Endocrinology, Diabetes, and Metabolism Commons^™

Spatial Definition Of The Human Progesterone Receptor-B Transcriptional Complex, Xinzhe Yu, Ping Yi, Anil K Panigrahi, Lance Edward V Lumahan, John P Lydon, David M Lonard, Steven J Lutdke, Zhao Wang, Bert W O'Malley

Faculty, Staff and Students Publications

We report the quaternary structure of core transcriptional complex for the full-length human progesterone receptor-B (PR-B) homodimer with primary coactivator steroid receptor coactivator-2 (SRC-2) and the secondary coactivator p300/CREB-binding protein (CBP). The PR-B homodimer engages one SRC-2 mainly through its activation function 1 (AF1) in N-terminus. SRC-2 is positioned between PR-B and p300 leaving space for direct interaction between PR-B and p300 through PR-B's C-terminal AF2 and its unique AF3. Direct AF3/p300 interaction provides long-desired structural insights into the known functional differences between PR-B and the PR-A isoform lacking AF3. We reveal the contributions of each AF and demonstrate their …

The Roles Of Sleep And Eating Patterns In Adiposity Gain Among Preschool-Aged Children, Amy R Goetz, Ishita Jindal, Jennette P Moreno, Maurice R Puyau, Anne L Adolph, Salma Musaad, Nancy F Butte, Fida Bacha

Faculty, Staff and Students Publications

BACKGROUND: Short sleep durations are related to risks for obesity in preschool children. However, the underlying mechanism or mechanisms are not clear.

OBJECTIVES: We evaluated the relationships between sleep characteristics and body composition, energetics, and weight-regulating behaviors in preschool-aged children, as well as the longitudinal associations between children's sleep and eating patterns and body composition at a 1-year follow-up.

METHODS: Data were drawn from a longitudinal study of 118 children aged 3-5 years. Sleep (duration, midpoint, regularity) and physical activity (PA) were measured by accelerometry over 6 consecutive days; total energy expenditure (TEE) was measured using the doubly labeled water …

Optimal Cardiometabolic Health And Risk Of Heart Failure In Type 2 Diabetes: An Analysis From The Look Ahead Trial, Kershaw V Patel, Muhammad Shahzeb Khan, Matthew W Segar, Judy L Bahnson, Katelyn R Garcia, Jeanne M Clark, Ashok Balasubramanyam, Alain G Bertoni, Muthiah Vaduganathan, Michael E Farkouh, James L Januzzi, Subodh Verma, Mark Espeland, Ambarish Pandey

Faculty, Staff and Students Publications

Aims: To evaluate the contribution of baseline and longitudinal changes in cardiometabolic health (CMH) towards heart failure (HF) risk among adults with type 2 diabetes (T2D).

Methods and results: Participants of the Look AHEAD trial with T2D and without prevalent HF were included. Adjusted Cox models were used to create a CMH score incorporating target levels of parameters weighted based on relative risk for HF. The associations of baseline and changes in the CMH score with risk of overall HF, HF with preserved (HFpEF) and reduced ejection fraction (HFrEF) were assessed using Cox models. Among the 5080 participants, 257 incident …

Aging-Associated Regγ Proteasome Decline Predisposes To Tauopathy, Jialu Tu, Haiyang Zhang, Ting Yang, Yun Liu, Solomon Kibreab, Yunpeng Zhang, Liangcai Gao, Robb E Moses, Bert W O'Malley, Jianru Xiao, Xiaotao Li

Faculty, Staff and Students Publications

The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found …

Predicting The Disease Severity In Male Individuals With Ornithine Transcarbamylase Deficiency, Svenja Scharre, Roland Posset, Sven F Garbade, Florian Gleich, Marie J Seidl, Ann-Catrin Druck, Jürgen G Okun, Andrea L Gropman, Sandesh C S Nagamani, Georg F Hoffmann, Stefan Kölker, Matthias Zielonka, Urea Cycle Disorders Consortium (Ucdc) And The European Registry And Network For Intoxication Type Metabolic Diseases (E-Imd) Consortia Study Group

Faculty, Staff and Students Publications

Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity.

Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with …

Re-Examining The Widespread Policy Of Stopping Sodium-Glucose Cotransporter-2 Inhibitors During Acute Illness: A Perspective Based On The Updated Evidence, Kamlesh Khunti, Vanita R Aroda, Deepak L Bhatt, Biykem Bozkurt, John B Buse, Hiddo L Heerspink, Silvio E Inzucchi, Carolyn S P Lam, Nikolaus Marx, John J V Mcmurray, Scott D Solomon, Mikhail N Kosiborod

Faculty, Staff and Students Publications

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or …

Clinical Characteristics And Associated Factors Of Colonic Polyps In Acromegaly, Guiliang Peng, Xing Li, Yuanyuan Zhou, Jianying Bai, Pian Hong, Weixing Li, Yuling Zhang, Lei Zhang, Qian Liao, Mingyu Liao, Ling Zhou, Zheng Sun, Rufei Shen, Hongting Zheng, Min Long

Faculty, Staff and Students Publications

PURPOSE: To investigate the clinical characteristics and associated factors of colonic polyps in patients with acromegaly.

METHODS: Clinical characteristics and colonoscopy findings of 86 acromegaly patients who received treatment were retrospectively reviewed, and colonoscopy findings and the correlation with growth hormone (GH)-secreting pituitary adenoma (GHPA) volume and hormonal/metabolic levels were analyzed.

RESULTS: The prevalence of colonic polyps in acromegaly patients was 40.7% and increased significantly with advanced age, especially in those ≥50 years. Multiple polyps (62.8%) and colonic polyps in the left colon (54.2%) were detected more frequently. Compared to acromegaly patients without polyps, those with polyps displayed higher insulin-like …

Butyrate-Producing Bacteria And Insulin Homeostasis: The Microbiome And Insulin Longitudinal Evaluation Study (Miles), Jinrui Cui, Gautam Ramesh, Martin Wu, Elizabeth T Jensen, Osa Crago, Alain G Bertoni, Chunxu Gao, Kristi L Hoffman, Patricia A Sheridan, Kari E Wong, Alexis C Wood, Yii-Der I Chen, Jerome I Rotter, Joseph F Petrosino, Stephen S Rich, Mark O Goodarzi

Faculty, Staff and Students Publications

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis, whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole-metagenome shotgun sequencing with taxonomic profiling. We examined associations among 36 butyrate-producing taxa (n = 7 genera and 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, BMI, and race. The genus Coprococcus …

Sensitive Image-Based Chromatin Binding Assays Using Inducible Erα To Rapidly Characterize Estrogenic Chemicals And Mixtures, Adam T Szafran, Maureen G Mancini, Fabio Stossi, Michael A Mancini

Faculty, Staff and Students Publications

The United States Environmental Protection Agency (EPA) has been pursuing new high throughput in vitro assays to characterize endocrine disrupting chemicals (EDCs) that interact with estrogen receptor signaling. We characterize two new PRL-HeLa cell models expressing either inducible C-terminal (iGFP-ER) or N-terminal (iER-GFP) tagged estrogen receptor-α (ERα) that allows direct visualization of chromatin binding. These models are an order of magnitude more sensitive, detecting 87 - 93% of very weak estrogens tested compared to only 27% by a previous PRL-HeLa variant and compares favorably to the 73% detected by an EPA-developed computational model using in vitro data. Importantly, the chromatin …

Cgas-Sting Activation Contributes To Podocyte Injury In Diabetic Kidney Disease, Nan Zang, Chen Cui, Xinghong Guo, Jia Song, Huiqing Hu, Mengmeng Yang, Mingyue Xu, Lingshu Wang, Xinguo Hou, Qin He, Zheng Sun, Chuan Wang, Li Chen

Faculty, Staff and Students Publications

Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or …

First Steps: Primary Outcomes Of A Randomized, Stepped-Care Behavioral Clinical Trial For Parents Of Young Children With New-Onset Type 1 Diabetes, Marisa E Hilliard, Carrie Tully, Maureen Monaghan, Tom Hildebrandt, Christine H Wang, John R Barber, Lauren Clary, Katherine Gallagher, Wendy Levy, Fran Cogen, Celia Henderson, Lefkothea Karaviti, Randi Streisand

Faculty, Staff and Students Publications

OBJECTIVE: Despite the emotional challenges of parental adjustment to a child's type 1 diabetes diagnosis and the unique complexities of early childhood, there are few programs designed to meet the needs of parents of young children at new onset. This study evaluated First STEPS (Study of Type 1 in Early childhood and Parenting Support), a stepped-care behavioral intervention designed to support parents' psychosocial functioning and promote children's glycemic outcomes.

RESEARCH DESIGN AND METHODS: Using a two-site randomized clinical trial design, parents (n = 157) of children aged 1-6 years completed baseline data within 2 months of diabetes diagnosis and were …

Glycemia Reduction In Type 2 Diabetes - Glycemic Outcomes, David M Nathan, John M Lachin, Ashok Balasubramanyam, Henry B Burch, John B Buse, Nicole M Butera, Robert M Cohen, Jill P Crandall, Steven E Kahn, Heidi Krause-Steinrauf, Mary E Larkin, Neda Rasouli, Margaret Tiktin, Deborah J Wexler, Naji Younes

Faculty, Staff and Students Publications

BACKGROUND: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.

METHODS: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, …

Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes Of The Young (Mody), Mustafa Tosur, Louis H Philipson

Faculty, Staff and Students Publications

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require …

Extracellular Vesicles In Β Cell Biology: Role Of Lipids In Vesicle Biogenesis, Cargo, And Intercellular Signaling, Rebecca S Aguirre, Abhishek Kulkarni, Matthew W Becker, Xiaoyong Lei, Soumyadeep Sarkar, Sasanka Ramanadham, Edward A Phelps, Ernesto S Nakayasu, Emily K Sims, Raghavendra G Mirmira

Faculty, Staff and Students Publications

BACKGROUND: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between β cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been seen as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by β cells constitute an additional and biologically important mechanism for transmitting signals to within the islet.

SCOPE OF REVIEW: This review summarizes the general mechanisms of EV formation, with …

Dietary Fat Composition Shapes Bile Acid Metabolism And Severity Of Liver Injury In A Pig Model Of Pediatric Nafld, Rodrigo Manjarín, Kayla Dillard, Morgan Coffin, Gabriella V Hernandez, Victoria A Smith, Trista Noland-Lidell, Tanvi R Gehani, Hayden J Smart, Kevin Wheeler, Kimberly A Sprayberry, Mark S Edwards, Rob K Fanter, Hunter Glanz, Chad Immoos, Tasha M Santiago-Rodriguez, Jason M Blank, Douglas G Burrin, Brian D Piccolo, Mohammed Abo-Ismail, Michael R La Frano, Magdalena Maj

Faculty, Staff and Students Publications

The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-day-old Iberian pigs pair-housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 wk: 1) lard-enriched (LAR; n = 5 pens), 2) olive oil-enriched (OLI; n = 5), and 3) coconut oil-enriched (COC; n = 5). Animals were euthanized on week 10 after blood sampling, and liver, colon, and distal ileum (DI) were …

Lifestyle Intervention Strategy To Treat Diabetes In Older Adults: A Randomized Controlled Trial, Alessandra Celli, Yoann Barnouin, Bryan Jiang, Dean Blevins, Georgia Colleluori, Sanjay Mediwala, Reina Armamento-Villareal, Clifford Qualls, Dennis T Villareal

Faculty, Staff and Students Publications

OBJECTIVE: Lifestyle intervention is recommended as first-line treatment of diabetes at all ages; however, little is known about the efficacy of lifestyle intervention in older adults with diabetes. We aimed to determine whether lifestyle intervention would improve glycemic control and age-relevant outcomes in older adults with diabetes and comorbidities.

RESEARCH DESIGN AND METHODS: A total of 100 older adults with diabetes were randomly assigned to 1-year intensive lifestyle intervention (ILI) (diet and exercise at a facility transitioned into community-fitness centers and homes) or healthy lifestyle (HL) group. The primary outcome was change in HbA1c. Secondary outcomes included glucoregulation, body composition, …

Sex Differences In Physical Activity Among Individuals With Type 2 Diabetes Across The Life Span: A Systematic Review And Meta-Analysis, Mary O Whipple, Ana J Pinto, Layla A Abushamat, Audrey Bergouignan, Kristina Chapman, Amy G Huebschmann, Kevin S Masters, Kristen J Nadeau, Rebecca L Scalzo, Irene E Schauer, Deirdre Rafferty, Jane E B Reusch, Judith G Regensteiner

Faculty, Staff and Students Publications

BACKGROUND: Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear.

PURPOSE: To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the life span.

DATA SOURCES: Systematic searches (CRD42021254246) were conducted with Ovid MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), APA PsychInfo, and SPORTDiscus.

STUDY SELECTION: We included studies with assessment of PA, sedentary behaviors (SB), or …

Rna Binding Protein Rbm46 Regulates Mitotic-To-Meiotic Transition In Spermatogenesis, Baomei Qian, Yang Li, Ruoyu Yan, Shenglin Han, Zhiwen Bu, Jie Gong, Bangjin Zheng, Zihan Yuan, Sen Ren, Qing He, Jinwen Zhang, Chen Xu, Ruilin Wang, Zheng Sun, Mingyan Lin, Jian Zhou, Lan Ye

Faculty, Staff and Students Publications

Meiosis entry during spermatogenesis requires reprogramming from mitotic to meiotic gene expression profiles. Transcriptional regulation has been extensively studied in meiosis entry, but gain of function for master transcription factors is insufficient to down-regulate mitotic genes. RNA helicase YTHDC2 and its partner MEIOC emerge as essential posttranscriptional regulators of meiotic entry. However, it is unclear what governs the RNA binding specificity of YTHDC2/MEIOC. Here, we identified RNA binding protein RBM46 as a component of the YTHDC2/MEIOC complex. Testis-specific Rbm46 knockout in mice causes infertility with defective mitotic-to-meiotic transition, phenocopying global Ythdc2 or Meioc knockout. RBM46 binds to 3′ UTR of …

The Roles Of Gut Microbiome And Plasma Metabolites In The Associations Between Abo Blood Groups And Insulin Homeostasis: The Microbiome And Insulin Longitudinal Evaluation Study (Miles), Ruifang Li-Gao, Kirk Grubbs, Alain G Bertoni, Kristi L Hoffman, Joseph F Petrosino, Gautam Ramesh, Martin Wu, Jerome I Rotter, Yii-Der Ida Chen, Anne M Evans, Richard J Robinson, Laura Sommerville, Dennis Mook-Kanamori, Mark O Goodarzi, Gregory A Michelotti, Patricia A Sheridan

Faculty, Staff and Students Publications

Non-O blood groups are associated with decreased insulin sensitivity and risk of type 2 diabetes. A recent study pinpointed the associations between ABO blood groups and gut microbiome, which may serve as potential mediators for the observed increased disease risks. We aimed to characterize associations between ABO haplotypes and insulin-related traits as well as potential mediating pathways. We assessed insulin homeostasis in African Americans (AAs; n = 109) and non-Hispanic whites (n = 210) from the Microbiome and Insulin Longitudinal Evaluation Study. The ABO haplotype was determined by six SNPs located in the ABO gene. Based on prior knowledge, …

Adiposity, Insulin Resistance, Cardiorespiratory Fitness, And Bone Health In Hispanic Children, Reem S Shawar, Maurice Puyau, Roman Shypailo, Salma Musaad, Nancy F Butte, Fida Bacha

Faculty, Staff and Students Publications

CONTEXT: Childhood obesity disproportionately affects Hispanic youth. The skeletal system appears to be a target organ of the adverse effects of obesity. Yet, the relationship between adiposity and bone health in youth and the modulating factors are not well understood.

OBJECTIVE: This work aims to examine the relationship between adiposity, insulin resistance (IR), cardiorespiratory fitness (CRF), and bone mass in Hispanic youth.

METHODS: A total of 951 Hispanic youth (50% male), aged 4 to 19 years, participated in this cross-sectional design study from the Viva La Familia Study at Children's Nutrition Research Center. Bone mineral content (BMC) and density (BMD), …

Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 Regulates Hepatic Fuel Metabolism, Brittany A Stork, Adam Dean, Andrea R Ortiz, Pradip Saha, Nagireddy Putluri, Maricarmen D Planas-Silva, Iqbal Mahmud, Kimal Rajapakshe, Cristian Coarfa, Stefan Knapp, Philip L Lorenzi, Bruce E Kemp, Benjamin E Turk, John W Scott, Anthony R Means, Brian York

Faculty, Staff and Students Publications

OBJECTIVE: The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined.

METHODS: To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2

RESULTS: Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin …

Effect Of The Covid-19 Pandemic Lockdown On The Management Of Diabetic Retinopathy: A Cross-Sectional Study, Vaishali Prajapati, Krishna Shah, Dhruvi Shah, Mayur B Wanjari, Deepika Singhal

Faculty, Staff and Students Publications

Introduction Worldwide, diabetic retinopathy (DR) is one of the leading causes of vision loss. Early treatment and screening for DR have a major role in reducing the rate of the disease and the coronavirus disease 2019 (COVID-19) pandemic-related restrictions have altered real-world practice patterns in managing DR. Aims and objectives To evaluate the impact of the COVID-19 pandemic on the management of DR amongst patients presenting to a tertiary eye care center in Gujarat, India. Methods This is a cross-sectional study comparison of ophthalmic findings of 72 patients who presented to a tertiary care hospital with the manifestation of DR …

Maladaptive Positive Feedback Production Of Chrebpβ Underlies Glucotoxic Β-Cell Failure, Liora S Katz, Gabriel Brill, Pili Zhang, Anil Kumar, Sharon Baumel-Alterzon, Lee B Honig, Nicolás Gómez-Banoy, Esra Karakose, Marius Tanase, Ludivine Doridot, Alexandra Alvarsson, Bennett Davenport, Peng Wang, Luca Lambertini, Sarah A Stanley, Dirk Homann, Andrew F Stewart, James C Lo, Mark A Herman, Adolfo Garcia-Ocaña, Donald K Scott

Faculty, Staff and Students Publications

Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell "glucolipotoxicity" can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-mediated cell death is …

An Integrated Proteomic And Glycoproteomic Investigation Reveals Alterations In The N-Glycoproteomic Network Induced By 2-Deoxy-D-Glucose In Colorectal Cancer Cells, Cheng Ma, Hong-Yuan Tsai, Qi Zhang, Lakmini Senavirathna, Lian Li, Lih-Shen Chin, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

As a well-known glycolysis inhibitor for anticancer treatment, 2-Deoxy-D-glucose (2DG) inhibits the growth and survival of cancer cells by interfering with the ATP produced by the metabolism of D-glucose. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to endoplasmic reticulum (ER) stress and unfolded protein responses in cancer cells. However, the molecular details underlying the impact of 2DG on protein glycosylation remain largely elusive. With an integrated approach to glycoproteomics and proteomics, we characterized the 2DG-induced alterations in N-glycosylation, as well as the cascading impacts on the whole proteome using the HT29 colorectal cancer …

A Role For Insulin-Like Growth Factor 1 In The Generation Of Epileptic Spasms In A Murine Model, Carlos J Ballester-Rosado, John T Le, Trang T Lam, Carrie A Mohila, Sandi Lam, Anne E Anderson, James D Frost, John W Swann

Faculty, Staff and Students Publications

Objective: Infantile spasms are associated with a wide variety of clinical conditions, including perinatal brain injuries. We have created a model in which prolonged infusion of tetrodotoxin (TTX) into the neocortex, beginning in infancy, produces a localized lesion and reproduces the behavioral spasms, electroencephalogram (EEG) abnormalities, and drug responsiveness seen clinically. Here, we undertook experiments to explore the possibility that the growth factor IGF-1 plays a role in generating epileptic spasms.

Methods: We combined long-term video EEG recordings with quantitative immunohistochemical and biochemical analyses to unravel IGF-1's role in spasm generation. Immunohistochemistry was undertaken in surgically resected tissue from infantile …

Association Of Rare Apoe Missense Variants V236e And R251g With Risk Of Alzheimer Disease, Yann Le Guen, Michael E Belloy, Benjamin Grenier-Boley, Itziar De Rojas, Atahualpa Castillo-Morales, Iris Jansen, Aude Nicolas, Céline Bellenguez, Carolina Dalmasso, Fahri Küçükali, Sarah J Eger, Katrine Laura Rasmussen, Jesper Qvist Thomassen, Jean-François Deleuze, Zihuai He, Valerio Napolioni, Philippe Amouyel, Frank Jessen, Patrick G Kehoe, Cornelia Van Duijn, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Giacomina Rossi, Mikko Hiltunen, Rebecca Sims, Wiesje M Van Der Flier, Alfredo Ramirez, Ole A Andreassen, Ruth Frikke-Schmidt, Julie Williams, Agustín Ruiz, Jean-Charles Lambert, Michael D Greicius, Members Of The Eadb, Gr@Ace, Degesco, Demgene, Gerad, And Eadi Groups, Beatrice Arosio, Luisa Benussi, Anne Boland, Barbara Borroni, Paolo Caffarra, Delphine Daian, Antonio Daniele, Stéphanie Debette, Carole Dufouil, Emrah Düzel, Daniela Galimberti, Vilmantas Giedraitis, Timo Grimmer, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Deckert Jürgen, Teemu Kuulasmaa, Aad Van Der Lugt, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre De Mendonça, Susanne Moebus, Benedetta Nacmias, Gael Nicolas, Robert Olaso, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Oliver Peters, Yolande A L Pijnenburg, Julius Popp, Innocenzo Rainero, Inez Ramakers, Steffi Riedel-Heller, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Hilkka Soininen, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John Van Swieten, Thomas J Tegos, Lucio Tremolizzo, Frans Verhey, Martin Vyhnalek, Jens Wiltfang, Mercè Boada, Pablo García-González, Raquel Puerta, Luis M Real, Victoria Álvarez, María J Bullido, Jordi Clarimon, José María García-Alberca, Pablo Mir, Fermin Moreno, Pau Pastor, Gerard Piñol-Ripoll, Laura Molina-Porcel, Jordi Pérez-Tur, Eloy Rodríguez-Rodríguez, Jose Luís Royo, Raquel Sánchez-Valle, Martin Dichgans, Dan Rujescu

Faculty, Staff and Students Publications

IMPORTANCE: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.

OBJECTIVE: To determine whether rare missense variants on APOE are associated with AD risk.

DESIGN, SETTING, …

Activating Connexin43 Gap Junctions Primes Adipose Tissue For Therapeutic Intervention, Yi Zhu, Na Li, Mingyang Huang, Xi Chen, Yu A An, Jianping Li, Shangang Zhao, Jan-Bernd Funcke, Jianhong Cao, Zhenyan He, Qingzhang Zhu, Zhuzhen Zhang, Zhao V Wang, Lin Xu, Kevin W Williams, Chien Li, Kevin Grove, Philipp E Scherer

Faculty, Staff and Students Publications

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic …

Relationship Between Arterial Stiffness And Subsequent Cardiac Structure And Function In Young Adults With Youth-Onset Type 2 Diabetes: Results From The Today Study, Amy S Shah, Samuel S Gidding, Laure El Ghormli, Jeanie B Tryggestad, Kristen J Nadeau, Fida Bacha, Lorraine E Levitt Katz, Steven M Willi, Joao Lima, Elaine M Urbina

Faculty, Staff and Students Publications

BACKGROUND: Higher arterial stiffness may contribute to future alterations in left ventricular systolic and diastolic function. We tested this hypothesis in individuals with youth-onset type 2 diabetes from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

METHODS: Arterial stiffness (pulse wave velocity [carotid-femoral, femoral-foot, and carotid-radial], augmentation index, brachial distensibility) was measured in 388 participants with type 2 diabetes (mean age, 21 years; diabetes duration, 7.7 ± 1.5 years). To reflect overall (composite) vascular stiffness, the five arterial stiffness measures were aggregated. An echocardiogram was performed in the same cohort 2 years later. Linear regression …

Impact Of The Covid-19 Pandemic On Visual Outcomes Of Diabetic Macular Edema Patients At A Tertiary Care Veterans Affairs Center, Philip Zhou, Jie Gao, Xiaofan Huang, Kristen A Staggers, Kristin Biggerstaff, Silvia Orengo-Nania, Roomasa Channa

Faculty, Staff and Students Publications

PURPOSE: There are limited studies on factors that impacted retina clinic patient outcomes during the COVID-19 pandemic. We aimed to evaluate visual and anatomic outcomes in patients with diabetic macular edema (DME) requiring anti-VEGF injections at the veterans' affairs tertiary care eye clinic in Houston, TX.

METHODS: Patient volume from April 2020 was compared to that of April 2019 to determine attendance changes. To evaluate outcomes, we reviewed patients with DME who had scheduled appointments during April 2020. We tracked changes in central foveal thickness (CFT) and Snellen visual acuity (VA) measurements. Patient outcomes were classified as poor (defined as …

Circadian Clock, Diurnal Glucose Metabolic Rhythm, And Dawn Phenomenon, Fei Peng, Xin Li, Fang Xiao, Ruxing Zhao, Zheng Sun

Faculty, Staff and Students Publications

The circadian clock provides cue-independent anticipatory signals for diurnal rhythms of baseline glucose levels and glucose tolerance. The central circadian clock is located in the hypothalamic suprachiasmatic nucleus (SCN), which comprises primarily GABAergic neurons. The SCN clock regulates physiological diurnal rhythms of endogenous glucose production (EGP) and hepatic insulin sensitivity through neurohumoral mechanisms. Disruption of the molecular circadian clock is associated with the extended dawn phenomenon (DP) in type 2 diabetes (T2D), referring to hyperglycemia in the early morning without nocturnal hypoglycemia. The DP affects nearly half of patients with diabetes, with poorly defined etiology and a lack of targeted …