Translational Medical Research Commons^™

Nur77 Mitigates Endothelial Dysfunction Through Activation Of Both Nitric Oxide Production And Anti-Oxidant Pathways, Lin Lu, Soohwa Jang, Jiaqi Zhu, Qing Qin, Lijun Sun, Jianxin Sun

Center for Translational Medicine Faculty Papers

BACKGROUND: Nur77 belongs to the member of orphan nuclear receptor 4A family that plays critical roles in maintaining vascular homeostasis. This study aims to determine whether Nur77 plays a role in attenuating vascular dysfunction, and if so, to determine the molecular mechanisms involved.

METHODS: Both Nur77 knockout (Nur77 KO) and Nur77 endothelial specific transgenic mice (Nur77-Tg) were employed to examine the functional significance of Nur77 in vascular endothelium in vivo. Endothelium-dependent vasodilatation to acetylcholine (Ach) and reactive oxygen species (ROS) production was determined under inflammatory and high glucose conditions. Expression of genes was determined by real-time PCR and western blot …

The Importance Of Stigma Theory For Clinical Decisions Related To Diabetic Foot Amputations, Rachael Garcia, Callie Bartkowiak, Alison Nesbitt Do

Clinical Research in Practice: The Journal of Team Hippocrates

The authors examine the unconsidered impact of social stigma theory on the shared clinical decision-making process for a patient with foot osteomyelitis and MRSA bacteremia facing the prospect of an amputation.

Metformin Monotherapy Is An Effective Alternative For Management Of Gestational Diabetes Mellitus In Patients Refusing Insulin Monotherapy, Tyler Russeth

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Ghomian N, Vahed SHM, Firouz S, Yaghoubi MA, Mohebbi M, Sahebkar A. The efficacy of metformin compared with insulin in regulating blood glucose levels during gestational diabetes mellitus: A randomized clinical trial. J Cell Physiol. 2019;234(4):4695-4701. https://doi.org/10.1002/jcp.27238

for a patient with gestational diabetes mellitus (GDM) who does not wish to undergo insulin monotherapy.

The Effect Of Nurse Case Coordination On Management Of Chronic Conditions, Aayush Mittal Ms-Hsm

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Ishani A, Greer N, Taylor BC, et al. Effect of nurse case management compared with usual care on controlling cardiovascular risk factors in patients with diabetes: a randomized controlled trial. Diabetes Care. 2011;34(8):1689-1694. https://doi.org/10.2337/dc10-2121

for a patient requiring care coordination for management of hypertension, diabetes, and hyperlipidemia.

Prediction Of Neonatal Birthweight Associated With Maternal Obesity And Diabetes, Laura Gleason, Rebekah Mccurdy, Md, Mph

Phase 1

Introduction: To design a model that will predict neonatal birth weight within obese mothers by diabetic status.

Methods: A secondary data analysis of an RCT (NCT 02909582) was utilized to create a neonatal birth weight prediction model. Women (n=325) with a BMI > 35 kg/m2 from a tertiary academic institution, 2016 – 2019, were included to estimate the risk of large for gestational age (LGA) infants and neonatal birth weight based on maternal prepregnancy BMI and diabetic status. LGA was defined as an infant birth weight > 90th percentile. Analysis included Chi-square, t-test, multivariate logistic and linear regression.

Results: Mean birthweight did …

Nighttime Melatonin Administration And Insulin Sensitivity, Albert Mchugh, Cynthia Cheng, Md, Phd

Phase 1

Introduction: Previous studies have shown melatonin effects on insulin sensitivity, but with conflicting results. The inconsistency between these studies may be due to differences in melatonin dosage and subject age. Low melatonin dosages, generally <5 mg, have been used in prior research. We studied the effect of melatonin 9 mg for 6 weeks on insulin resistance, peripheral microvascular function, and sleep in non-diabetic, non-hypertensive middle-aged and geriatric patients.

Methods: Subjects with a history of hypertension or diabetes were excluded from the study. The geriatric cohort included 5 subjects 60-80 years old while the younger cohort was comprised of 14 subjects age 27-45 years old. Fifteen subjects were randomized to the melatonin treatment group and took 9 mg of controlled-release melatonin by mouth 30 minutes before bedtime for 6 weeks; the four subjects in …

The Histone Deacetylase Inhibitor Tubacin Mitigates Endothelial Dysfunction By Up-Regulating The Expression Of Endothelial Nitric Oxide Synthase., Jihui Chen, Jian Zhang, Noor F. Shaik, Bing Yi, Xin Wei, Xiao-Feng Yang, Ulhas P. Naik, Ross Summer, Guijun Yan, Xinyun Xu, Jianxin Sun

Center for Translational Medicine Faculty Papers

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo.Wefound that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found …

Abstracts From The 25th Annual Health Care Systems Research Network Conference, April 8–10, 2019, Portland, Oregon

Journal of Patient-Centered Research and Reviews

The Health Care Systems Research Network (HCSRN) is made up of nonprofit health systems with embedded research departments whose scientists are dedicated to public domain research. The network’s annual conference serves as a forum for research teams to disseminate study findings, stimulate new collaborations, and share insights about conducting research in real-world care settings. Abstracts accepted for presentation at HCSRN 2019 are published in this supplement of Journal of Patient-Centered Research and Reviews, the official scientific journal of the conference.

Sphk2−/− Mice Are Protected From Obesity And Insulin Resistance, Shwetha Ravichandran, Brian S. Finlin, Philip A. Kern, Sabire Özcan

Clinical and Translational Science Faculty Publications

Sphingosine kinases phosphorylate sphingosine to sphingosine 1‑phosphate (S1P), which functions as a signaling molecule. We have previously shown that sphingosine kinase 2 (Sphk2) is important for insulin secretion. To obtain a better understanding of the role of Sphk2 in glucose and lipid metabolism, we have characterized 20- and 52-week old Sphk2^−/− mice using glucose and insulin tolerance tests and by analyzing metabolic gene expression in adipose tissue. A detailed metabolic characterization of these mice revealed that aging Sphk2^−/− mice are protected from metabolic decline and obesity compared to WT mice. Specifically, we found that 52-week old …

Pim-1 Kinase Phosphorylates Cardiac Troponin I And Regulates Cardiac Myofilament Function., Ni Zhu, Bing Yi, Zhifu Guo, Guanxin Zhang, Shengdong Huang, Yongwen Qin, Xianxian Zhao, Jianxin Sun

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Pim-1 is a serine/threonine kinase that is highly expressed in the heart, and exerts potent cardiac protective effects through enhancing survival, proliferation, and regeneration of cardiomyocytes. Its myocardial specific substrates, however, remain unknown. In the present study, we aim to investigate whether Pim-1 modulates myofilament activity through phosphorylation of cardiac troponin I (cTnI), a key component in regulating myofilament function in the heart.

METHODS: Coimmunoprecipitation and immunofluorescent assays were employed to investigate the interaction of Pim-1 with cTnI in cardiomyocytes. Biochemical, site directed mutagenesis, and mass spectrometric analyses were utilized to identify the phosphorylation sites of Pim1 in cTnI. …

A Clinico-Pathological Study Of The Structural And Functional Changes In The Retina And Optic Nerve Following Diabetic Retinopathy Treatments, Richard Filek

Electronic Thesis and Dissertation Repository

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on …

Addressing Diabetes Prevention At The American Indian Summer Medical Wellness Camp, Mahpiya Vanderbilt, Francine Gachupin, Phd, Mph

Journal of Health Disparities Research and Practice

American Indian youth ages 10-19 are nine times more likely of being diagnosed with type 2 diabetes compared to non-Hispanic whites. A family history of diabetes, being overweight, and being inactive are the main risk factors for type 2 diabetes. The American Indian Summer Medical Wellness Camp is a six day camp for American Indian youth where they are taught about nutrition and fitness in an effort to prevent diabetes. What I looked at is if students who have attended the camp in previous years make different choices than the youth who have never attended camp. I hypothesize that if …

An Intervention To Promote Navajo Gardening, Nutrition, And Community Wellness, Sonia Avitia, Mark C. Bauer, Phd, Linda Garcia

Journal of Health Disparities Research and Practice

The rates of diabetes and obesity in Navajo communities are higher than national rates. A healthy diet of fresh fruits and vegetables will help to prevent and reduce such rates. So the project focuses on promoting gardening to make vegetables and fruits more accessible at the comfort of one’s own home. Previous research in this area shows that gardeners consume 2 more servings of fruits and vegetables than nongardeners. Thirty participants were recruited by flyer distribution at chapter houses, senior centers, and community centers, from four Navajo targeted areas: Shiprock, NM; Tsaile, AZ; Lukachukai, AZ, and Hogback, NM. With the …

Prescription Drug Costs: Does Neighborhood Matter?, Abigayle Alexander, Lisa M. Lapeyrouse, Phd

Journal of Health Disparities Research and Practice

The price of pharmaceuticals can impact one’s ability to purchase needed medication(s). If one cannot afford necessary prescriptions the resulting medication noncompliance can lead to further health complications, increasing the risk of disability, disease progression, and mortality (Mojtabai & Olfson, 2003; Sherbourne, Hays, Ordway, DiMatteo, & Kravitz, 2010).

In this research study we aim to answer two questions: (1) Is there a relationship between neighborhood characteristics (population size, race/ethnic composition, median income, and crime) and access to pharmacies?; and (2) Is there a relationship between neighborhood characteristics and pharmaceutical prices? Using 2009-2013 American Community Survey Data, Census block group data …

Traditional Medicine As A Treatment For Type Ii Diabetes Mellitus, Ronalei Ronny, Christopher U. Kitalong, Phd

Journal of Health Disparities Research and Practice

Diabetes is a common life-long health condition. It is a serious and costly metabolic disease which is now one of a growing concern in the whole world including the Republic of Palau. There are two main types of diabetes: Type I diabetes and type II diabetes mellitus (T2DM). People living with diabetes may have to deal with short-term or long-term complications as a result of their condition. Short-term complications include hypoglycaemia diabetic ketoacidosis (DKA), and hyperosmolar hyperglycaemic state (HHS). Long-term complications include how diabetes affects your eyes (retinopathy), heart (cardiovascular disease), kidneys (nephropathy), and nerves and feet (neuropathy). In the …

Effectiveness Of Traditional Treatments Of Diabetes In Pohnpei, Federated States Of Micronesia, Sonsha Padock, Nacanieli Tuivavalagi, Phd, Fredson Ardos, As, Jackson Philip, Bs, Paul Dacanay, Md

Journal of Health Disparities Research and Practice

Diabetes is the second leading cause of death in Pohnpei – next only to heart disease. However, households in Pohnpei are struggling to make ends meet and find it difficult to afford hospital treatments. The objective of this study is to assess the effectiveness of selected traditional treatment methods for diabetes using local plant products. We hypothesize that the traditional treatment methods of diabetes could also be effective.

Data was collected through interviews and discussions with 17 diabetic patients who have undergone different forms of treatments, and with five medical practitioners. Effects of five treatments were explored: lime and lemon …

Unhealthy Eating Habits In The Marshall Islands Result From Deteriorating Reef Systems, Josephine Lalita, Lyla Lemari, Aa

Journal of Health Disparities Research and Practice

Small Island nations such as the Marshall Islands (RMI) have limited resources. In order to provide food to its population of about 60,000, the Marshallese have had to replace traditional food with foreign imports. A result of this is the prevalence of obesity and non-communicable diseases (NCDs). The most common NCD is diabetes. Diabetic patients are encouraged to follow strict diets that include mostly traditional, local food such as fish; however, because of environmental factors, fish populations are threatened.

The objective of this study was to understand the relationship between healthy reefs, healthy fish populations and the health of communities …

Aspartame: An Investigation Of The Use Of Artificial Sweeteners, Carlson John, Alvin Page, Bsc

Journal of Health Disparities Research and Practice

Aspartame is an artificial, non-saccharide sweetener used as a sugar substitute in many foods and beverages. Aspartame is two hundred times sweeter than regular sugar. Many people prefer to use artificial sweeteners like aspartame as it does not affect blood sugar in the same way as natural sweeteners, does not promote tooth decay, and has been shown to be beneficial in weight control. However, it has also been linked with the development or aggravation of diabetes mellitus, convulsions, headaches, depression, hypertension, arthritis, and other medical conditions. We hypothesize that natural sweeteners are healthier than artificial sweeteners, like Splenda.

Artificial sweeteners …

Impact Of Sleep And Circadian Disruption On Energy Balance And Diabetes: A Summary Of Workshop Discussions, Deanna M. Arble, Joseph Bass, Cecilia Diniz Behn, Matthew P. Butler, Etienne Challet, Charles Czeisler, Christopher M. Depner, Joel Elmquist, Paul Franken, Michael A. Grandner, Erin C. Hanlon, Alex C. Keene, Michael J. Joyner, Ilia Karatsoreos, Philip A. Kern, Samuel Klein, Christopher J. Morris, Allan I. Pack, Satchidananda Panda, Louis J. Ptacek, Naresh M. Punjabi, Paolo Sassone-Corsi, Frank A. Scheer, Richa Saxena, Elizabeth R. Seaquest, Matthew S. Thimgan, Eve Van Cauter, Kenneth P. Wright

Clinical and Translational Science Faculty Publications

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact …

Regulation Of Pten Inhibition By The Pleckstrin Homology Domain Of P-Rex2 During Insulin Signaling And Glucose Homeostasis, Cindy Hodakoski, Benjamin D. Hopkins, Douglas Barrows, Sarah M. Mense, Megan Keniry, Karen E. Anderson, Philip A. Kern, Phillip T. Hawkins, Len R. Stephens, Ramon Parsons

Clinical and Translational Science Faculty Publications

Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic …

Community-Based Partnerships For Improving Chronic Disease Management, James Plumb, Laura Carson Weinsten, Rickie Brawer, Kevin Scott

Department of Family & Community Medicine Faculty Papers

With the growing burden of chronic disease, the medical and public health communities are re-examining their roles and opportunities for more effective prevention and clinical interventions. The potential to significantly improve chronic disease prevention and have an impact on morbidity and mortality from chronic conditions is enhanced by adopting strategies that incorporate a social ecology perspective, realigning the patient-physician relationship, integrating population health perspectives into the Chronic Care Model, and effectively engaging communities using established principles of community engagement.

Copyright © 2012 Elsevier Inc. All rights reserved.

Oxpat/Pat-1 Is A Ppar-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization, Nathan E. Wolins, Benjamin K. Quaynor, James R. Skinner, Anatoly Tzekov, Michelle A. Croce, Matthew C. Gropler, Vijayalakshmi Varma, Aiwei Yao-Borengasser, Neda Rasouli, Philip A. Kern, Brian N. Finck, Perry E. Bickel

Clinical and Translational Science Faculty Publications

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse …

Pioglitazone Induces Apoptosis Of Macrophages In Human Adipose Tissue, Angela M. Bodles, Vijayalakshmi Varma, Aiwei Yao-Borengasser, Bounleut Phanavanh, Charlotte A. Peterson, Robert E. Mcgehee Jr., Neda Rasouli, Martin Wabitsch, Philip A. Kern

Clinical and Translational Science Faculty Publications

Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. TUNEL-positive cells were identified, and there was a significant 42% increase in TUNEL-positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody …

The Translational Regulation Of Lipoprotein Lipase In Diabetic Rats Involves The 3′-Untranslated Region Of The Lipoprotein Lipase Mrna, Gouri Ranganathan, Chunling Li, Philip A. Kern

Clinical and Translational Science Faculty Publications

Adipose tissue lipoprotein lipase (LPL) activity is decreased in patients with poorly controlled diabetes, and this contributes to the dyslipidemia of diabetes. To study the mechanism of this decrease in LPL, we studied adipose tissue LPL expression in male rats with streptozotocin-induced diabetes. Heparin releasable and extractable LPL activity in the epididymal fat decreased by 75-80% in the diabetic group and treatment of the rats with insulin prior to sacrifice reversed this effect. Northern blot analysis indicated no corresponding change in LPL mRNA levels. However, LPL synthetic rate, measured using [³⁵S]methionine pulse labeling, was decreased by 75% in …

Exposure To 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (Tcdd) Is Associated With Hyperinsulinemia And Insulin Resistance, Morris Cranmer, Shirley Louie, Richard H. Kennedy, Philip A. Kern, Vivian A. Fonseca

Clinical and Translational Science Faculty Publications

High exposures of Vietnam veterans to 2,3,7,8-Tetrachlorodibenzo-p- dioxin, a dioxin contained in the herbicide mixture Agent Orange, have previously been demonstrated to be associated with an increased prevalence of diabetes and hyperinsulinemia in non-diabetic subjects. Sixty-nine persons were identified who were in good health and had normal glucose levels during glucose tolerance testing. These subjects lived within 25 miles of the Vertac/Hercules Superfund site located in Jacksonville, Arkansas. The blood sera lipid concentrations of TCDD for the 69 subjects ranged between 2 and 94 ppt. When subjects with blood sera lipid TCDD levels in the top 10% (TCDD > 15 ppt, …

Role Of Protein Kinase C In The Translational Regulation Of Lipoprotein Lipase In Adipocytes, Gouri Ranganathan, Rami Kaakaji, Philip A. Kern

Clinical and Translational Science Faculty Publications

The hypertriglyceridemia of diabetes is accompanied by decreased lipoprotein lipase (LPL) activity in adipocytes. Although the mechanism for decreased LPL is not known, elevated glucose is known to increase diacylglycerol, which activates protein kinase C (PKC). To determine whether PKC is involved in the regulation of LPL, we studied the effect of 12-O-tetradecanoyl phorbol 13-acetate (TPA) on adipocytes. LPL activity was inhibited when TPA was added to cultures of 3T3-F442A and rat primary adipocytes. The inhibitory effect of TPA on LPL activity was observed after 6 h of treatment, and was observed at a concentration of 6 nM. …

Thiazolidinediones Inhibit Lipoprotein Lipase Activity In Adipocytes, Subramanian Ranganathan, Philip A. Kern

Clinical and Translational Science Faculty Publications

The thiazolidinediones troglitazone and BRL 49653 improve insulin sensitivity in humans and animals with insulin resistance. Adipose tissue lipoprotein lipase is an insulin-sensitive enzyme. We examined the effects of thiazolidinediones on lipoprotein lipase expression in adipocytes. When added to 3T3-F442A, 3T3-L1, and rat adipocytes in culture, troglitazone and BRL 49653 inhibited lipoprotein lipase activity. This inhibition was observed at concentrations as low as 0.1 μM and within 2 h after addition of the drug. Lipoprotein lipase activity was inhibited in differentiated adipocytes as well as the differentiating cells. Despite this decrease in enzyme activity, these drugs increased mRNA levels in …

Effects Of Tumor Necrosis Factor-Α On Glucose Metabolism In Cultured Human Muscle Cells From Nondiabetic And Type 2 Diabetic Subjects, Theodore P. Ciaraldi, Leslie Carter, Sunder Mudaliar, Philip A. Kern, Robert R. Henry

Clinical and Translational Science Faculty Publications

The effects of tumor necrosis factor-a (TNFα) on glucose uptake and glycogen synthase (GS) activity were studied in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. In nondiabetic muscle cells, acute (90-Min) exposure to TNFα (5 ng/ml) stimulated glucose uptake (73 ± 14% increase) to a greater extent than insulin (37 ± 4%; P < 0.02). The acute uptake response to TNFα in diabetic cells (51 ± 6% increase) was also greater than that to insulin (31 ± 3%; P < 0.05). Prolonged (24-h) exposure of nondiabetic muscle cells to TNFα resulted in a further stimulation of uptake (152 ± 31%; P < 0.05), whereas the increase in cells from type 2 diabetics was not significant compared with that in cells receiving acute treatment. After TNFα treatment, the level of glucose transporter-1 protein was elevated in nondiabetic (4.6-fold increase) and type 2 (1.7-fold) cells. Acute TNFα treatment had no effect on the fractional velocity of GS in either nondiabetic or type 2 cells. Prolonged exposure reduced the GS fractional velocity in both nondiabetic and diabetic cells. In summary, both acute and prolonged treatment with TNFα up-regulate glucose uptake activity in cultured human muscle cells, but reduce GS activity. Increased skeletal muscle glucose uptake in conditions of TNFα excess may serve as a compensatory mechanism in the insulin resistance of type 2 diabetes.