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The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of physiological actions that contribute to the maintenance of normal glucose tolerance. GLP-1 agonists have recently been approved for clinical... more
The incretin hormone glucagon-like peptide 1 (GLP-1) is well known for exerting a wide range of physiological actions that contribute to the maintenance of normal glucose tolerance. GLP-1 agonists have recently been approved for clinical use in the treatment of type 2 diabetes, with evidence suggesting that the central GLP-1 system may act directly on specific peripheral tissues involved in the regulation of glucose metabolism. However, whether pancreatic β-cells are directly regulated by neuronal GLP-1 receptors (GLP-1R) is currently unknown. In order to unravel the role of brain GLP-1R on β-cell function, we administered intracerebroventricular (ICV) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), both in an acute and a chronic setting. We observed that acute ICV GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired the glucose excursion after a glucose load. However, sustained activation of CNS GLP-1R did not produce any effect, neither on GSIS nor on glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with ICV GLP-1 displayed no differences as compared to controls. Additionally, in mice fed a high-fat diet (HFD) we observed that acute ICV GLP-1 infusion improves glucose tolerance without changes in GSIS, while chronic GLP-1R activation has no effect on glucose homeostasis. Our results indicate that, under non clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents.
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Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing... more
Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
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Research Interests: Endocrinology, Diabetes, Biology, Calcium, Immunohistochemistry, and 15 moreConfocal Microscopy, Medicine, Energy Homeostasis, Internal Medicine, Glucagon, Diabetes mellitus, Mice, Animals, Leptin, Leptin Receptor, Exocytosis, Glucose Homeostasis, Leptin Receptors, Alpha cell, and Medical and Health Sciences
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Research Interests: Biology, Drug Discovery, Medicine, Molecular endocrinology, Rodentia, and 15 moreEnergy Metabolism, Cannabinoids, Adipose tissue, Humans, Animals, Clinical Sciences, Veterinary Sciences, Regulator, Type 2 Diabetes Mellitus, Molecular Targeted Therapy, Ligands, Gene Expression Regulation, Cannabinoid Receptor, G Protein Coupled Receptors, and Paediatrics and reproductive medicine
Research Interests: Endocrinology, Biology, Immunohistochemistry, Cell Biology, Confocal Microscopy, and 15 moreMedicine, Biological Sciences, Adenosine, Internal Medicine, Glucose, Glucagon, Mice, Animals, Calcium Signaling, Purinergic Receptors, Extracellular, Extracellular Space, Adenosine Triphosphate, Medical and Health Sciences, and In Vitro Techniques
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Research Interests: Endocrinology, Biology, Autophagy, Medicine, Genetic Engineering, and 15 moreInsulin Resistance, Internal Medicine, Glucose, Insulin, Hyperinsulinemia, Mice, Animals, Male, Leptin, Calcium Signaling, Genetic Recombination, Leptin Receptors, Glucose Tolerance Test, Intracellular Space, and Intracellular
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Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two... more
Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight ga...
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OBJECTIVE—Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic �-cells, inhibiting insulin... more
OBJECTIVE—Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic �-cells, inhibiting insulin secretion, and, thus, modulating glucose homeostasis. However, despite the importance of glucagon secretion in glucose homeostasis, the role of leptin in �-cell function has not been studied in detail. In the present study, we have investigated this functional interaction. RESEARCH DESIGN AND METHODS—The presence of leptin receptors (ObR) was demonstrated by RT-PCR analysis, Western blot, and immunocytochemistry. Electrical activity was analyzed by patch-clamp and Ca 2 � signals by confocal microscopy. Exocytosis and glucagon secretion were assessed using fluorescence methods and radioimmunoassay, respectively. RESULTS—The expression of several ObR isoforms (a–e) was
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1 Instituto de Bioingenieria, Universidad Miguel Hernandez, Elche, Spain. 2 CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Spain. Instituto Nacional de Pesquisa em Obesidade e Diabetes, Department of Physiology and... more
1 Instituto de Bioingenieria, Universidad Miguel Hernandez, Elche, Spain. 2 CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Spain. Instituto Nacional de Pesquisa em Obesidade e Diabetes, Department of Physiology and Biophysics, Institute of Biology, Unicamp, Campinas SP, Brazil Endocrinology and Diabetes Unit, Laboratory of Diabetes and Obesity, IDIBAPS-Fundacio Clinic, Hospital Clinic, Barcelona, Spain. Institut de Malalties Digestives i Metaboliques, Hospital Clinic, Barcelona, Spain
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Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β-cells undergo adaptive responses... more
Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β-cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on β-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized in two groups: high insulin sensitive (aged-HIS) and low insulin sensitive (aged-LIS). Aged-LIS mice were hyperinsulinemic, glucose intolerant and displayed impaired glucose-stimulated insulin and C-peptide secretion, whereas aged-HIS animals showed characteristics in glucose homeostasis similar to controls. In isolated β-cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with agi...
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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... more
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 l...
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BACKGROUND Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycaemia. However, although pancreatic alpha-cells play a key role in glucose... more
BACKGROUND Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycaemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy. MATERIAL AND METHODS Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA. RESULTS Pregnant mice on G18.5 exhibited alpha-cell hypertrophy as well as augmented alpha-cell area and mass. This alpha-cell mass expansion was mainly due to increased proliferation. No changes in alpha-cell apoptosis, ductal neogenesis, or alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonaemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated alpha-cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α-TC1.9 cells at low glucose levels. CONCLUSIONS The pancreatic alpha-cell in mice undergoes several morphofunctional changes during late pregnancy, which may contribute to proper glucose homeostasis. Gestational hormones are likely involved in these processes.
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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... more
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, due to mitochondria involvement in so many crucial cellular processes in metabolic relevant tissues, mitochondrial dysfunction has been linked to different metabolic diseases, including insulin resistance and type 2 diabetes. Herein...
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Ca-activated ion channels shape membrane excitability in response to elevations in intracellular Ca. The most extensively studied Ca-sensitive ion channels are Ca-activated K channels, whereas the physiological importance of Ca-activated... more
Ca-activated ion channels shape membrane excitability in response to elevations in intracellular Ca. The most extensively studied Ca-sensitive ion channels are Ca-activated K channels, whereas the physiological importance of Ca-activated Cl channels has been poorly studied. Here we show that a Ca-activated Cl currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells. Electrophysiological recording of mouse sympathetic neurons in an 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 Ca-dependent currents: the K [I] and CaCC. When the I was larger, an afterhyperpolar...
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Energy balance involves the adjustment of food intake, energy expenditure and body fat reserves through homeostatic pathways. These pathways include a multitude of biochemical reactions, as well as hormonal cues. Dysfunction of this... more
Energy balance involves the adjustment of food intake, energy expenditure and body fat reserves through homeostatic pathways. These pathways include a multitude of biochemical reactions, as well as hormonal cues. Dysfunction of this homeostatic control system results in common metabolism-related pathologies, which include obesity and type 2 diabetes mellitus. Metabolism-disrupting chemicals (MDCs) are a particular class of endocrine-disrupting chemicals that affect energy homeostasis. MDCs affect multiple endocrine mechanisms and thus different cell types that are implicated in metabolic control. MDCs affect gene expression and the biosynthesis of key enzymes, hormones and adipokines that are essential for controlling energy homeostasis. This multifaceted spectrum of actions precludes compensatory responses and favours metabolic disorders. Herein, we review the main mechanisms used by MDCs to alter energy balance. This work should help to identify new MDCs, as well as novel targets ...
Research Interests: Obesity, Gene expression, Energy Metabolism, Adipose tissue, Humans, and 15 moreMetabolic diseases, Endocrine disruptors, Hypothalamus, Female, Animals, Male, Exercise, Adipokines, Homeostasis, Gastrointestinal Tract, Endocrine Disruptors, Thermogenesis, Type 2 Diabetes Mellitus, Energy Intake, and Basal Metabolism
Pathophysiological conditions such as obesity and type 2 diabetes (T2D) are reportedly associated to over-activation of the endocannabinoid system (ECS). Therefore, modulation of the ECS offers potential therapeutic benefits on those... more
Pathophysiological conditions such as obesity and type 2 diabetes (T2D) are reportedly associated to over-activation of the endocannabinoid system (ECS). Therefore, modulation of the ECS offers potential therapeutic benefits on those diseases. GPR55, the receptor for L-α-lysophosphatidylinositol (LPI) that has also affinity for various cannabinoid ligands, is distributed at the central and peripheral level and it is involved in several physiological processes. This review summarizes the localization and role of GPR55 in tissues that are crucial for the regulation of glucose metabolism, and provides an update on its contribution in obesity and insulin resistance. Finally, the therapeutic potential of targeting the GPR55 receptor is also discussed.
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GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological... more
GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.
Research Interests: Drug Discovery, Molecular endocrinology, Rodentia, Energy Metabolism, Cannabinoids, and 11 moreAdipose tissue, Humans, G protein-coupled receptors, Animals, Clinical Sciences, Veterinary Sciences, Type 2 Diabetes Mellitus, Molecular Targeted Therapy, Ligands, Gene Expression Regulation, and Paediatrics and reproductive medicine
Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a... more
Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired gl...
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Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined.... more
Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Leprflox/flox Syn-cre mice). Within the hypothalamus, leptin signaling was disrupted in the lateral hypothalamic area (LHA) and ventral premammillary nucleus (PMV) but remained intact in the arcuate hypothalamic nucleus and ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and nucleus of the tractus solitarius. To investigate the role of LHA/PMV neuronal leptin signaling, we examined glucose and energy homeostasis in Leprflox/flox Syn-cre mice and Leprflox/flox littermates under basal and diet-induced obese conditions and tested the role of LHA/PMV neurons in lept...
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Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of... more
Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis.
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Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing... more
Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
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The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby... more
The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of α-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on α-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to α-cell function are also discussed in...
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Research Interests: Endocrinology, Chemistry, Biology, Medicine, Patch-clamp and imaging techniques, and 15 moreBiological Sciences, Glucose, Insulin, Insulin Secretion, Fasting, Mice, Secretory Pathway, Animals, Male, Homeostasis, Body Weight, Review of Literature Protein Energy Malnutrition, Electric Capacitance, Down-Regulation, and Medical and Health Sciences
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... more
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 nece...
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s / Can J Diabetes 36 (2012) S24eS76 S63 (RIP-Cre) were used to produce the vectors. AAV8s were delivered by intraperitoneal, subcutaneous and intra-amniotic injection to wild type, non-obese diabetic NOD, and mT/mG reporter mice.... more
s / Can J Diabetes 36 (2012) S24eS76 S63 (RIP-Cre) were used to produce the vectors. AAV8s were delivered by intraperitoneal, subcutaneous and intra-amniotic injection to wild type, non-obese diabetic NOD, and mT/mG reporter mice. Transgene expression and function of the targeted cells were analyzed at different timepoints post-injection. Additionally, body weight, blood glucose, arginine and glucose tolerance, and plasma hormone levels were examined. AAVRIP-GFP and AAVRIP-Cre delivery resulted in specific b-cell GFP and Cre expression, respectively. Cre activity was confirmed by delivery of AAVRIP-Cre to reporter mT/mGmice, inwhich EGFP was expressed upon Cre-mediated recombination. Further studies will determine whether Cre expression triggered by AAVRIP-Cre may impair glucose tolerance and b-cell [Ca]i as observed in transgenic RIPCre mice. AAVGCG-EGFP delivery allowed for exclusive EGFP expression in a-cells, which exhibited normal [Ca]I, and did not produce alterations in body weight, blood glucose, arginine and glucose tolerance, or plasma hormone levels. We conclude that AAV8s may be suitable vectors to specifically and acutely target gene expression in aand b-cells.
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Research Interests: Endocrinology, Chemistry, Biology, Medicine, Biological Sciences, and 15 moreGlucose, Insulin, Insulin Secretion, Fasting, Mice, Secretory Pathway, Animals, Male, Homeostasis, Body Weight, Protein energy malnutrition among 5 year children, Review of Literature Protein Energy Malnutrition, Electric Capacitance, Down-Regulation, and Medical and Health Sciences
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OBJECTIVE Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic β-cells, inhibiting insulin... more
OBJECTIVE Leptin released from adipocytes plays a key role in the control of food intake, energy balance, and glucose homeostasis. In addition to its central action, leptin directly affects pancreatic β-cells, inhibiting insulin secretion, and, thus, modulating glucose ...
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s / Can J Diabetes 36 (2012) S24eS76 S63 (RIP-Cre) were used to produce the vectors. AAV8s were delivered by intraperitoneal, subcutaneous and intra-amniotic injection to wild type, non-obese diabetic NOD, and mT/mG reporter mice.... more
s / Can J Diabetes 36 (2012) S24eS76 S63 (RIP-Cre) were used to produce the vectors. AAV8s were delivered by intraperitoneal, subcutaneous and intra-amniotic injection to wild type, non-obese diabetic NOD, and mT/mG reporter mice. Transgene expression and function of the targeted cells were analyzed at different timepoints post-injection. Additionally, body weight, blood glucose, arginine and glucose tolerance, and plasma hormone levels were examined. AAVRIP-GFP and AAVRIP-Cre delivery resulted in specific b-cell GFP and Cre expression, respectively. Cre activity was confirmed by delivery of AAVRIP-Cre to reporter mT/mGmice, inwhich EGFP was expressed upon Cre-mediated recombination. Further studies will determine whether Cre expression triggered by AAVRIP-Cre may impair glucose tolerance and b-cell [Ca]i as observed in transgenic RIPCre mice. AAVGCG-EGFP delivery allowed for exclusive EGFP expression in a-cells, which exhibited normal [Ca]I, and did not produce alterations in body weight, blood glucose, arginine and glucose tolerance, or plasma hormone levels. We conclude that AAV8s may be suitable vectors to specifically and acutely target gene expression in aand b-cells.
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Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing... more
Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
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Glucagon secreted from pancreatic α-cells plays a critical role in glycemia, mainly by hepatic glucose mobilization. In diabetic patients, an impaired control of glucagon release can worsen glucose homeostasis. Despite its importance, the... more
Glucagon secreted from pancreatic α-cells plays a critical role in glycemia, mainly by hepatic glucose mobilization. In diabetic patients, an impaired control of glucagon release can worsen glucose homeostasis. Despite its importance, the mechanisms that regulate its secretion are still poorly understood. Since α-cells are particularly sensitive to neural and paracrine factors, in this report we studied the role of purinergic receptors and extracellular ATP, which can be released from nerve terminals and β-cell secretory granules. Using immunocytochemistry, we identified in α-cells the P2 receptor subtype P2Y1, as well as the P1 receptors A1 and A2A. In contrast, only P2Y1 and A1 receptors were localized in β-cells. To analyze the role of purinergic receptors in α-cell function, we studied their participation in Ca2+ signaling. At low glucose concentrations, mouse α-cells exhibited the characteristic oscillatory Ca2+ signals that lead to secretion. Application of ATP (1–10 μM) aboli...
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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... more
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
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The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models,... more
The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined. A direct inhibitory effect of leptin on mouse and human α-cells has been demonstrated at the levels of electrical activity, calcium signaling, and glucagon secretion. In the present study we employed the Cre- loxP strategy to generate Lepr flox/flox Gcg-cre mice, which specifically lack leptin receptors in glucagon-secreting α-cells, to determine whether leptin resistance in α-cells contributes to hyperglucagonemia, and also whether leptin action in α-cells is required to improve glycemia in type 1 diabetes with leptin therapy. Immunohistochemical analysis of pancreas sections r...