Irene Cozar-Castellano

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeut...

The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzhe...

Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes. Materials and methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) f...

Background and aims: Insulin-degrading enzyme (IDE) is a ubiquitous metalloprotease that degrades insulin and glucagon among other substrates. By decades, its main function has been attributed to hepatic insulin clearance, a process that regulates availability of insulin levels. Recent studies indicate a more important role of this protein in insul...

The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed...

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,...

The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount aspect to understand how this enzyme can per...

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor in Chief. This paper is being retracted due to many inaccuracies in the original data in Figures 1D, 1E, 2A, 2B, 2E, 3B, 4B, 5A bein...

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn2+-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity...

Objectives Vascular occlusive disease is a leading cause of death and disability worldwide. One of the major barriers of the current surgical therapeutic approaches is restenosis of the target vessel due to dedifferentiation of the vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2DM) has a major impact on restenosis, with patients exhibitin...

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissu...

The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet. Objective: These studies were undertaken to further investi...

Neurodegenerative diseases are age-related disorders caused by progressive neuronal death in different regions of the nervous system. Neuroinflammation, modulated by glial cells, is a crucial event during the neurodegenerative process; consequently, there is an urgency to find new therapeutic products with anti-glioinflammatory properties. Five new...

Insulin resistance in humans and mice is an important hallmark of metabolic diseases. Therefore, assessment of insulin sensitivity/resistance in animal models provides valuable information in the pathophysiology of diabetes and obesity. Depending on the nature of the information required, we can choose between direct and indirect techniques availab...

Insulin is a hormone produced and secreted by the β-cells of the pancreatic islets of Langerhans in response to increased blood glucose levels after a meal. The hormone binds to its receptor located on the plasma membrane triggering an intracellular signaling cascade. This signaling pathway is responsible for the pleiotropic actions of insulin on d...

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecu...

Insulin Degrading Enzyme (IDE) is a metalloprotease known by its ability to degrade insulin and other peptides such as glucagon. Ide genetic locus has been associated with type-2 diabetes mellitus. Our research group has previously reported that IDE is expressed in pancreatic beta-and alpha-cells of both rodents and humans, having higher expression...

Inhibition of insulin degrading enzyme has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handlin...

The cyclic depsipeptide cereulide toxin it is a very well‐known potassium electrogenic ionophore particularly sensitive to pancreatic beta cells. The mechanistic details of its specific activity are unknown. Here, we describe a series of synthetic substituted cereulide potassium ionophores that cause impressive selective activation of glucose‐induc...

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. METHODS: We generated mice with liver-speci...

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. Objective: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. Methods: We generated mice with liver-spe...

Insulin Degrading Enzyme (IDE) is an endopeptidase that degrades insulin and glucagon. Ide gene has been associated with type-2 diabetes mellitus (DM2). However, the physiological role(s) of IDE in glucose homeostasis and its potential therapeutic benefit remain not completely known. To contribute in the understanding of IDE's role in glucose metab...

Nine new cembranoids 1–9 containing an α–methylene–γ–butyrolactone together with the known diterpenes 10–15 have been isolated from a crude extract of Eunicea sp. and their structures were established by spectroscopic methods. The proliferative effect of six of these compounds on insulin-producing cells (beta–cells) was evaluated.

Two new chloro-furanocembranolides (1, 2) and two new 1,4-diketo cembranolides (3, 4) were isolated from the crude extract of Leptogorgia sp. together with a new seco-furanocembranolide (5) and the known Z-deoxypukalide (6), rubifolide (7), scabrolide D (8) and epoxylophodione (9). Their structures were determined based on spectroscopic evidence. F...

Two new chloro-furanocembranolides (1, 2) and two new 1,4-diketo cembranolides (3, 4) were isolated from the crude extract of Leptogorgia sp. together with a new seco-furanocembranolide (5) and the known Z-deoxypukalide (6), rubifolide (7), scabrolide D (8) and epoxylophodione (9). Their structures were determined based on spectroscopic evidence. F...

Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in...

Hepatocyte growth factor (HGF) is a cytokine that increases glucose transport ex vivo in skeletal muscle. The aim of this work was to decipher the impact of whether conditional overexpression of HGF in vivo could improve glucose homeostasis and insulin sensitivity in mouse skeletal muscle. Following tetracyclin administration, muscle HGF levels wer...

Aim/hypothesis: Diabetes is a consequence of a decrease on functional β-cell mass. We have recently demonstrated that epoxypukalide (Epoxy) is a natural compound with beneficial effects on primary cultures of rat islets. In this study, we extend our previous investigations to test the hypothesis that Epoxy protects β-cells and improves glucose met...

Aging remains the main risk factor to suffer Alzheimer's disease (AD), though epidemiological studies also support that type 2 diabetes (T2D) is a major contributor. In order to explore the close relationship between both pathologies we have developed an animal model presenting both AD and T2D, by crossing APP/PS1 mice (AD model) with db/db mice (T...

Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines generate a destructive environment for β-cells known as insulitis, which results in loss of β-cell mass and impaired insulin secretion, leading to diabet...

To evaluate the impact of the pro-inflammatory cytokine hepatocyte growth factor (HGF) on the regulation of glucose and lipid placental metabolism. HGF levels were quantified in amniotic fluid and placenta from control and obese women. 2-deoxy-glucose (2-DOG) uptake, glycolysis, fatty acid oxidation (FAO), fatty acid esterification, de novo fatty a...

Activation of pancreatic beta-cell proliferation has been proposed as an approach to replace reduced functional beta-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3 or cyclin E induces pancreatic beta-cell proliferation....

Placental metabolism is an important mechanism for the regulation of fetal growth and long-term health of the newborns. In this study, we investigated the effects of maternal metabolic environment on human placental fatty acid and glucose metabolism. We used placental explants from uncomplicated pregnancies or pregnancies complicated with gestation...

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, including Alzheimer's disease (AD), and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS) morphological alt...

Alzheimer’s disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and have no successful treatment. On the other hand, type 2 diabetes (T2D) seems to be a relevant risk factor to suffer dementia and epidemiological studies support a close relationship between T2D and AD-VaD, leading to the description of a complex syndrom...

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test...

[This corrects the article on p. e52862 in vol. 8.].

Aim/hypothesis: Placenta of women with gestational diabetes mellitus (GDM) exhibits an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high-glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human p...

There is an urgency to find new treatments for the devastating epidemic of diabetes. Pancreatic β-cells viability and function are impaired in the two most common forms of diabetes, type 1 and type 2. Regeneration of pancreatic β-cells has been proposed as a potential therapy for diabetes. In a preliminary study, we screened a collection of marine...

Alzheimer’s disease (AD) and vascular dementia (VD) are the most common causes of dementia although the ultimate neurotoxic mechanisms have not been completely elucidated. Previous clinical and epidemiological studies suggest that insulin resistance and type 2 diabetes mellitus (T2D) are relevant risks factors to suffer both AD and VD. On the other...

Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell...

Whereas Alzheimer’s disease (AD) is the most common cause of dementia the ultimate neurotoxic mechanisms are not known. Epidemiological studies reveal that type 2 diabetes mellitus (T2D) is a risk factor to suffer AD, although establishing whether there is a direct relationship between T2DM and AD remains elusive. In this study we have focused on e...

Alzheimer’s disease (AD) and vascular dementia (VD) are the most common causes of dementia although the ultimate neurotoxic mechanisms have not been completely elucidated. Multiple epidemiological studies reveal that type 2 diabetes mellitus (T2D) is a risk factor to suffer AD and VD. However to our knowledge only a handful of studies have intended...

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypot...

Type 2 Diabetes Mellitus (DM2) is a well known risk factor of the Alzheimer disease. Alzheimer is the most common cause of dementia among elderly people, At present many clinical studies have shown a relationship between both illnesses, however it remains unclear whether there is a cause-effect association between both of them and how diabetes migh...

Alzheimer’s disease and vascular dementia are the two most common causes of dementia. The ultimate cause has not been elucidated; however type 2 Diabetes Mellitus (DM2) may play a role in the onset and development of the illness. Following this idea recent clinical studies strongly relate DM2 with dementia, although the underlying mechanisms remain...

Diabetes is a well known risk factor for dementia and Alzheimer’s disease. At present many clinical studies have shown a relationship between both illnesses, however it remains unclear whether there is a cause-effect association between both of them and how diabetes might be implicated in the onset and development of Alzheimer’s disease. This study...

Apolipoprotein D (ApoD) is an atypical apolipoprotein with an incompletely understood function in the regulation of triglyceride and glucose metabolism. We have demonstrated that elevated ApoD production in mice results in improved postprandial triglyceride clearance. This work studies the role of ApoD deficiency in the regulation of triglyceride a...

Multiple myeloma (MM) is an incurable disease accompanied by low plasma levels of low-density lipoprotein cholesterol (LDL-c). The significance of altered cholesterol metabolism in the pathophysiology of MM remains elusive. Although it has been hypothesized that myeloma cells depend on exogenous cholesterol for its survival, the role of LDL-c on my...

Most knowledge on human beta-cell cycle control derives from immunoblots of whole human islets, mixtures of beta-cells and non-beta-cells. We explored the presence, subcellular localization, and function of five early G1/S phase molecules-cyclins D1-3 and cdk 4 and 6-in the adult human beta-cell. Immunocytochemistry for the five molecules and their...

To comprehensively inventory the proteins that control the G1/S cell cycle checkpoint in the human islet and compare them with those in the murine islet, to determine whether these might therapeutically enhance human beta-cell replication, to determine whether human beta-cell replication can be demonstrated in an in vivo model, and to enhance human...

Arterial expression of PTH-related protein is markedly induced by angioplasty. PTH-related protein contains a nuclear localization signal (NLS). PTH-related protein mutants lacking the NLS (ANLS- PTH-related protein) are potent inhibitors of arterial vascular smooth muscle cell (VSMC) proliferation in vitro. This is of clinical relevance because ad...

Rodent insulinoma cell lines may serve as a model for designing continuously replicating human beta-cell lines and provide clues as to the central cell cycle regulatory molecules in the beta-cell. We performed a comprehensive G1/S proteome analysis on the four most widely studied rodent insulinoma cell lines and defined their flow cytometric profil...

Animal studies show that G(1/S) regulatory molecules (D-cyclins, cdk-4, p18, p21, p27) are critical for normal regulation of beta-cell proliferation, mass, and function. The retinoblastoma protein, pRb, is positioned at the very end of a cascade of these regulatory proteins and is considered the final checkpoint molecule that maintains beta-cell cy...

p21(cip1), a regulatory molecule upstream of the G(1/0) checkpoint, is increased in beta-cells in response to mitogenic stimulation. Whereas p21(cip1) can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21(cip1) acts as an inhibitor in the pancreatic beta-cell. To determine the functional role of p21(cip1) in vi...

Parathyroid hormone-related protein (PTHrP) is present in vascular smooth muscle (VSM), is markedly upregulated in response to arterial injury, is essential for normal VSM proliferation, and also markedly accentuates neointima formation following rat carotid angioplasty. PTHrP contains a nuclear localization signal (NLS) through which it enters the...

Type 1 and type 2 diabetes both result from inadequate production of insulin by the beta-cells of the pancreatic islet. Accordingly, strategies that lead to increased pancreatic beta-cell mass, as well as retained or enhanced function of islets, would be desirable for the treatment of diabetes. Although pancreatic beta-cells have long been viewed a...

We hypothesized that combined transgenic overexpression of hepatocyte growth factor (HGF) and placental lactogen in islets would lead to even greater increases in beta-cell mass and replication than either growth factor alone. This did not occur, suggesting that beta-cell replication is saturable or subject to molecular restraint. We therefore perf...

Recent studies have demonstrated that human islet allograft transplantation can be a successful therapeutic option in the treatment of patients with Type I diabetes. However, this impressive recent advance is accompanied by a very important constraint. There is a critical paucity of pancreatic islets or pancreatic beta cells for islet transplantati...

Objective To identify new autoantigens related to Sjögren's syndrome and to determine their prevalence in patients and healthy individuals. Material and methods Serological sampling was performed in a patient with Sjögren's syndrome through the use of a human brain expression genotec (SEREX technique) to determine expression of known autoantigens...

To identify new autoantigens related to Sjögren's syndrome and to determine their prevalence in patients and healthy individuals. Serological sampling was performed in a patient with Sjögren's syndrome through the use of a human brain expression genotec (SEREX technique) to determine expression of known autoantigens and previously undescribed prote...