisms that regulate α- and δ-cell secretion are still under study. Here, we will consider the glucose-induced signaling mechanisms in each cell type and the mathematical models that explain Ca(2+) dynamics.

Pancreatic Islets

Homeostasis

Blood sugar regulation

Insulin oscillation

10.2976/1.3364560

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Citations (14)

Endocrine-disrupting chemicals and the regulation of energy balance

Nature Reviews Endocrinology (2017)

Ãngel Nadal Iván Quesada Eva Tudurí Rubén Nogueiras Paloma Alonso‐Magdalena

Energy homeostasis

Homeostasis

10.1038/nrendo.2017.51

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Citations (179)

Leptin Administration Enhances Islet Transplant Performance in Diabetic Mice

Diabetes (2013)

Heather C. Denroche Whitney L. Quong Jennifer E. Bruin Eva Tudurí Ali Asadi

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice.

10.2337/db12-1684

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Citations (18)

Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes

Journal of Endocrinology (2018)

Laura Marroquí Eva Tudurí Paloma Alonso‐Magdalena Iván Quesada Ãngel Nadal

Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function. EDCs can affect multiple cellular processes, including some related to energy production and utilization, leading to alterations in energy homeostasis. Mitochondria are primarily implicated in cellular energy conversion, although they also participate in other processes, such as hormone secretion and apoptosis. In fact, mitochondrial dysfunction due to reduced oxidative capacity, impaired lipid oxidation and increased oxidative stress has been linked to insulin resistance and type 2 diabetes. Herein, we review the main mechanisms whereby metabolism-disrupting chemical (MDC), a subclass of EDCs that disturbs energy homeostasis, cause mitochondrial dysfunction, thus contributing to the establishment of insulin resistance and type 2 diabetes. We conclude that MDC-induced mitochondrial dysfunction, which is mainly characterized by perturbations in mitochondrial bioenergetics, biogenesis and dynamics, excessive reactive oxygen species production and activation of the mitochondrial pathway of apoptosis, seems to be a relevant mechanism linking MDCs to type 2 diabetes development.

Energy homeostasis

10.1530/joe-18-0362

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Citations (57)

Impaired Ca2+ Signaling in β-Cells Lacking Leptin Receptors by Cre-loxP Recombination

PLoS ONE (2013)

Eva Tudurí Jennifer E. Bruin Heather C. Denroche Jessica K. Fox James D. Johnson

Obesity is a major risk factor for diabetes and is typically associated with hyperleptinemia and a state of leptin resistance. The impact of chronically elevated leptin levels on the function of insulin-secreting β-cells has not been elucidated. We previously generated mice lacking leptin signaling in β-cells by using the Cre-loxP strategy and showed that these animals develop increased body weight and adiposity, hyperinsulinemia, impaired glucose-stimulated insulin secretion and insulin resistance. Here, we performed several in vitro studies and observed that β-cells lacking leptin signaling in this model are capable of properly metabolizing glucose, but show impaired intracellular Ca(2+) oscillations and lack of synchrony within the islets in response to glucose, display reduced response to tolbutamide and exhibit morphological abnormalities including increased autophagy. Defects in intracellular Ca(2+) signaling were observed even in neonatal islets, ruling out the possible contribution of obesity to the β-cell irregularities observed in adults. In parallel, we also detected a disrupted intracellular Ca(2+) pattern in response to glucose and tolbutamide in control islets from adult transgenic mice expressing Cre recombinase under the rat insulin promoter, despite these animals being glucose tolerant and secreting normal levels of insulin in response to glucose. This unexpected observation impeded us from discerning the consequences of impaired leptin signaling as opposed to long-term Cre expression in the function of insulin-secreting cells. These findings highlight the need to generate improved Cre-driver mouse models or new tools to induce Cre recombination in β-cells.

Cre-Lox recombination

10.1371/journal.pone.0071075

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Citations (9)