Ortega-Molina A.,Tumor Suppression Group |
Efeyan A.,Tumor Suppression Group |
Lopez-Guadamillas E.,Tumor Suppression Group |
Munoz-Martin M.,Tumor Suppression Group |
And 12 more authors.
Cell Metabolism | Year: 2012
Aging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten tg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence. Interestingly, Pten tg mice have an increased energy expenditure and protection from metabolic pathologies. The brown adipose tissue (BAT) of Pten tg mice is hyperactive and presents high levels of the uncoupling protein Ucp1, which we show is a target of Foxo1. Importantly, a synthetic PI3K inhibitor also increases energy expenditure and hyperactivates the BAT in mice. These effects can be recapitulated in isolated brown adipocytes and, moreover, implants of Pten tg fibroblasts programmed with Prdm16 and Cebpβ form subcutaneous brown adipose pads more efficiently than wild-type fibroblasts. These observations uncover a role of Pten in promoting energy expenditure, thus decreasing nutrient storage and its associated damage. © 2012 Elsevier Inc.
Jimenez A.,Hospital Clinic Universitari |
Casamitjana R.,Hospital Clinic Universitari |
Casamitjana R.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Casamitjana R.,Institute DInvestigacions Biomediques August Pi Sunyer IDIBAPS |
And 6 more authors.
Diabetes Care | Year: 2013
OBJECTIVE-Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP. RESEARCH DESIGN AND METHODS-Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9-39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. RESULTS-Infusion of exendin-(9-39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9-39) 116.5 ± 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9-39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P > 0.001), but no change in glucagon (P = 0.258) responses. CONCLUSIONS-The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DMafter RYGBP may be explained bymechanisms beyond enhancement of GLP-1 action. © 2013 by the American Diabetes Association.
Vidal J.,Hospital Clinic Universitari |
Vidal J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Vidal J.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS |
Jimenez A.,Hospital Clinic Universitari
Current Atherosclerosis Reports | Year: 2013
The parallel occurrence of improved glucose tolerance and increased glucagon-like peptide 1 (GLP-1) response to meal intake following metabolic surgery (MS) demonstrated in several studies has led to the notion that GLP-1 is the culprit for the impressive rates of remission of type 2 diabetes mellitus (T2DM) following MS. In this article, we critically review current evidence supporting this view. Recent studies specifically designed to elucidate a causative role of GLP-1 in the antidiabetic effects of MS call into question GLP-1 as a key player for T2DM outcome following MS procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy in morbidly obese subjects. Whether GLP-1 plays a more prominent role in the remission of T2DM following MS in subjects with moderate obesity warrants further studies. Appraisal of the mechanisms involved in the amelioration of hyperglycemia following MS is a priority, as it could help in the battle against the current combined epidemics of obesity and T2DM. © 2013 Springer Science+Business Media New York.
Allen H.L.,University of Exeter |
Flanagan S.E.,University of Exeter |
Shaw-Smith C.,University of Exeter |
De Franco E.,University of Exeter |
And 9 more authors.
Nature Genetics | Year: 2012
Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.
Griffeth R.J.,Research Center Principe Felipe |
Carretero J.,University of Salamanca |
Burks D.J.,Research Center Principe Felipe |
Burks D.J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas
PLoS ONE | Year: 2013
Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. Clinical studies suggest that diabetes and obesity diminish male fertility. However, the role of IRS proteins in male reproduction is unknown. We observed that testis weight is reduced by 45% in Irs2-deficient mice as compared with control males. The weight of these organs in Irs1-/- males was similar to controls; however, since Irs1-deficient mice are 50% smaller, testis weight:body weight was increased in this model. Neonatal Irs2-/- mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development. Histological examination of testicular cross sections from Irs2-/- mice revealed normal cellular associations without obvious abnormalities in the seminiferous epithelium. Reduced testicular weight was associated with fewer Sertoli cells, spermatogonia, spermatocytes, elongated spermatids, and epididymal spermatozoa. However, Leydig cell number and the concentration of serum testosterone were equivalent between Irs2-deficient and control males. Testicular weight was reduced similarly in non-diabetic and diabetic Irs2-/- mice, indicating that hyperglycemia does not compound the effects of Irs2 deletion on impaired testis development. Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development. © 2013 Griffeth et al.
Valverde A.M.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM |
Valverde A.M.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Gonzalez-Rodriguez A.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM |
Gonzalez-Rodriguez A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas
Archives of Physiology and Biochemistry | Year: 2011
Type 2 Diabetes mellitus (T2D) is the most common endocrine disorder associated to metabolic syndrome (MS) and occurs when insulin secretion can no compensate peripheral insulin resistance. Among peripheral tissues, the liver controls glucose homeostasis due to its ability to consume and produce glucose. The molecular mechanism underlying hepatic insulin resistance is not completely understood; however, it involves the impairment of the insulin signalling network. Among the critical nodes of hepatic insulin signalling, insulin receptor substrate 2 (IRS2) and protein tyrosine phosphatase 1B (PTP1B) modulate the phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 pathway that controls the suppression of gluconeogenic genes. In this review, we will focus on recent findings regarding the molecular mechanism by which IRS2 and PTP1B elicit opposite effects on carbohydrate metabolism in the liver in response to insulin. Finally, we will discuss the involvement of the critical nodes of insulin signalling in non-alcoholic fatty liver disease (NAFLD) in humans. © 2011 Informa UK, Ltd.
Astudillo A.M.,Institute Biologia y Genetica Molecular |
Astudillo A.M.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Balgoma D.,Institute Biologia y Genetica Molecular |
Balgoma D.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
And 4 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2012
The development of mass spectrometry-based techniques is opening new insights into the understanding of arachidonic acid (AA) metabolism. AA incorporation, remodeling and release are collectively controlled by acyltransferases, phospholipases and transacylases that exquisitely regulate the distribution of AA between the different glycerophospholipid species and its mobilization during cellular stimulation. Traditionally, studies involving phospholipid AA metabolism were conducted by using radioactive precursors and scintillation counting from thin layer chromatography separations that provided only information about lipid classes. Today, the input of lipidomic approaches offers the possibility of characterizing and quantifying specific molecular species with great accuracy and within a biological context associated to protein and/or gene expression in a temporal frame. This review summarizes recent results applying mass spectrometry-based lipidomic approaches to the identification of AA-containing glycerophospholipids, phospholipid AA remodeling and synthesis of oxygenated metabolites. © 2011 Elsevier B.V.
Duran J.,Barcelona Institute for Research in Biomedicine |
Duran J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Saez I.,Barcelona Institute for Research in Biomedicine |
Saez I.,University of Barcelona |
And 5 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2013
Glycogen is the only carbohydrate reserve of the brain, but its overall contribution to brain functions remains unclear. Although it has traditionally been considered as an emergency energetic reservoir, increasing evidence points to a role of glycogen in the normal activity of the brain. To address this long-standing question, we generated a brain-specific Glycogen Synthase knockout (GYS1Nestin-KO) mouse and studied the functional consequences of the lack of glycogen in the brain under alert behaving conditions. These animals showed a significant deficiency in the acquisition of an associative learning task and in the concomitant activity-dependent changes in hippocampal synaptic strength. Long-term potentiation (LTP) evoked in the hippocampal CA3-CA1 synapse was also decreased in behaving GYS1Nestin-KO mice. These results unequivocally show a key role of brain glycogen in the proper acquisition of new motor and cognitive abilities and in the underlying changes in synaptic strength. © 2013 ISCBFM All rights reserved.
Duran J.,Barcelona Institute for Research in Biomedicine |
Duran J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Guinovart J.J.,Barcelona Institute for Research in Biomedicine |
Guinovart J.J.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Guinovart J.J.,University of Barcelona
Molecular Aspects of Medicine | Year: 2015
Glycogen is present in the brain at much lower concentrations than in muscle or liver. However, by characterizing an animal depleted of brain glycogen, we have shown that the polysaccharide plays a key role in learning capacity and in activity-dependent changes in hippocampal synapse strength. Since glycogen is essentially found in astrocytes, the diverse roles proposed for this polysaccharide in the brain have been attributed exclusively to these cells. However, we have demonstrated that neurons have an active glycogen metabolism that contributes to tolerance to hypoxia. However, these cells can store only minute amounts of glycogen, since the progressive accumulation of this molecule leads to neuronal loss. Loss-of-function mutations in laforin and malin cause Lafora disease. This condition is characterized by the presence of high numbers of insoluble polyglucosan bodies, known as Lafora bodies, in neuronal cells. Our findings reveal that the accumulation of this aberrant glycogen accounts for the neurodegeneration and functional consequences, as well as the impaired autophagy, observed in models of this disease. Similarly glycogen synthase is responsible for the accumulation of corpora amylacea, which are polysaccharide-based aggregates present in the neurons of aged human brains. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism is important under stress conditions and that neuronal glycogen accumulation contributes to neurodegenerative diseases and to aging-related corpora amylacea formation. © 2015 Elsevier Ltd.
Cordero-Herrera I.,Institute of Food Science and Technology and Nutrition ICTAN |
Martin M.A.,Institute of Food Science and Technology and Nutrition ICTAN |
Martin M.A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas |
Bravo L.,Institute of Food Science and Technology and Nutrition ICTAN |
And 2 more authors.
Molecular Nutrition and Food Research | Year: 2013
Scope: Cocoa and (-)-epicatechin (EC), a main cocoa flavanol, have been suggested to exert beneficial effects in diabetes, but the mechanism for their insulin-like effects remains unknown. In this study, the modulation of insulin signalling by EC and a cocoa phenolic extract (CPE) on hepatic HepG2 cells was investigated by analysing key proteins of the insulin pathways, namely insulin receptor, insulin receptor substrate (IRS) 1 and 2, PI3K/AKT and 5′-AMP-activated protein kinase (AMPK), as well as the levels of the glucose transporter GLUT-2 and the hepatic glucose production. Methods and results: EC and CPE enhanced the tyrosine phosphorylation and total insulin receptor, IRS-1 and IRS-2 levels and activated the PI3K/AKT pathway and AMPK in HepG2 cells. CPE also enhanced the levels of GLUT-2. Interestingly, EC and CPE modulated the expression of phosphoenolpyruvate carboxykinase, a key protein involved in the gluconeogenesis, leading to a diminished glucose production. In addition, EC- and CPE-regulated hepatic gluconeogenesis was prevented by the blockage of AKT and AMPK. Conclusion: Our data suggest that EC and CPE strengthen the insulin signalling by activating key proteins of that pathway and regulating glucose production through AKT and AMPK modulation in HepG2 cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.