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1.
Am J Physiol Endocrinol Metab ; 324(6): E488-E505, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37134142

RESUMEN

Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical and chemical effects. Of the latter, the release of endocrine disrupting chemicals (EDCs) has consequences on the prevalence of human diseases related to the endocrine system. Bisphenols (BPs) and phthalates are two groups of EDCs commonly found in plastics that migrate into the environment and make low-dose human exposure ubiquitous. Here we review epidemiological, animal, and cellular studies linking exposure to BPs and phthalates to altered glucose regulation, with emphasis on the role of pancreatic ß-cells. Epidemiological studies indicate that exposure to BPs and phthalates is associated with diabetes mellitus. Studies in animal models indicate that treatment with doses within the range of human exposure decreases insulin sensitivity and glucose tolerance, induces dyslipidemia, and modifies functional ß-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of ß-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by ß-cells to adapt to metabolic stress such as chronic nutrient excess. Studies at the cellular level demonstrate that BPs and phthalates modify the same biochemical pathways involved in adaptation to chronic excess fuel. These include changes in insulin biosynthesis and secretion, electrical activity, expression of key genes, and mitochondrial function. The data summarized here indicate that BPs and phthalates are important risk factors for diabetes mellitus and support a global effort to decrease plastic pollution and human exposure to EDCs.


Asunto(s)
Diabetes Mellitus , Disruptores Endocrinos , Animales , Humanos , Insulina , Fenómenos Fisiológicos Celulares , Glucosa
2.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-36674557

RESUMEN

Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic ß-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis by altering pancreatic ß-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic MDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. We found that cell viability was moderately affected after bisphenol-A (BPA), bisphenol-F (BPF), and perfluorooctanesulfonic acid (PFOS) exposure, although cytotoxicity was relatively low. In addition, all bisphenols, as well as di(2-ethylhexyl) phthalate (DEHP) and cadmium chloride (CdCl2), promoted a marked decreased on glucagon secretion, together with changes in the expression of glucagon and/or transcription factors involved in cell function and identity, such as Foxo1 and Arx. Overall, our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology.


Asunto(s)
Disruptores Endocrinos , Contaminantes Ambientales , Humanos , Glucagón , Supervivencia Celular , Contaminantes Ambientales/toxicidad , Insulina , Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Expresión Génica
3.
Diabetologia ; 65(8): 1375-1389, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35652923

RESUMEN

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. METHODS: We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining. RESULTS: Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. CONCLUSIONS/INTERPRETATION: We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Glucagón , Células Secretoras de Insulina , Insulisina , Animales , Proliferación Celular/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucagón/metabolismo , Células Secretoras de Glucagón/metabolismo , Hiperplasia/genética , Hiperplasia/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulisina/genética , Insulisina/metabolismo , Ratones , alfa-Sinucleína/metabolismo
4.
Diabetologia ; 65(3): 490-505, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34932133

RESUMEN

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 gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. CONCLUSIONS/INTERPRETATION: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.


Asunto(s)
Antipsicóticos , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Animales , Antipsicóticos/efectos adversos , Aripiprazol/metabolismo , Aripiprazol/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Islotes Pancreáticos/metabolismo , Ratones , Olanzapina/efectos adversos , Olanzapina/metabolismo
6.
Diabetologia ; 62(9): 1667-1680, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31250031

RESUMEN

AIMS/HYPOTHESIS: Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 diabetes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα) and ß (ERß). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. METHODS: Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100 µg/kg per day for 4 days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the normalisation method based on the processing algorithm 'robust multi-array average'. Whole islets or dispersed islets from C57BL/6J or oestrogen receptor ß (ERß) knockout (Erß-/-) mice were treated with vehicle or BPA (1 nmol/l) for 48 h. Whole-cell patch-clamp recordings were used to measure Na+ and K+ currents. mRNA expression was evaluated by quantitative real-time PCR. RESULTS: Microarray analysis showed that BPA modulated the expression of 1440 probe sets (1192 upregulated and 248 downregulated genes). Of these, more than 50 genes, including Scn9a, Kcnb2, Kcnma1 and Kcnip1, encoded important Na+ and K+ channel subunits. These findings were confirmed by quantitative RT-PCR in islets from C57BL/6J BPA-treated mice or whole islets treated ex vivo. Electrophysiological measurements showed a decrease in both Na+ and K+ currents in BPA-treated islets. The pharmacological profile indicated that BPA reduced currents mediated by voltage-activated K+ channels (Kv2.1/2.2 channels) and large-conductance Ca2+-activated K+ channels (KCa1.1 channels), which agrees with BPA's effects on gene expression. Beta cells from ERß-/- mice did not present BPA-induced changes, suggesting that ERß mediates BPA's effects in pancreatic islets. Finally, BPA increased burst duration, reduced the amplitude of the action potential and enlarged the action potential half-width, leading to alteration in beta cell electrical activity. CONCLUSIONS/INTERPRETATION: Our data suggest that BPA modulates the expression and function of Na+ and K+ channels via ERß in mouse pancreatic islets. Furthermore, BPA alters beta cell electrical activity. Altogether, these BPA-induced changes in beta cells might play a role in the diabetogenic action of BPA described in animal models.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Receptor beta de Estrógeno/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Fenoles/farmacología , Animales , Receptor alfa de Estrógeno/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Potasio/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Sodio/metabolismo
7.
Diabetologia ; 59(4): 755-65, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26813254

RESUMEN

AIMS/HYPOTHESIS: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. METHODS: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. RESULTS: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. CONCLUSIONS/INTERPRETATION: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.


Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas de Homeodominio/metabolismo , Células Secretoras de Insulina/metabolismo , Factores de Transcripción Paired Box/metabolismo , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Diabetes Mellitus Tipo 1/patología , Femenino , Células Secretoras de Insulina/patología , Masculino , Ratones , Ratones Mutantes
8.
Amino Acids ; 47(8): 1533-48, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25940922

RESUMEN

Taurine (Tau) regulates ß-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in ß-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and ß-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating ß-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.


Asunto(s)
Suplementos Dietéticos , Glucagón/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Taurina/administración & dosificación , Taurina/metabolismo , Animales , Glucemia/metabolismo , Calcio/metabolismo , Homeostasis/efectos de los fármacos , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Leptina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Taurina/sangre
9.
Nutr Res Rev ; 27(1): 48-62, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24721112

RESUMEN

Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and ß-cells, respectively. While ß-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus , Dieta , Metabolismo Energético , Células Secretoras de Glucagón/metabolismo , Glucagón/metabolismo , Receptores de Glucagón/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Homeostasis , Humanos , Hiperglucemia/terapia , Metabolismo de los Lípidos , Obesidad/metabolismo , Obesidad/terapia
10.
J Clin Invest ; 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38713514

RESUMEN

Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

11.
J Cell Sci ; 124(Pt 5): 727-34, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21303931

RESUMEN

We have studied how the F-actin cytoskeleton is involved in establishing the heterogeneous intracellular Ca(2+) levels ([Ca(2+)](i)) and in the organization of the exocytotic machinery in cultured bovine chromaffin cells. Simultaneous confocal visualization of [Ca(2+)](i) and transmitted light studies of the cytoskeleton showed that, following cell stimulation, the maximal signal from the Ca(2+)-sensitive fluorescent dye Fluo-3 was in the empty cytosolic spaces left by cytoskeletal cages. This was mostly due to the accumulation of the dye in spaces devoid of cytoskeletal components, as shown by the use of alternative Ca(2+)-insensitive fluorescent cytosolic markers. In addition to affecting the distribution of such compounds in the cytosol, the cytoskeleton influenced the location of L- and P-Q-type Ca(2+) channel clusters, which were associated with the borders of cytoskeletal cages in resting and stimulated cells. Indeed, syntaxin-1 and synaptotagmin-1, which are components of the secretory machinery, were present in the same location. Furthermore, granule exocytosis took place at these sites, indicating that the organization of the F-actin cytoskeletal cortex shapes the preferential sites for secretion by associating the secretory machinery with preferential sites for Ca(2+) entry. The influence of this cortical organization on the propagation of [Ca(2+)](i) can be modelled, illustrating how it serves to define rapid exocytosis.


Asunto(s)
Actinas/metabolismo , Células Cromafines/citología , Células Cromafines/metabolismo , Citoesqueleto/metabolismo , Exocitosis/fisiología , Compuestos de Anilina/metabolismo , Animales , Calcio/metabolismo , Canales de Calcio/metabolismo , Bovinos , Células Cultivadas , Gránulos Cromafines/metabolismo , Citoplasma/metabolismo , Citoesqueleto/ultraestructura , Colorantes Fluorescentes/metabolismo , Fusión de Membrana/fisiología , Proteínas Qa-SNARE/metabolismo , Sinaptotagminas/metabolismo , Xantenos/metabolismo
12.
Environ Pollut ; 316(Pt 2): 120633, 2023 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-36370973

RESUMEN

Understanding the individual and global impact of pesticides on human physiology and the different stages of life is still a challenge in environmental health. We analyzed here whether administration of the organophosphate insecticide malathion before pregnancy could affect glucose homeostasis during pregnancy and, in addition, generate possible later consequences in mothers and offspring. For this, adult Wistar rats were allocated into two groups and were treated daily (intragastric) with malathion (14 or 140 mg/kg, body mass (bm)) for 21-25 days. Corn oil was used as vehicle in the Control group. Subgroups were defined based on the absence (nulliparous) or presence (pregnant) of a copulatory plug. Pregnant rats were followed by an additional period of 2 months after the term (post-term), without continuing malathion treatment. Fetuses and adult offspring of males and females were also evaluated. We ran an additional experimental design with rats exposed to malathion before pregnancy at a dose of 0.1 mg/kg bm. Malathion exposure resulted in glucose intolerance in the mothers during pregnancy and post-term period, regardless of the exposure dose. This was accompanied by increased visceral adipose tissue mass, dyslipidemia, unchanged pancreatic ß-cell mass, and varying insulin responses to glucose in vivo. The number of total newborns and birthweight was not affected by malathion exposure. Adult offspring from both sexes also became glucose-intolerant, regardless of the pesticide dose their dams were exposed to. This alteration could be associated with changes at the epigenomic level, as reduced hepatic mRNA content of DNA methylases and demethylases was found. We demonstrated that periconceptional exposure to malathion with doses aiming to mimic from work environment to indirect contamination predisposes progenitors and offspring rats to glucose intolerance. Thus, we conclude that subchronic exposure to malathion is a risk factor for gestational diabetes and prediabetes later in life.


Asunto(s)
Intolerancia a la Glucosa , Efectos Tardíos de la Exposición Prenatal , Recién Nacido , Embarazo , Masculino , Femenino , Ratas , Animales , Humanos , Malatión/toxicidad , Glucemia , Ratas Wistar , Homeostasis , Glucosa , Efectos Tardíos de la Exposición Prenatal/inducido químicamente
13.
Ageing Res Rev ; 80: 101674, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35724861

RESUMEN

The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt ß-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic ß-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of ß-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as ß-cell proliferation, apoptosis and cell identity that can influence ß-cell mass. Age-related changes also affect ß-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on ß-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of ß-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of ß-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of ß-cells to age-associated T2D and may boost new therapeutic strategies.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Células Secretoras de Insulina , Envejecimiento/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Ratones
14.
J Gerontol A Biol Sci Med Sci ; 77(3): 405-415, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-34562079

RESUMEN

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 ß cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of ß-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on ß-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized into 2 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 ß cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with aging, particularly in the aged-LIS group. Glucose-induced islet NAD(P)H production was decreased in aged mice, suggesting impaired mitochondrial function. In contrast, voltage-gated Ca2+ currents were higher in aged-LIS ß cells, and pancreatic islets of both aged groups displayed increased glucose-induced Ca2+ signaling and augmented insulin secretion compared with controls. Morphological analysis of pancreas sections also revealed augmented ß-cell mass with aging, especially in the aged-LIS group, as well as ultrastructural ß-cell changes. Altogether, these findings indicate that aged mouse ß cells compensate for the aging-induced alterations in the stimulus-secretion coupling, particularly by adjusting their Ca2+ influx to ensure insulin secretion. These results also suggest that decreased peripheral insulin sensitivity exacerbates the effects of aging on ß cells.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Células Secretoras de Insulina , Islotes Pancreáticos , Envejecimiento , Animales , Calcio , Glucosa , Insulina/farmacología , Islotes Pancreáticos/fisiología , Masculino , Ratones
15.
Chemosphere ; 265: 129051, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33250229

RESUMEN

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic ß-cells from wild type (WT) and estrogen receptor ß (ERß) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in ß-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in ß-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERß pathways. Molecular dynamics simulations indicated differences in ERß ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERß whose activation alters three key cellular events in ß-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.


Asunto(s)
Receptor beta de Estrógeno , Receptores de Estrógenos , Animales , Compuestos de Bencidrilo/toxicidad , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Insulina , Canales Iónicos , Ratones , Fenoles , Receptores de Estrógenos/genética
16.
Hormones (Athens) ; 9(2): 118-26, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20687395

RESUMEN

The aim of this review was to analyze the potential effects of environmental chemicals on homeostatic control related to glycemia and energy balance. Many of the environmental chemicals can mimic or interfere with the action of hormones and are generally referred to as "endocrine disruptors". Among these compounds, polychlorinated biphenyls, dioxins, phthalates and bisphenol-A have been correlated with alterations in blood glucose homeostasis in humans. In rodents it has been demonstrated that small doses of bisphenol-A have profound effects on glucose metabolism. Therefore, this altered blood glucose homeostasis may enhance the development of type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/inducido químicamente , Disruptores Endocrinos/efectos adversos , Contaminantes Ambientales/efectos adversos , Estrógenos no Esteroides/efectos adversos , Fenoles/efectos adversos , Animales , Compuestos de Bencidrilo , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Metabolismo Energético/efectos de los fármacos , Estradiol/metabolismo , Medicina Basada en la Evidencia , Homeostasis , Humanos , Medición de Riesgo , Factores de Riesgo
17.
Metabolism ; 102: 153963, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31593706

RESUMEN

BACKGROUND: Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycemia. 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 hypoglucagonemia. 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.


Asunto(s)
Adaptación Fisiológica/fisiología , Edad Gestacional , Células Secretoras de Glucagón/citología , Células Secretoras de Glucagón/fisiología , Animales , Recuento de Células , Tamaño de la Célula , Células Cultivadas , Femenino , Glucagón/metabolismo , Islotes Pancreáticos/citología , Islotes Pancreáticos/fisiología , Ratones , Ratones Endogámicos C57BL , Hormonas Placentarias/fisiología , Embarazo
18.
Food Chem Toxicol ; 145: 111681, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32805339

RESUMEN

Bisphenol-A (BPA) is a widespread endocrine disrupting chemical that constitutes a risk factor for type 2 diabetes mellitus (T2DM). Data from animal and human studies have demonstrated that early exposure to BPA results in adverse metabolic outcomes in adult life. In the present work, we exposed pregnant heterozygous estrogen receptor ß (ERß) knock out (BERKO) mice to 10 µg/kg/day BPA, during days 9-16 of pregnancy, and measured ß-cell mass and proliferation in wildtype (WT) and BERKO male offspring at postnatal day 30. We observed increased pancreatic ß-cell proliferation and mass in WT, yet no effect was produced in BERKO mice. Dispersed islet cells in primary culture treated with 1 nM BPA showed an enhanced pancreatic ß-cell replication rate, which was blunted in pancreatic ß-cells from BERKO mice and mimicked by the selective ERß agonist WAY200070. This increased ß-cell proliferation was found in male adult as well as in neonate pancreatic ß-cells, suggesting that BPA directly impacts ß-cell division at earliest stages of life. These findings strongly indicate that BPA during pregnancy upregulates pancreatic ß-cell division and mass in an ERß-dependent manner. Thus, other natural or artificial chemicals may use this ERß-mediated pathway to promote similar effects.


Asunto(s)
Compuestos de Bencidrilo/toxicidad , Receptor beta de Estrógeno/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Exposición Materna/efectos adversos , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptor beta de Estrógeno/genética , Femenino , Humanos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Noqueados , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética
19.
J Agric Food Chem ; 68(5): 1266-1275, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31937103

RESUMEN

Diabetes (T2DM) is a major global health issue, and developing new approaches to its prevention is of paramount importance. We hypothesized that abnormalities in lipid metabolism are involved in alpha-cell deregulation. We therefore studied the metabolic factors underlying alpha-cell dysfunction in T2DM progression after a dietary intervention (Mediterranean and low-fat). Additionally, we evaluated whether postprandial glucagon levels may be considered as a predictive factor of T2DM in cardiovascular patients. Non-T2DM participants from the CORDIOPREV study were categorized by tertiles of the area under the curve (AUC) for triacylglycerols and also by tertiles of AUC for glucagon. Our results showed that patients with higher triacylglycerols levels presented elevated postprandial glucagon (P = 0.009). Moreover, we observed higher risk of T2DM (hazard ratio: 2.65; 95% confidence interval: 1.56-4.53) in subjects with elevated glucagon. In conclusion, high postprandial lipemia may induce alpha-cell dysfunction in cardiovascular patients. Our results also showed that postprandial glucagon levels could be used to predict T2DM development.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Glucagón/metabolismo , Hiperlipidemias/metabolismo , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Progresión de la Enfermedad , Femenino , Glucagón/metabolismo , Humanos , Hiperlipidemias/complicaciones , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Periodo Posprandial , Estudios Prospectivos , Triglicéridos/metabolismo
20.
J Physiol ; 587(Pt 21): 5031-7, 2009 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-19687125

RESUMEN

Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of beta-cell mass. It is not completely understood why, in some individuals, beta-cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the beta-cell response to maternal hormones may play a key part. The role of the maternal hormone 17beta-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on beta-cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase beta-cell proliferation but it is involved in beta-cell survival. Classical oestrogen receptors ERalpha and ERbeta, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity.


Asunto(s)
Estrógenos/metabolismo , Resistencia a la Insulina/fisiología , Islotes Pancreáticos/citología , Islotes Pancreáticos/fisiología , Embarazo/metabolismo , Transducción de Señal/fisiología , Animales , Femenino , Humanos
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