Endocrinology, Diabetes, and Metabolism Commons^™

Sodium-Myoinositol Cotransporter-1, Smit1, Mediates The Production Of Reactive Oxygen Species Induced By Hyperglycemia In The Heart, Anne Van Steenbergen, Magali Balteau, Audrey Ginion, Laura Ferté, Sylvain Battault, Christophe De Meester De Ravenstein, Jean-Luc Balligand, Evangelos-Panagiotis Daskalopoulos, Patrick Gilon, Florin Despa, Sanda Despa, Jean-Louis Vanoverschelde, Sandrine Horman, Hermann Koepsell, Gerard Berry, Louis Hue, Luc Bertrand, Christophe Beauloye

Pharmacology and Nutritional Sciences Faculty Publications

Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to …

Factors Regulating Features Of Metabolic Syndrome, Sonja S. Pijut

Theses and Dissertations--Pharmacy

The collective presence of central obesity, low HDL-cholesterol, and elevated triglycerides, blood pressure, and fasting blood glucose constitutes Metabolic Syndrome (MetS), a disease state that increases the risk of cardiovascular disease (CVD) and Type 2 Diabetes Mellitus (T2DM). Nonalcoholic fatty liver disease (NAFLD), present in up to 90% of obese adults, is also linked to MetS. As in CVD, disruptions in cholesterol metabolism play a contributing role in the development of T2DM and NAFLD. Genes involved in cholesterol synthesis, secretion, and catabolism are diurnally regulated in the liver and adipose. Disruptions in the sleep-wake cycle are thought to potentiate metabolic …

The Development Of Bsn272 From Prevention Of Diet-Induced Hyperlipidemia In Mice To A Potential Therapy For Prader-Willi Syndrome In Humans, Jarrod B. Williams

Theses and Dissertations--Pharmacy

While type 2 diabetes mellitus (T2DM) is distinguished as a disorder of blood glucose homeostasis, the vast majority of patients afflicted with this disease in the US present with the entire complement of the metabolic syndrome: abdominal obesity, hypertriglyceridemia, low HDL levels, elevated blood pressure, and elevated fasting plasma glucose. Current guidelines aim to treat each of these disorders, but do so individually even though they are manifestations of common pathologies. In other words, a patient will be prescribed different medications for diabetes, blood pressure, CVD prevention, etc., while the only single treatment aimed at the myriad of disorders together …

The Role Of Progesterone Receptor Membrane Component 1 In Receptor Trafficking And Disease, Kaia K. Hampton

Theses and Dissertations--Pharmacology and Nutritional Sciences

The progesterone receptor membrane component 1 (PGRMC1) is a multifunctional protein with a heme-binding domain that promotes cellular signaling via receptor trafficking, and is essential for some elements of tumor growth and metastasis. PGRMC1 is upregulated in breast, colon, lung and thyroid tumors. We expanded the analysis of PGRMC1 in the clinical setting, and report the first analysis of PGRMC1 in human oral cavity and ovarian tumors and found PGRMC1 to correlate with lung and ovarian cancer patient survival. Furthermore, we discovered a specific role for PGRMC1 in cancer stem cell viability. PGRMC1 directly associates with the epidermal growth factor …

The Impact Of Sglt2 Inhibitors, Compared With Insulin, On Diabetic Bone Disease In A Mouse Model Of Type 1 Diabetes, Kathryn M. Thrailkill, Jeffry S. Nyman, R. Clay Bunn, Sasidhar Uppuganti, Katherine L. Thompson, Charles K. Lumpkin, Evangelia Kalaitzoglou, John L. Fowlkes

Barnstable Brown Diabetes Center Faculty Publications

Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complications. As such, chronic hyperglycemia is undoubtedly a major contributor to these outcomes, despite standard insulin-replacement therapy. Therefore, using the streptozotocin (STZ)-induced model of hypoinsulinemic hyperglycemia in DBA/2J male mice, we compared the effects of two glucose lowering therapies on the fracture resistance of bone and markers of bone turnover. Twelve week-old diabetic (DM) mice were treated for 9 weeks with: 1) oral canagliflozin (CANA, dose range ~10-16 mg/kg/day), an inhibitor of …

Glycemic Variability Predicts Inflammation In Adolescents With Type 1 Diabetes, Robert P. Hoffman, Amanda S. Dye, Hong Huang, John A. Bauer

Pediatrics Faculty Publications

Background: Adolescents with type 1 diabetes (T1D) have increased risk of cardiovascular disease as well as elevations in biomarkers of systemic inflammation, plasma protein oxidation and vascular endothelial injury. It is unclear whether hyperglycemia itself, or variations in blood glucose are predictors of these abnormalities.

Methods: This study was designed to determine the relationship of inflammatory (C-reactive protein, CRP), oxidative (total anti-oxidative capacity, TAOC) and endothelial injury (soluble intracellular adhesion molecule 1, sICAM1) markers to glycemic control measures from 3 days of continuous glucose monitoring (CGM) and to hemoglobin A_1c (HbA_1c), and HbA_1c×duration area under …

A Case Of Pituitary Abscess Presenting Without A Source Of Infection Or Prior Pituitary Pathology, Derick Adams, Philip A. Kern

Internal Medicine Faculty Publications

Pituitary abscess is a relatively uncommon cause of pituitary hormone deficiencies and/or a suprasellar mass. Risk factors for pituitary abscess include prior surgery, irradiation and/or pathology of the suprasellar region as well as underlying infections. We present the case of a 22-year-old female presenting with a spontaneous pituitary abscess in the absence of risk factors described previously. Her initial presentation included headache, bitemporal hemianopia, polyuria, polydipsia and amenorrhoea. Magnetic resonance imaging (MRI) of her pituitary showed a suprasellar mass. As the patient did not have any risk factors for pituitary abscess or symptoms of infection, the diagnosis was not suspected …

Serum Amyloid A Impairs The Antiinflammatory Properties Of Hdl, Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O'Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. De Beer, Frederick C. De Beer, William R. Osborne, Keith B. Elkon, Alan Chait

Physiology Faculty Publications

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO₃ fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO₃-injected mice lacking Saa1.1 …

Evaluation Of A Diabetes Self-Management Program For Hispanics In Lexington Kentucky: A Pilot Study, Miguel A. Gamboa Oropeza

Theses and Dissertations--Nutrition and Food Systems

Hispanics are more affected by diabetes than non-Hispanic whites and they tend to experience more severe complications. Research shows that although self-management is poor among ethnic minorities, it is even more so among Hispanics. The “Taking Ownership of Your Diabetes” (TOYD) program has been shown to be successful in helping individuals manage their diabetes. However, no work has been conducted with Hispanic audiences in Kentucky. TOYD program allows individuals to modify lifestyle risks and solve problems related to diabetes management. The program was translated from English to Spanish. Hispanics males and females between ages 19 to 75 years …

Effect Of Enteral Feeding Timing In Septic Shock Patients, Shane D. Slone

DNP Projects

The goal of this research project was to identify the effect of the timing of enteral nutrition (EN) initiation timing on in-hospital mortality, ICU LOS and hospital LOS among patients with septic shock requiring norepinephrine. The study design was a cross-sectional analysis of retrospective electronic health record data. Patients who had received norepinephrine for septic shock were divided into early EN initiation (within 48 hours of ICU admission) and late EN initiation (Greater than or equal to 48 hours after ICU admission) groups. 680 subjects were included; 469 in the early group and 211 in the late group. Demographics, comorbidities, …

Sglt2 Inhibitor Therapy Improves Blood Glucose But Does Not Prevent Diabetic Bone Disease In Diabetic Dba/2j Male Mice, Kathryn M. Thrailkill, R. Clay Bunn, Jeffry S. Nyman, Mallikarjuna R. Rettiganti, Gael E. Cockrell, Elizabeth C. Wahl, Sasidhar Uppuganti, Charles K. Lumpkin, John L. Fowlkes

Barnstable Brown Diabetes Center Faculty Publications

Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10 weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by …

Effect Of Vitamins C And E On Endothelial Function In Type 1 Diabetes Mellitus, Rachel-Marie Cazeau, Hong Huang, John A. Bauer, Robert P. Hoffman

Pediatrics Faculty Publications

Background/Objectives. Endothelial dysfunction due to hyperglycemia-induced oxidative damage is an important predictor of future cardiovascular risk in patients with type 1 diabetes mellitus (T1DM) and is present in adolescent T1DM. We hypothesized that combined treatment with the antioxidant vitamins C and E might improve endothelial function (EF) and other biochemical risk factors in adolescents with T1DM. Subjects/Methods. Open-label antioxidant supplementation was given for six weeks with endpoint measurements collected at baseline and study completion. Endpoints measured included EF and plasma measurements of biochemical endothelial risk. Results. Two males and 7 females were studied. Mean age was 12.9 ± 0.9 yrs; …

An Evaluation Of The Screening And Management Of Patients With Type 2 Diabetes, Laura A. Cahoe

DNP Projects

Purpose: This purpose of this project was to evaluate preventive screening practices and adherence to guidelines for patients with type 2 diabetes (T2DM) as recommended by the American Diabetes Association (ADA) and United States Preventive Services Task Force (USPSTF) in the primary care setting. The specific aims were to: 1) determine the percentage of patients who received recommended screenings from the ADA, 2) determine the percentage of patients who received recommended screenings from the USPSTF, and 3) determine if the proportion of patients to receive the recommended screenings met established benchmarks set by Healthy People 2020 (HP2020).

Methods: A retrospective …

Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism In High Fat Diet-Induced Obesity, R. Grace Walton, Beibei Zhu, Resat Unal, Michael Spencer, Manjula Sunkara, Andrew J. Morris, Richard Charnigo, Wendy S. Katz, Alan Daugherty, Deborah A. Howatt, Philip A. Kern, Brian S. Finlin

Barnstable Brown Diabetes Center Faculty Publications

Lipid accumulation in liver and skeletal muscle contributes to co-morbidities associated with diabetes and obesity. We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage. These mice (Adipoq-LPL) have improved glucose and insulin tolerance as well as increased energy expenditure when challenged with a high fat diet (HFD). To identify the mechanism(s) involved, we determined whether the Adipoq-LPL mice diverted dietary lipid to adipose tissue to reduce peripheral lipotoxicity, but we found no evidence for this. Instead, characterization …

Self-Management Education In Hispanic Women With Gestational Diabetes Mellitus (Gdm), Laura B. Hieronymus

DNP Projects

The purpose of this Practice Inquiry Project was to develop, implement, and evaluate the effectiveness of a diabetes self-management education intervention in a population of Hispanic women at risk for gestational diabetes mellitus within a CenteringPregnancy(R) model of care.

Measuring Providers’ Adherence To The American Diabetes Association Screening Recommendation For Prevention Of Diabetic Nephropathy, Whitney R. Munroe

DNP Projects

Purpose: The purpose of this study was to evaluate provider adherence to the ADA’s recommendation for an annual screening urinary albumin excretion level to check for the presence of microalbuminuria. A secondary objective was to assess for adequate treatment (i.e. ACE inhibitor or ARB prescription) in those patients with microalbuminuria present.

Methods: A retrospective chart review was conducted on 60 randomly selected patients seen within a primary care practice in an urban university setting between January 1^st, 2014 and December 31^st, 2014. Inclusion criteria included age ≥ 18 years and an active diagnosis of type 2 …

Are Type 2 Diabetes Patients Receiving Diabetes Self-Management Education In The Primary Care Setting?, Erica Mahone

DNP Projects

Diabetes is a growing health concern in the United States, with approximately 1.7 million new cases diagnosed yearly. A management option to help patients gain glycemic control is the participation in diabetes self-management education (DSME). DSME aims to teach patients how and why they need to perform self-care, and not solely rely on medications to manage diabetes. A literature review of 10 studies between 2007 and 2014 was conducted and found favorable health outcomes for participants of DSME. Patients who participated in DSME had improved glycemic control, achieved blood pressure and cholesterol goals, and lost weight. An analysis of the …

Pioglitazone Treatment Reduces Adipose Tissue Inflammation Through Reduction Of Mast Cell And Macrophage Number And By Improving Vascularity, Michael L. Spencer, Lin Yang, Akosua Adu, Brian S. Finlin, Beibei Zhu, Lindsey Rae Shipp, Neda Rasouli, Charlotte A. Peterson, Philip A. Kern

Internal Medicine Faculty Publications

Context and Objective

Adipose tissue in insulin resistant subjects contains inflammatory cells and extracellular matrix components. This study examined adipose pathology of insulin resistant subjects who were treated with pioglitazone or fish oil.

Design, Setting and Participants

Adipose biopsies were examined from nine insulin resistant subjects before/after treatment with pioglitazone 45 mg/day for 12 weeks and also from 19 subjects who were treated with fish oil (1,860 mg EPA, 1,500 mg DHA daily). These studies were performed in a clinical research center setting.

Results

Pioglitazone treatment increased the cross-sectional area of adipocytes by 18% (p = 0.01), and also increased …

Regulation Of Glucose Homeostasis By The Phlpp1 Phosphatase, Kara L. Larson

Theses and Dissertations--Molecular and Cellular Biochemistry

Type 2 diabetes mellitus is a metabolic disease that affects one in ten people in the United States. It is caused by a combination of genetics and lifestyle factors. Disease progression begins with insulin resistance in peripheral tissues followed by pancreatic beta-cell failure. The mechanisms behind disease progression are not completely understood. PH domain leucine rich repeat protein phosphatase 1 (PHLPP1) is a known regulator of Akt and other members of the AGC kinase family. Akt has been established to play a role in numerous metabolic signaling pathways, including insulin action. It is hypothesized that as a regulator of Akt, …

Effects Of Exercise On Ampk Signaling And Downstream Components To Pi3k In Rat With Type 2 Diabetes, Shicheng Cao, Bowen Li, Xuejie Yi, Bo Chang, Beibei Zhu, Zhenzhen Lian, Zhaoran Zhang, Gang Zhao, Huili Liu, He Zhang

Barnstable Brown Diabetes Center Faculty Publications

Exercise can increase skeletal muscle sensitivity to insulin, improve insulin resistance and regulate glucose homeostasis in rat models of type 2 diabetes. However, the potential mechanism remains poorly understood. In this study, we established a male Sprague-Dawley rat model of type 2 diabetes, with insulin resistance and β cell dysfunction, which was induced by a high-fat diet and low-dose streptozotocin to replicate the pathogenesis and metabolic characteristics of type 2 diabetes in humans. We also investigated the possible mechanism by which chronic and acute exercise improves metabolism, and the phosphorylation and expression of components of AMP-activated protein kinase (AMPK) and …

No Association Of Obesity And Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer, Cheryl L. Thompson, Sarah J. Plummer, Thomas C. Tucker, Graham Casey, Li Li

Markey Cancer Center Faculty Publications

Background: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer.

Methods: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls.

Results: None of these SNPs were …