Current Fellows
Soumya Adhikari, M.D.
Jennifer Shine Dyer, M.D.
Ellen C. Kaizer, M.D.
Bassil M. Kublaoui, M.D., Ph.D.
Mark Vanderwel, M.D.
Y. Annie Wang, M.D.
Former Fellows
Heidi Chamberlain Shea, M.D. (Post Graduate Researcher)
Soumya Adhikari, M.D.
Research Type: Clinical
Mentor: Perrin C. White, M.D.
Research Details
A Statistical Comparison of Three Bedside Glucose Meters in the Evaluation of Patients with Diabetes or other Disorders of Blood Sugar Regulation during Periods of Acute Illness
The purpose of this research is to determine the most reliable instrument for the evaluation of blood sugar values for patients with diabetes mellitus during periods of acute illness amongst three well recognized institutional bedside meters.
Bedside glucose meters have continued to show improvements in functionality, accuracy and ease of use over the past several years. Many of these meters have been studied and shown to be as reliable as gold standard serum glucose analyzers for the routine care of diabetic patients in the home setting.
In the hospital environment, however, physicians are often faced with the challenge of managing patients with during periods of poor control of their disease process, which is to say when their serum glucoses are at the extremes of either hyperglycemia or hypoglycemia. While most glucose meters available on the market have been well studied in the management of well controlled diabetic patients, there exists in the literature today lack of adequate information on the reliability of bedside glucose meters during such conditions of illness.
In this hospital as in many others, many clinical decisions are made based on the bedside evaluation of capillary or venous glucoses with such meters during the management of these acutely ill patients.
To further our understanding of the utility and reliability of bedside glucose meters in the evaluation of patients under conditions of extremes of hypo- or hyperglycemia, we will concurrently evaluate three institutional models of well recognized blood glucose meters: 1) the Abbott PCX Plus, 2) the LifeScan Sure Step Flexx and 3) the Roche Accu-Chek Advantage.
Currently patients who present for evaluation of blood sugar abnormalities to the emergency room at Children’s Medical Center, Dallas are managed per standard protocols, and often require frequent laboratory monitoring of their acid-base status and their blood sugar levels in addition to other parameters. Blood is typically obtained via an intravenous line which is placed during the initial evaluation of these patients.
Clinical decision making is based on both I-Stat and serum glucose values as these results become available to practitioners, and these values are typically monitored every 1-4 hours depending on the severity of illness. We propose to evaluate the reliability of the previously named study meters by measuring venous blood glucose values on each of the study meters (in addition to on the I-Stat) at each point in time when standard management protocol calls for checking the patients’ glucose values. At the same time, any surplus blood in the syringe used for the original blood draw will be sent to the laboratory where a serum glucose determination will be made to allow comparison to the accepted gold standard.
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Jennifer Shine Dyer, M.D.
Research Type: Clinical
Mentor: Dana S. Hardin, M.D.
Research Details
Metabolic Syndrome in Neonates
The Metabolic Syndrome (MSX) as defined in adults consists of abdominal obesity, dyslipidemia, hypertension, insulin resistance, and a proinflammatory and prothrombotic state resulting in increased risk of cardiovascular disease. Obesity is an ever-increasing problem in children and is associated with development of type 2 diabetes, hypertension, lipid abnormalities and sleep apnea. Although these features appear similar to the MSX described in adults, the problem has not been well studied in the pediatric population. It is likely that the definition and pathogenesis of MSX may change with age. Description of the evolving pathogenesis in children could lead to development of age-specific definitions, and targeting age-specific pathology could greatly impact clinical care.
We hypothesize that the MSX in children is associated with early presentation of peripheral and hepatic insulin resistance, but normal insulin secretion, and that progressive worsening of insulin resistance leads to defects of insulin secretion secondary to glucose toxicity. We further hypothesize that fatty acid metabolism is abnormal leading to lipotoxic damage and further insulin resistance. We propose cross-sectional metabolic studies to characterize the metabolic changes associated with MSX in defined age groups (infants, toddlers, prepubertal children and adolescents). We will recruit 15 LGA, 15 AGA and 15 SGA infants and 15 MSX and 15 normals from ages: toddler, young children, prepubertal and adolescents recruited from the Children's Medical Center and Parkland Medical Centers in Dallas.
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Ellen C. Kaizer, M.D.
Research Type: Translational
Mentor: Virginia Pascual, M.D.
Research Details
Blood Gene Signatures in Pediatric Patients with Newly Diagnosed IDDM
The purpose of this research is to analyze the blood gene signatures of newly diagnosed juvenile diabetes patients.
Cytokines are key players in immunity and autoimmunity. Type I interferons (IFN-a/b), major effectors in response to viral infection, play a major role in Systemic Lupus Erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. TNF, a major factor in response to bacterial infection, plays a major role in Rheumatoid Arthritis. Immunity and autoimmunity can therefore be viewed as dynamic systems driven by opposite vectors, for example, IFN-a/b and TNF. When balanced, both cytokines synergize in protective immunity. When one of the cytokines prevails beyond a certain threshold, autoimmunity may occur. These cytokines will drive differentiation of distinct types of dendritic cells (DCs), for example an excess of TNF results in TNF-DCs, while excess of IFN-a/b leads to IFN-DCs. These different DCs will present different autoantigens leading to different autoimmune responses, i.e., IFN-DCs driving SLE and TNF-DCs driving Arthritis. Therefore, immunity can be viewed as a dynamic system driven by sets of opposite vectors like IFN-a/b/TNF and IFN-g/IL-4.
Cytokine imbalances leading to abnormal immune responses can be detected using microarray technology. We have reported that peripheral blood mononuclear cell RNA from pediatric patients suffering from SLE and Juvenile Arthritis are characterized by the expression of unique gene signatures. We now propose that pediatric patients with new onset Insulin Dependent Diabetes Mellitus (IDDM) will also display unique blood gene signatures as a result of being exposed to unique cytokines.
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Bassil M. Kublaoui, M.D., Ph.D.
Research Type: Basic
Mentor: Andrew Zinn, M.D., Ph.D.
Research Details
Mutations of the SIM1gene cause obesity in mice and humans:
SIM1 encodes a transcription factor and member of the bHLH-PAS family. It is expressed in the paraventricular nucleus (PVN) of the hypothalamus, a nucleus that is important in the central regulation of feeding and energy expenditure. The goal of this project is to characterize the relationship of SIM1 to other known regulators of feeding at the level of the PVN.
Aim 1. Characterize the expression pattern of genes known to regulate feeding and energy expenditure in the hypothalamus in Sim1 heterozygous mice.:
Sim1 heterozygote mice are obese and have elevated leptin levels. By evaluating the expression pattern of proopiomelanocortin (Pomc), neuropeptide Y (Npy), Agouti-related peptide (Agrp) and their receptors we may be able to gain insight into the mechanism by which Sim1 haploinsufficiency induces obesity.
Aim 2. Characterize the feeding, weight, and energy expenditure of Sim1 transgenic mice as well as the expression patterns of genes known to regulate feeding and energy expenditure in the hypothalamus.:
Sim1 transgenic mice may have a complementary phenotype to heterozygotes. By characterizing these mice we may be able to gain insight into the mechanism of Sim1 action in the hypothalamus.
Aim 3. Characterize the relationship between SIM1 and the melanocortin-4 receptor (MC4R) in hypothalamic cell lines and begin to define signaling pathways important for SIM1 regulation.:
Sim1 heterozygote mice have a similar phenotype to MC4R knockout mice, and both genes are expressed in the PVN. Also patients with mutations in SIM1 are similar to patients with mutations in the MC4R. Using cells that express both SIM1 and MC4R we aim to examine crosstalk between these two genes.
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Mark Vanderwel, M.D.
Research Type: Clinical
Mentor: Dana S. Hardin, M.D.
Research Details
Metabolic Abnormalities in Hispanic Children with Cystic Fibrosis:
Hispanic children with Cystic Fibrosis generally have a worsened course of disease than their non-Hispanic counterparts with cystic fibrosis (CF). Unfortunately, the precise reasons why have not been determined. The purpose of this study is to explore potential metabolic reasons for the worsened clinical status of Hispanic children with CF. We believe that the Hispanic heredity predisposes an individual toward insulin resistance, which in turn, causes high blood sugars occur at a younger age in Hispanics with CF. We also hypothesize that Hispanic children with CF are also more likely to break down protein because of resistance to insulin in the liver, predisposing the child to a catabolic state that hinders muscle growth.
This study involves recruiting twelve Hispanic prepubertal children aged 7 to 12 and twelve Hispanic adolescents aged 15 to 17 from the CF Centers at University of Texas Southwestern and Baylor College of Medicine in Houston. Information obtained from these subjects will be compared to 12 prepubertal and 12 adolescent Caucasian children with CF recruited from the same CF centers. Subjects will be categorized according to their ability to maintain normal blood sugars despite drinking a sugar-water solution, as well as their ability to produce, release and respond to insulin when stimulated by dextrose-containing IV fluids. We will compare the information of socio-economic status and family history. The patients’ current state of health will be characterized by measuring lung function and using a standard CF clinical rating developed by the NIH. We will learn how Hispanic patients with CF metabolize carbohydrate and protein by using a non-radioactive label. We will measure the patients’ ability to manufacture sugar by using a special Hydrogen molecule that they will drink with water. Nutritional status will be determined by three day food journals, and intake will be compared to energy needs comparing caloric intake to the energy the patients use at rest.
Our proposed studies will provide better understanding of the origins of CF-related diabetes in children and will especially provide new understanding about Hispanic children with Cystic Fibrosis.
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Y. Annie Wang, M.D.
Research Type: TBD
Mentor:TBD
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Former Fellows
Heidi Chamberlain Shea, M.D.
Research Type: Basic
Mentor: David W. Russell, Ph.D.
Fellowship Research Summary
In July 2002, Dr. Shea began fulfilling the research component of her endocrinology fellowship in the Department of Molecular Genetics with Dr. David W. Russell. She selected his laboratory because Dr. Russell is a superb scientist and has an established record of successfully mentoring trainees to become independent investigators. During her post-doctoral research year she will continue to work in Dr. Russell’s lab on the following two projects.
The first project involved generating a knockout mouse for the C27-3ß hydroxysteroid dehydrogenase gene, which encodes an enzyme required for bile acid synthesis. Her hypothesis was that the absence of this gene will provide an inducible model of neonatal cholestasis. In addition to providing insight into childhood liver disease, this animal model will be useful in examining the effects of end-stage liver failure in adults. As of this writing, she had successfully generated the desired mutant mice, and developed a special diet that allows the knockout mice to survive. She is now expanding the colony and beginning to characterize lipid metabolism and liver disease in these mutant mice.
A second project involved an analysis of glucose metabolism in mice deficient in the nuclear receptor, small heterodimer partner (SHP). SHP is known to repress the activities of several transcription factors, including the hepatocyte nuclear factors (HNF). HNF proteins prevent maturity onset diabetes of the young (MODY). In addition, SHP mutations in humans have been described in obese Japanese adolescents with Type II diabetes. These patients provide insight into the potential phenotype of SHP knockout mice. To initiate this project, she backcrossed the SHP mutation onto an isogenic background (C57BL/6). Using these mice, she will now analyze the role of SHP in insulin resistance and obesity by conducting insulin tolerance and other metabolic experiments. These studies will provide insight into the role SHP may play in glucose metabolism.
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