Medicine and Health Sciences Commons^™

Multi-Tissue Epigenetic Analysis Identifies Distinct Associations Underlying Insulin Resistance And Alzheimer's Disease At Cpt1a Locus, Chloé Sarnowski, Tianxiao Huan, Yiyi Ma, Roby Joehanes, Alexa Beiser, Charles S Decarli, Nancy L Heard-Costa, Daniel Levy, Honghuang Lin, Ching-Ti Liu, Chunyu Liu, James B Meigs, Claudia L Satizabal, Jose C Florez, Marie-France Hivert, Josée Dupuis, Philip L De Jager, David A Bennett, Sudha Seshadri, Alanna C Morrison

Journal Articles

BACKGROUND: Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.

METHODS: We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified …

Genome-Wide Association Study And Functional Characterization Identifies Candidate Genes For Insulin-Stimulated Glucose Uptake, Alice Williamson, Dougall M Norris, Xianyong Yin, K Alaine Broadaway, Anne H Moxley, Swarooparani Vadlamudi, Emma P Wilson, Anne U Jackson, Vasudha Ahuja, Mette K Andersen, Zorayr Arzumanyan, Lori L Bonnycastle, Stefan R Bornstein, Maxi P Bretschneider, Thomas A Buchanan, Yi-Cheng Chang, Lee-Ming Chuang, Ren-Hua Chung, Tine D Clausen, Peter Damm, Graciela E Delgado, Vanessa D De Mello, Josée Dupuis, Om P Dwivedi, Michael R Erdos, Lilian Fernandes Silva, Timothy M Frayling, Christian Gieger, Mark O Goodarzi, Xiuqing Guo, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Gad Hatem, Sandra Herrmann, Kurt Højlund, Katrin Horn, Willa A Hsueh, Yi-Jen Hung, Chii-Min Hwu, Anna Jonsson, Line L Kårhus, Marcus E Kleber, Peter Kovacs, Timo A Lakka, Marie Lauzon, I-Te Lee, Cecilia M Lindgren, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Jian'an Luan, Dina Mansour Aly, Elisabeth Mathiesen, Angela P Moissl, Andrew P Morris, Narisu Narisu, Nikolaos Perakakis, Annette Peters, Rashmi B Prasad, Roman N Rodionov, Kathryn Roll, Carsten F Rundsten, Chloé Sarnowski, Kai Savonen, Markus Scholz, Sapna Sharma, Sara E Stinson, Sufyan Suleman, Jingyi Tan, Kent D Taylor, Matti Uusitupa, Dorte Vistisen, Daniel R Witte, Romy Walther, Peitao Wu, Anny H Xiang, Björn Zethelius, Emma Ahlqvist, Richard N Bergman, Yii-Der Ida Chen, Francis S Collins, Tove Fall, Jose C Florez, Andreas Fritsche, Harald Grallert, Leif Groop, Torben Hansen, Heikki A Koistinen, Pirjo Komulainen, Markku Laakso, Lars Lind, Markus Loeffler, Winfried März, James B Meigs, Leslie J Raffel, Rainer Rauramaa, Jerome I Rotter, Peter E H Schwarz, Michael Stumvoll, Johan Sundström, Anke Tönjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Robert Wagner, Inês Barroso, Mark Walker, Niels Grarup, Michael Boehnke, Nicholas J Wareham, Karen L Mohlke, Eleanor Wheeler, Stephen O'Rahilly, Daniel J Fazakerley, Claudia Langenberg

Journal Articles

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Does A Family History Of Type 2 Diabetes Affect Exercise Induced Improvements In Insulin Sensitivity, Metabolic Flexibility, And Myokine Expression In Mexican-American Males?, Manuel Amador

Open Access Theses & Dissertations

A family history of diabetes (FH+) is considered a risk factor for the development of insulin resistance and type 2 diabetes. However, it is not known whether exercise induced improvement in insulin sensitivity (IS) and metabolic flexibility (MF) are impacted by a FH+. Purpose: To determine if a FH+ limits exercise induced improvements in Insulin sensitivity, MF, body composition, and strength following an 8-week combined aerobic and resistance training intervention compared to those without a family history of diabetes (FH-). Methods: 19 (FH- n=9, age 21.89 ± 0.60 years, BMI 27.51 ± 1.68 kg/m2; FH+ n=10, age 23.41 ± 0.86 …

Oral Glucose Insulin Secretion Test For Identifying Patients With Insulin Resistance, David Kershner

Walden Dissertations and Doctoral Studies

Insulin resistance is an increasing public health issue with the current literature, suggesting reduced sensitivity of insulin leads to adult onset diabetes and associated downstream pathologies that reduce life expectancy. The main objectives of this study were to evaluate the ability of the Oral Glucose Insulin Secretion Test (OGIST) to identify insulin resistance and examine differences in the insulin sensitivity based on gender, age, and ethnicity. This study was supported by the insulin resistance theory which focuses on the reduced ability of insulin to bind to the cellular insulin receptor, reducing the sensitivity of insulin. The OGIST lab results of …

Follicular Dynamics In Insulin Resistant Mares, Julio Cesar Prado

Masters Theses

Obesity and insulin resistance have been linked to prolonged interovulatory period, aberrations in the estrous cycle, and continuous reproductive activity during the non-breeding season. EMS has been determined to influence the intrafollicular environment of mare ovaries. In humans, insulin resistance has been linked to polycystic ovaries as part of Polycystic Ovarian Syndrome (PCOS). A study was conducted to determine 1) the impact of insulin resistance on follicle growth and size at ovulation, and 2) whether predicted ovulatory follicles respond to hCG administration in Insulin-resistant (IR) mares. Mares were selected for the study based on insulin sensitivity and separated into an …

The Role Of Pxr And Ikkβ Signaling In Cardiometabolic Disease, Robert N. Helsley

Theses and Dissertations--Pharmacology and Nutritional Sciences

Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. …

Non-Invasive Determination Of Pre-Clinical Markers Of Cardiovascular Diseases In Low Birth Weight And Maternal Western Diet Guinea Pig Offspring Exposed To A Postnatal Western Diet, Jacky Chiu

Electronic Thesis and Dissertation Repository

Low birth weight (LBW), and maternal Western Diet (WD) consumption have both been independently implicated to increase the risk of developing cardiovascular diseases (CVDs) in later life. These fetal programmed risks are also believed to exacerbate the effects of a postnatal WD pattern. Therefore, resulting in the development of pre-clinical markers of CVDs, such as insulin resistance (IR), coronary circulation disruptions. This thesis aimed to elucidate the roles of sub-optimal in utero growth through placental insufficiency, or chronic maternal WD consumption, and postnatal WD consumption on the long-term programming of CVDs in a guinea pig model. Early pre-clinical markers of …

Cd47 Deficiency Protects Mice From Diet-Induced Obesity And Improves Whole Body Glucose Tolerance And Insulin Sensitivity, Hasiyeti Maimaitiyiming, Heather Norman, Qi Zhou, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were …

Aspirin And Low-Molecular Weight Heparin Combination Therapy Effectively Prevents Recurrent Miscarriage In Hyperhomocysteinemic Women., Pratip Chakraborty, Sayani Banerjee, Piyali Saha, Shyam Sundar Nandi, Sunita Sharma, Sourendra K. Goswami, Baidyanath Chakravarty, Syed N. Kabir

Journal Articles: Cellular & Integrative Physiology

The management of recurrent pregnancy loss (RPL) still remains a great challenge, and women with polycystic ovarian syndrome (PCOS) are at a greater risk for spontaneous abortion. Treatment with low-molecular-weight heparin (LMWH) has become an accepted treatment option for women with RPL; however, the subgroup of women, who are likely to respond to LMWH, has not been precisely identified. The present study evaluated the efficacy of LMWH with reference to PCOS and associated metabolic phenotypes including hyperhomocysteinemia (HHcy), insulin resistance (IR) and obesity. This prospective observational study was conducted at Institute of Reproductive Medicine, Kolkata, India. A total of 967 …

Mice Deficient In Gem Gtpase Show Abnormal Glucose Homeostasis Due To Defects In Beta-Cell Calcium Handling, Jenny E. Gunton, Mary Sisavanh, Rebecca A. Stokes, Jon Satin, Leslie S. Satin, Min Zhang, Sue M. Liu, Weikang Cai, Kim Cheng, Gregory J. Cooney, D. Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T. Grey, Douglas A. Andres, Michael S. Rolph, Charles R. Mackay

Physiology Faculty Publications

AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.

METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in …