Research Summaries in Diabetes (Types 1 and 2) and Obesity
Clifton Bogardus, MD: Etiology and Pathogenesis of Type 2 Diabetes Mellitus in Pima Indians
The scientific aim of this work, conducted in Phoenix, Arizona, is to understand the causes of obesity, diabetes and their complications in pathophysiologic and molecular genetic terms. Physiologic studies are carried out in a large clinical research center and lab-based work is conducted in adjoining laboratories. Detailed clinical studies, including measures of insulin sensitivity and secretion, and biopsies of adiposeand skeletal muscle tissues are done to analyze gene and protein expression levels in lean and obese, and in insulin-resistant vs. insulin-sensitive non-diabetic Pima Indians. DNA samples are also collected for screening of candidate genes that may increase risk of obesity and diabetes.
Francesco S. Celi, MD: Peripheral Conversion of Thyroid Hormone and the Modulation of Thyroid Hormone Action
Dr. Celi studies deiodinase-regulated peripheral metabolism of thyroid hormone and its effect on modulating the hormone’s tissue-specific actions. Dr. Celi’s studies include in vitro cell culture systems, and clinical studies. The clinical protocol aims to analyze the interaction between the peripheral metabolism of thyroid hormone and glucose, energy, and lipid homeostasis.
Giovanni Cizza, MD, PhD: Role of Neuroendocrine Factors in the Pathogenesis of Certain Obesity Syndromes in Humans
Dr. Cizza studies the appetite stimulating neuropeptide named orexin as a cause of weight gain in subjects with narcolepsy (a sleep disorder characterized by a central orexin deficiency and by a reduction in the normal circadian rhythmicity of circulating leptin, a satiety signal). Other clinical studies include the potential role of another neuropeptide (corticotrophin-releasing hormone or CRH) on the regulation of appetite control by using a novel CRH antagonist.
Samuel W. Cushman, PhD: Role of Adipose Cell Turnover in the Insulin Resistance of Type 2 Diabetes and Obesity
Microarray analysis of adipose cell gene expression in high-risk insulin-resistant human subjects suggests that a reduced rate of adipose cell turnover is associated with enhanced adipose cell size and systemic insulin resistance. Induction of increased adipogenesis in genetically obese rats with enlarged adipose cells is associated with amelioration of systemic insulin resistance. New technologies now permit detection and isolation of smaller adipose cells, which may be in the process of active differentiation, and characterization of the adipose cell secretory proteome, which plays a role in systemic metabolic signaling.
Marvin C. Gershengorn, MD: Factor Promoting Differentiation of Human Endocrine Pancreas into Mature, Hormone Producing Cells
One aspect of research in our laboratory involves the study of the factors responsible for and the genes expressed during the differentiation of human endocrine pancreas into mature, hormone (insulin, glucagon, somatostatin and pancreatic polypeptide)-producing cells of the pancreatic islets of Langerhans. The goal is to delineate a milieu in vitro in which human progenitor cells can be made to proliferate and then differentiate into islets by determining which growth and differentiation factors are necessary for development of these cells.
Phillip Gorden, MD: Recombinant Leptin in the Treatment of the Diabetic, Dyslipidemic, and Hepatic Complications of Lipodystrophy
Dr. Gorden has long been interested in the natural history and pathophysiology of extreme forms of insulin resistance including insulin receptor mutations, autoantibodies to the insulin receptor and the various forms of lipodystrophic diabetes. His current research efforts include two clinical trials treating patients with recombinant leptin therapy.
Derek LeRoith, MD, PhD: Mouse Models of Type 2 Diabetes
Dr. LeRoith has developed a mouse model of type 2 diabetes. Like human disease, the model shows progression from pre-diabetes to diabetes, beginning with severe insulin resistance in muscle, progressing to fat and liver resistance, and eventually to the loss of beta cell function. The model demonstrates the role of lipotoxicity and glucotoxicity in the pathogenesis of Type 2 diabetes and is currently being used to study the role of leptin, adiponectin and other adipokines in this process.
Nadya Lumelsky, PhD: In Vitro Models of Islet Cell Expansion
Dr. Lumelsky has extensive research expertise in in vitro culture systems of pancreatic differentiation derived from adult pancreatic tissue and from embryonic stem cells. Her current research efforts are directed toward optimizing these culture systems to allow efficient generation of functional islet cells to serve as a source of transplantable islet tissue for the treatment of diabetes. These in vitro systems are also used for studies of the mechanisms of pancreatic development and differentiation.
Klaus U. Pechhold, MD: Mouse Experimental Autoimmune Diabetes Model to Study Type 1 Diabetes Mellitus (T1DM) Immunopathogenesis
Dr. Pechhold utilizes various transgenic mouse models to further explore the immunopathogenic mechanisms underlying T1DM and other autoimmune illnesses. These in vivo model systems allow him to carefully dissect the role of the major histocompatibility complex (MHC) coupled with cognate antigen as it interacts with antigen-specific T cells, the different antigen presenting cells capable of presenting self-antigens, the phenotype of T lymphocytes activated by various stimuli, and the in vivo relevance of various proposed autoantigens. He also studies the capacity of putative cellular precursors to restore beta cell function in various mouse models.
Kristina I. Rother, MD: Clinical Protocols Testing Approaches Designed to Promote Beta Cell Function in T1DM
Dr. Rother's research interests mainly relate to type 1 diabetes mellitus (T1DM). Current clinical protocols include: (a) studying whether orally administered alpha interferon can delay or prevent continued beta cell loss in individuals with recent onset disease, (b) whether tight glycemia control and a glucagon-like peptide 1 (GLP-1) agonist, with or without concomitant immunosuppression, can promote endogenous pancreatic islet function in patients with long-standing disease, and (c) detailed metabolic follow-up of islet transplant recipients.
Anne E. Sumner, MD: Clinical Protocols Studying the Effect of Insulin Resistance on Lipid Metabolism in African-Americans
Dr. Sumner oversees clinical protocols studying the effect of insulin resistance on triglyceride metabolism in African-American women with the long-range goal being a better understanding of the metabolic factors that contribute to their obesity and high body fat content. Of particular interest, insulin resistance in African-American men and women often co-exists with surprisingly normal triglyceride levels. Preliminary data suggest that in African-Americans, insulin resistance is not associated with impaired lipoprotein lipase activity, and this in turn promotes normal triglyceride clearance. Dr. Sumner is extending these initial observations by studying the effect of insulin resistance on free fatty acid turnover in African-Americans.
Lee S. Weinstein, MD: Gsa-cAMP Pathways in the Regulation of Islet Function, Energy Metabolism, Insulin Action, and Adipocyte Development
Dr. Weinstein studies the role of Gsa, the heterotrimeric G protein a-subunit that mediates receptor-stimulated cyclic AMP production, in the regulation of energy and glucose metabolism. The human disorder Albright hereditary osteodystrophy, which is caused by inactivating Gsa mutations, is associated with obesity. His laboratory has generated numerous germline and tissue-specific Gsa knockout models that are presently being studied to examine the role of Gsa-cAMP pathways in the regulation of islet function, energy metabolism, insulin action, and adipocyte development.