Endocrine System Diseases Commons^™

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), …

Gray And White Matter Abnormality In Patients With T2dm-Related Cognitive Dysfunction: A Systemic Review And Meta-Analysis, Teng Ma, Ze-Yang Li, Ying Yu, Bo Hu, Yu Han, Min-Hua Ni, Yu-Xiang Huang, Hao-Han Chen, Wen Wang, Lin-Feng Yan, Guang-Bin Cui

Faculty, Staff and Student Publications

Aims/hypothesis

Brain structure abnormality in patients with type 2 diabetes mellitus (T2DM)-related cognitive dysfunction (T2DM-CD) has been reported for decades in magnetic resonance imaging (MRI) studies. However, the reliable results were still unclear. This study aimed to make a systemic review and meta-analysis to find the significant and consistent gray matter (GM) and white matter (WM) alterations in patients with T2DM-CD by comparing with the healthy controls (HCs).

Methods

Published studies were systemically searched from PubMed, MEDLINE, Cochrane Library and Web of Science databases updated to November 14, 2021. Studies reporting abnormal GM or WM between patients with T2DM-CD and …

Immunotherapy For Type 1 Diabetes Mellitus By Adjuvant-Free Schistosoma Japonicum-Egg Tip-Loaded Asymmetric Microneedle Patch (Stamp), Haoming Huang, Dian Hu, Zhuo Chen, Jiarong Xu, Rengui Xu, Yusheng Gong, Zhengming Fang, Ting Wang, Wei Chen

Faculty, Staff and Student Publications

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy …

Changes Of Brain Function In Patients With Type 2 Diabetes Mellitus Measured By Different Analysis Methods: A New Coordinate-Based Meta-Analysis Of Neuroimaging, Ze-Yang Li, Teng Ma, Ying Yu, Bo Hu, Yu Han, Hao Xie, Min-Hua Ni, Zhu-Hong Chen, Yang-Ming Zhang, Yu-Xiang Huang, Wen-Hua Li, Wen Wang, Lin-Feng Yan, Guang-Bin Cui

Faculty, Staff and Student Publications

OBJECTIVE: Neuroimaging meta-analysis identified abnormal neural activity alterations in patients with type 2 diabetes mellitus (T2DM), but there was no consistency or heterogeneity analysis between different brain imaging processing strategies. The aim of this meta-analysis was to determine consistent changes of regional brain functions in T2DM

METHODS: Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics, we further conducted a coordinate-based meta-analysis (CBMA) of the two categories of neuroimaging literature, which were grouped according to similar data processing methods: one group included regional homogeneity (ReHo), independent component analysis (ICA), and degree centrality (DC) studies, while …

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 …

Effect Of A Glp-1 Mimetic On The Insulin Response To Oral Sugar Testing In Horses, Darko Stefanovski, Mary A Robinson, Andrew Van Eps

Faculty, Staff and Student Publications

BACKGROUND: Insulin dysregulation (ID) is the most important risk factor for the development of laminitis in horses and therapies to control it are needed.

HYPOTHESIS/OBJECTIVES: To assess the effects of a single dose of the synthetic GLP-1 analog exenatide on postprandial insulin dynamics. We hypothesized that exenatide would improve insulin sensitivity and lower postprandial blood insulin concentrations.

STUDY DESIGN: Randomized, crossover, experimental study.

ANIMALS: Six horses (3 mares, 3 geldings; 2 with normal insulin regulation [NIR] and 4 with mild ID).

METHODS: Horses completed both study arms: subcutaneous administration of exenatide (or no treatment) 30 min before an oral sugar …

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 …

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 …

Regulation Of Age-Associated Insulin Resistance By Mt1-Mmp-Mediated Cleavage Of Insulin Receptor, Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin …

Estimating Circadian Phase In Elementary School Children: Leveraging Advances In Physiologically Informed Models Of Circadian Entrainment And Wearable Devices, Jennette P Moreno, Kevin M Hannay, Olivia Walch, Hafza Dadabhoy, Jessica Christian, Maurice Puyau, Abeer El-Mubasher, Fida Bacha, Sarah R Grant, Rebekah Julie Park, Philip Cheng

Faculty, Staff and Students Publications

STUDY OBJECTIVES: Examine the ability of a physiologically based mathematical model of human circadian rhythms to predict circadian phase, as measured by salivary dim light melatonin onset (DLMO), in children compared to other proxy measurements of circadian phase (bedtime, sleep midpoint, and wake time).

METHODS: As part of an ongoing clinical trial, a sample of 29 elementary school children (mean age: 7.4 ± .97 years) completed 7 days of wrist actigraphy before a lab visit to assess DLMO. Hourly salivary melatonin samples were collected under dim light conditions (<5 >lx). Data from actigraphy were used to generate predictions of circadian …

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 …

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 …

Constitutive Loss Of Dnmt3a Causes Morbid Obesity Through Misregulation Of Adipogenesis, Ayala Tovy, Jaime M Reyes, Linda Zhang, Yung-Hsin Huang, Carina Rosas, Alexes C Daquinag, Anna Guzman, Raghav Ramabadran, Chun-Wei Chen, Tianpeng Gu, Sinjini Gupta, Laura Ortinau, Dongsu Park, Aaron R Cox, Rachel E Rau, Sean M Hartig, Mikhail G Kolonin, Margaret A Goodell

Faculty, Staff and Students Publications

DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A …

The Ventromedial Hypothalamic Nucleus: Watchdog Of Whole-Body Glucose Homeostasis, Longlong Tu, Makoto Fukuda, Qingchun Tong, Yong Xu

Children’s Nutrition Research Center Staff Publications

The brain, particularly the ventromedial hypothalamic nucleus (VMH), has been long known for its involvement in glucose sensing and whole-body glucose homeostasis. However, it is still not fully understood how the brain detects and responds to the changes in the circulating glucose levels, as well as brain-body coordinated control of glucose homeostasis. In this review, we address the growing evidence implicating the brain in glucose homeostasis, especially in the contexts of hypoglycemia and diabetes. In addition to neurons, we emphasize the potential roles played by non-neuronal cells, as well as extracellular matrix in the hypothalamus in whole-body glucose homeostasis. Further, …

Multi-Ancestry Genetic Study Of Type 2 Diabetes Highlights The Power Of Diverse Populations For Discovery And Translation, Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie C Y Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro Della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor J Y Lim, Claudia H T Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond K Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Jack Flanagan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H Janaka De Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Suraj S Nongmaithem, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Kathryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M Van Dam, Jan B Van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Eleanor Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Ko Willems Van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, Finngen, Emerge Consortium, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne H H Sheu, Sharon L R Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald C W Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta Mckean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josée Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin N A Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth J F Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I Mccarthy, Andrew P Morris

Faculty, Staff and Student Publications

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS …

Berberine Remodels Adipose Tissue To Attenuate Metabolic Disorders By Activating Sirtuin 3, Dan Li, Chao Yang, Jian-Zhong Zhu, Eduardo Lopez, Tian Zhang, Qiang Tong, Cheng Peng, Li-Gen Lin

Faculty, Staff and Students Publications

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of …

Mitochondrial Sirtuin-3 (Sirt3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy By Modulating Protein Acetylation And Oxidative Stress, Mateusz M Tomczyk, Kyle G Cheung, Bo Xiang, Nahid Tamanna, Ana L Fonseca Teixeira, Prasoon Agarwal, Stephanie M Kereliuk, Victor Spicer, Ligen Lin, Jason Treberg, Qiang Tong, Vernon W Dolinsky

Faculty, Staff and Students Publications

BACKGROUND: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.

METHODS: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). …

Circadian Regulation Of Gene Expression And Metabolism In The Liver, Dongyin Guan, Mitchell A Lazar

Faculty, Staff and Students Publications

Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, including light/dark and feeding/fasting. Note that 24-hour rhythms of liver metabolic processes have been known for almost 100 years. Modern studies reveal that, like metabolism, hepatic gene expression is highly rhythmic. Genetic or environmental changes can disrupt the circadian rhythms of the liver, leading to metabolic disorders and hepatocellular carcinoma. In this review, we summarize the current understanding of mechanisms regulating rhythmic gene expression in the liver, highlighting the roles of transcription …

Temporal Trends In Outcomes In Patients With Adrenocortical Carcinoma: A Multidisciplinary Referral-Center Experience, Marilyne Daher, Jeena Varghese, Stephen K Gruschkus, Camilo Jimenez, Steven G Waguespack, Sara Bedrose, Lina Altameemi, Hadil Bazerbashi, Aung Naing, Vivek Subaiah, Matthew T Campbell, Amishi Y Shah, Miao Zhang, Rahul A Sheth, Jose A Karam, Christopher G Wood, Nancy D Perrier, Paul H Graham, Jeffery E Lee, Mouhammed Amir Habra

Faculty, Staff and Students Publications

CONTEXT: Reporting temporal trends in adrenocortical carcinoma (ACC) helps guide management strategies.

OBJECTIVE: This work aimed to report the trends in disease burden and clinical outcomes over time that cannot be adequately captured from individual clinical trials.

METHODS: A retrospective study was held of ACC patients seen at a referral cancer center between February 1998 and August 2019. Clinical outcomes were compared between an early cohort (February 1998-June 2007) and a late cohort (July 2007-August 2019).

RESULTS: A total of 621 patients included with a median age at diagnosis of 49.3 years (range, 0.5-86.6 years). There were 285 (45.9%) patients …

Neurofibromatosis Type 1 Has A Wide Spectrum Of Growth Hormone Excess, Fady Hannah-Shmouni, Giampaolo Trivellin, Pablo Beckers, Lefkothea P Karaviti, Maya Lodish, Christina Tatsi, Adekunle M Adesina, Fotini Adamidou, Gesthimani Mintziori, Jami L Josefson, Martha Quezado, Constantine A Stratakis

Faculty, Staff and Students Publications

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH …

The Role Of Palmitoleic Acid In Regulating Hepatic Gluconeogenesis Through Sirt3 In Obese Mice, Xin Guo, Xiaofan Jiang, Keyun Chen, Qijian Liang, Shixiu Zhang, Juan Zheng, Xiaomin Ma, Hongmei Jiang, Hao Wu, Qiang Tong

Faculty, Staff and Students Publications

Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. However, unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid is a monounsaturated fatty acid (16:1n7) that is available from dietary sources. Palmitoleic acid exhibits health beneficial effects on diabetes, insulin resistance, inflammation, and metabolic syndrome. However, the mechanism by which palmitoleate reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating NAD+-dependent protein deacetylase. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver’s response to nutrient deprivation, such as fatty …

Maternal Low Protein Diet And Fetal Programming Of Lean Type 2 Diabetes, Vidyadharan Alukkal Vipin, Chellakkan Selvanesan Blesson, Chandra Yallampalli

Faculty, Staff and Students Publications

Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood. Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy, and impaired nutrition has been an immense issue across the globe. In recent years, type 2 diabetes (T2D) has reached epidemic proportion and is a severe public health problem in many countries. Although plenty of research has already been conducted to tackle T2D which is associated with obesity, little is known regarding the etiology and pathophysiology of lean T2D, a variant of T2D. Recent studies have focused on …

Glynac (Glycine And N-Acetylcysteine) Supplementation In Mice Increases Length Of Life By Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities In Mitophagy And Nutrient Sensing, And Genomic Damage, Premranjan Kumar, Ob W Osahon, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis …

Effect Of Domperidone Therapy On Gastroparesis Symptoms: Results Of A Dynamic Cohort Study By Niddk Gastroparesis Consortium, Irene Sarosiek, Mark Van Natta, Henry P Parkman, Thomas Abell, Kenneth L Koch, Braden Kuo, Robert J Shulman, Gianrico Farrugia, Madhusudan Grover, Frank A Hamilton, Pankaj J Pasricha, Katherine P Yates, Laura Miriel, Laura Wilson, Goro Yamada, James Tonascia, Richard W Mccallum

Faculty, Staff and Students Publications

BACKGROUND & AIMS: The use of domperidone (DOM) for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) Registries (GpR).

METHODS: The GpCRC cohort consisted of patients with GP (75%) and with GP-like symptoms but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and GpR2. Patients who had previously taken or who were on DOM therapy at enrollment were excluded from this analysis. …

Isoform-Specific Functions Of Pparγ In Gene Regulation And Metabolism, Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar

Faculty, Staff and Students Publications

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, …

'Analogy-Based Comprehensive Diabetes Education' (Abcde) Improves Glycemic Control Of Diabetic Patients In An Underserved Population: Results Of A Retrospective Chart Analysis, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Diabetes is the leading global cause for blindness, kidney failure and amputations. Preventing these complications requires optimal glycemic control, and it is imperative that diabetic patients understand the fundamental concepts of diabetes care. Although patients attend formal diabetes education classes, many do not comprehend basic concepts of diabetes, and are often noncompliant with diet, exercise and medications. A novel approach termed 'analogy-based comprehensive diabetes education' (ABCDE) was developed to educate HIV-patients with diabetes about basic concepts of diabetes care. The object of this manuscript is to report the results of a retrospective chart review on the impact of ABCDE on …

Utilization Rates Of Sglt2 Inhibitors And Glp-1 Receptor Agonists And Their Facility-Level Variation Among Patients With Atherosclerotic Cardiovascular Disease And Type 2 Diabetes: Insights From The Department Of Veterans Affairs, Dhruv Mahtta, David J Ramsey, Michelle T Lee, Liang Chen, Mahmoud Al Rifai, Julia M Akeroyd, Elizabeth M Vaughan, Michael E Matheny, Karla Rodrigues Do Espirito Santo, Sankar D Navaneethan, Carl J Lavie, Yochai Birnbaum, Christie M Ballantyne, Laura A Petersen, Salim S Virani

Faculty, Staff and Students Publications

OBJECTIVE: There is mounting evidence regarding the cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) among patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM). There is paucity of data assessing real-world practice patterns for these drug classes. We aimed to assess utilization rates of these drug classes and facility-level variation in their use.

RESEARCH DESIGN AND METHODS: We used the nationwide Veterans Affairs (VA) health care system data set from 1 January 2020 to 31 December 2020 and included patients with established ASCVD and T2DM. Among these patients, …