A5081888387- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Diabetes and associated disorders
- Autophagy in Disease and Therapy
- Diet, Metabolism, and Disease
- PI3K/AKT/mTOR signaling in cancer
- RNA modifications and cancer
- Cannabis and Cannabinoid Research
- Diabetes Management and Research
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Receptor Mechanisms and Signaling
- Birth, Development, and Health
- MicroRNA in disease regulation
- Endoplasmic Reticulum Stress and Disease
- Genetics, Aging, and Longevity in Model Organisms
- Bariatric Surgery and Outcomes
- Epigenetics and DNA Methylation
- Pancreatitis Pathology and Treatment
- Regulation of Appetite and Obesity
- Growth Hormone and Insulin-like Growth Factors
- Glycosylation and Glycoproteins Research
- Hormonal and reproductive studies
- Galectins and Cancer Biology
University of Miami
2017-2024
Miami VA Healthcare System
2021-2023
University of New Orleans
2022
University of Michigan–Ann Arbor
2010-2020
University of Miami Health System
2017
Diabetes Australia
2012-2017
Michigan Medicine
2016
Hospital Universitario Puerta del Mar
2008-2013
Ann Arbor Center for Independent Living
2012
Abstract Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis insulin secretion by using mice with conditional ( βraKO) inducible MIP-βraKO f/f ) raptor deletion. Through genetic reconstitution downstream targets, identify mTORC1/S6K pathway as mechanism which regulates apoptosis, size...
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed chronic androgen using dihydrotestosterone (DHT) exhibit hyperinsulinemia insulin resistance associated with secondary pancreatic β cell failure, leading hyperglycemia. These abnormalities are not observed in lacking receptor (AR) cells partially neurons mediobasal hypothalamus (MBH) as well AR selectively neurons. Accordingly,...
Pancreatic β-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) the most-studied cause of mass loss by pro-inflammatory cytokine-induced apoptosis, influences environment on regenerative response have been poorly studied. In this study, we assess anti-proliferative effect cytokines glucose concentration rat pancreatic β cells potential protective role glucagon-like peptide (GLP-1). Apoptotic...
Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, mechanisms responsible for pancreatic α cell mass function are not completely understood. In current study, we identified mTOR complex 1 (mTORC1) as regulator glucagon secretion. Using mice with tissue-specific deletion mTORC1 Raptor cells (αRaptorKO), showed that signaling is dispensable development, but essential maturation transition from milk-based diet to chow-based after...
Poor fetal nutrition increases the risk of type 2 diabetes in offspring at least part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how nutrients factors impact β-cells during development to alter glucose homeostasis metabolism later life. The current experiments aimed test on endocrine these signals acting mTOR signaling regulate mass homeostasis.Pancreatic rudiments culture were used study role glucose, factors, amino acids development. number...
Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined architecture of targets that regulate GLP-1 action male cells. cooperates with enhance cAMP production at plasma membrane and endosomes via: (1) increased mitochondrial CO2, activating HCO3−-sensitive soluble adenylate...
OBJECTIVE The purpose of this study was to evaluate the role S6K arm mammalian target rapamycin complex 1 (mTORC1) signaling in regulation β-cell mass and function. Additionally, we aimed delineate importance vivo activation insulin extent which alteration receptor substrate (IRS) modulates RESEARCH DESIGN AND METHODS current experiments describe phenotype transgenic mice overexpressing a constitutively active form under control rat promoter. RESULTS Activation these improved secretion...
Regulation of glucose homeostasis by insulin depends on β-cell growth and function. Nutrients factor stimuli converge the conserved protein kinase mechanistic target rapamycin (mTOR), existing in two complexes, mTORC1 mTORC2. To understand functional relevance mTOR enzymatic activity development homeostasis, we generated mice overexpressing either one or copies a kinase-dead mutant (KD-mTOR) transgene exclusively β-cells. We examined function these fed control chow high-fat diet. Mice with...
The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first 3 wk life [by increasing number pups crowded-litter (CL) model] leads to extension mean maximal lifespan genetically normal mice. In this study, we aimed characterize impact early-life intervention glucose metabolism energy homeostasis CL our used mice from litters supplemented 12 or 15 compared those control limited...
Patients with type 1 diabetes (T1D) suffer from insufficient functional β-cell mass, which results infiltration of inflammatory cells and cytokine-mediated death. Previous studies demonstrated the beneficial effects agonists growth hormone-releasing hormone receptor (GHRH-R), such as MR-409 on preconditioning islets in a transplantation model. However, therapeutic potential protective mechanisms GHRH-R models T1D have not been explored. Using vitro vivo T1D, we assessed propertie GHRH...
Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) β cells, thus increasing NO levels and inducing apoptosis. The aim the current study to determine role (1) antiproliferative effect IL-1 , IFN- γ TNF- α on cultured islet cells (2) during insulitis stage prior onset using Biobreeding (BB) rat strain as T1DM model. Our results indicate that donors exert cell obtained from...
Elevation of glucagon levels and increase in α-cell mass are associated with states hyperglycemia diabetes. Our previous studies have highlighted the role nutrient signaling via mTOR complex 1 (mTORC1) regulation that controls secretion mass. In current we investigated effects activation by conditional deletion mTORC1 inhibitor, TSC2, α-cells (αTSC2KO). We showed is sufficient to induce chronic hyperglucagonemia as a result proliferation, cell size, expansion. Hyperglucagonemia αTSC2KO was...
In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of β-cells has been considered to be the first event directly responsible for β-cell mass reduction. Bio-Breeding (BB) rat, an in vivo model used study diabetes, is observed from 9 wk age and takes place after insulitis period that begins at earlier age. Previous studies by our group have shown antiproliferative effect cytokines on cultured Wistar rats, was partially reversed Exendin-4, analogue glucagon-like...
MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well plasma of patients. Here we investigated how miR-199 regulated β-cells by assessing precursors (primiR-199a1, primiR-199a2, primiR-199b) mature (miR-199-3p miR-199-5p) promoter transcriptional activity assays mouse insulinoma cells (MIN6) under different stimuli. We found that equally express miR-199-3p miR-199-5p. However, the primiRNA levels...
The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this is a major regulator glucose homeostasis and β-cell mass, proliferation, survival by increasing insulin receptor substrate (IRS2) levels identify novel feedback mechanism which mTORC1 signaling...
The dynamic regulation of autophagy in β-cells by cycles fasting-feeding and its effects on insulin secretion are unknown. In β-cells, mechanistic target rapamycin complex 1 (mTORC1) is inhibited while fasting rapidly stimulated during refeeding a single amino acid, leucine, glucose. Stimulation mTORC1 nutrients the initiator ULK1 transcription factor TFEB, thereby preventing when were continuously exposed to nutrients. Inhibition Raptor knockout mimicked inhibiting secretion, whereas...
Type 2 diabetes is a metabolic disorder associated with abnormal glucose homeostasis and characterized by intrinsic defects in β-cell function mass. Trimethylguanosine synthase 1 (TGS1) an evolutionarily conserved enzyme that methylates small nuclear nucleolar RNAs involved pre-mRNA splicing, transcription, ribosome production. However, the role of TGS1 β-cells had not been explored. Here, we show upregulated insulin islets Langerhans from mice exposed to high-fat diet human type donors....
MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well plasma of patients. Here we investigated how miR-199 regulated β-cells by assessing precursors (primiR-199a1, primiR-199a2, primiR-199b) mature (miR-199-3p miR-199-5p) promoter transcriptional activity assays mouse insulinoma cells (MIN6) under different stimuli. We found that equally express miR-199-3p miR-199-5p. However, the primiRNA levels...
The aim of this study was to investigate the relation between different bariatric surgeries and pancreatic β-cell turnover.We used healthy adult male Wistar rats undergo techniques. Three surgical techniques were developed (malabsorptive, Sleeve gastrectomy Roux-Y Gastric Bypass-), together with two control groups (Sham fasting control). Pancreatic mass measured, as well apoptosis, proliferation neogenesis related cellular turnover. Otherwise, we measured functional issues elucidate...
The current studies uncover a novel mechanism linking mTORC2 signaling to glucose-stimulated insulin secretion by modulation of the actin filaments. This work also underscores important role GLP-1 in rescuing defects modulating polymerization and suggests that this effect is independent signaling.