Research Activities

Carla Demeterco, MD, PhD is involved in developmental therapeutics for diabetes mellitus. She has worked extensively in the area of pancreatic beta cell biology with emphasis on inducing beta cell regeneration in the adult human pancreas. She previously reported a connection between cell-cell contact and hormone expression. She also showed abnormal signaling patterns in the beta-cells of patients with type 2 diabetes. More recently she has become interested in studying children with diabetes mellitus and obesity. She collaborated on a recent study of misdiagnosed monogenic diabetes in children. She is the local principal investigator investigating the effects of the bile acid sequestrant, colesevelam, in children with type 2 diabetes.

Michael Gottschalk, MD, PhD is involved in clinical trials related to diabetes mellitus in children, including studies on the immunomodulation of type 1 diabetes, pharmacokinetic/pharmacodynamic studies of exenatide in type 2 diabetes mellitus and behavioral modification of obese adolescents at risk for type 2 diabetes mellitus. He is also the local principal investigator studying a long acting growth hormone formulation for the treatment of children with growth hormone deficiency.

Alberto Hayek, MD research lab is involved in studies related to basic research in diabetes, with a focus on insulin-producing pancreatic endocrine cells, contained in cell clusters called in the so-called islets. His laboratory was the first to show replication of human islets in vitro when exposed to specific growth factors. Dr. Hayek’s laboratory was also one of the first to develop culture model-systems for human fetal and adult islets. This culture-system has provided a model for the identification of growth factors involved in islet cell differentiation and replication. At this time, Dr. Hayek’s work centers on human embryonic stem cells and induced pluripotent stem cells derived from skin biopsies of patients with type 1diabetes. The goal of this research is to contribute to the development of cell-based therapies for diabetes.

Andrew Hinton, PhD, has focused on understanding molecular mechanisms that regulate the vitro production of insulin-producing beta cells. This work is focused on characterization of microRNA profiles during human embryonic stem cell (hESC) differentiation, and the development of reporter cell lines that will allow isolation and characterization of target cell populations during hESC differentiation. Other cell lines are being developed that can inducibly express small RNAs in order to test their effects on current differentiation protocols.

Ulupi Jhala, PhD research is focused on unraveling the mechanisms that initiate and sustain beta cell death to result in diabetes. Current projects are focused on the role of cytokines and fatty acids in inducing inflammation and apoptosis. Specific emphasis areas include regulation of mitochondrial bioenergetic pathways and how they impinge on cell survival. A second interest of research is understanding the role that epigenetic events play in the binary cellular decision of differentiation versus growth of the beta cell.

Kenneth Lee Jones, MD, continues his interest in diabetes and obesity in children. He is studying the misdiagnosis of type 2 diabetes in children and unreported causes of monogenic diabetes. He is also pursuing investigation of unusual endocrine disorders in children, most recently thyrotoxic, hypokalemic periodic paralysis and generalized arterial calcification of infancy.

Jane Kim, MD investigates how insulin acts at the cellular level in different tissues to alter glucose metabolism and other physiologic events in diabetes. Presently Dr. Kim’s research identifies key factors that contribute to insulin resistance and pancreatic beta cell failure in type 2 diabetes. Adipose tissue is the body’s largest endocrine organ, representing a complex, essential and highly metabolic site of insulin action. Excess adiposity, or obesity, is associated with insulin resistance, diabetes, atherosclerosis, dyslipidemia and hypertension. Dr. Kim’s work has primarily focused on how transcription factors regulate adipose tissue metabolism. Her current research investigates epigenetic mechanisms that influence metabolism by studying how in changes in our diet alter gene transcription and our predisposition to insulin resistance. Discovering mechanisms that govern transcription factor function is expected to lead to novel treatments in treating diabetes.

Charles C. King, PhD is working to enhance the production of pancreatic progenitor cells from human embryonic stem cells (hESCs) through the manipulation of signal transduction pathways and microRNAs. Specifically, Dr. King is working to understand the biochemical signals that regulate the transition of hESC from pluripotent cells to definitive endoderm, a committed cell fate necessary for the generation of insulin-producing cells. His laboratory has identified a number >of compounds that inhibit a previously unrecognized signaling pathway necessary to maintain pluripotency. Addition of these compounds enhances definitive endoderm formation and significantly decreases teratoma formation. A second focus of the laboratory is to better understand the role microRNAs play in insulin cell genesis. Next Generation Sequencing is being used to map changes in microRNA expression of cells at defined points in differentiation.

Karen Klein, MD is studying precocious puberty in girls with the goal of optimizing growth, exploring new treatment methods, and defining pubertal progression after treatment. Dr. Klein is also studying the effect of weight gain and racial diversity on pubertal onset. Her laboratory runs an ultrasensitive yeast bioassay for estradiol. This unique technique enables her to study estrogen’s role in growth and pubertal development in the above settings. A third area of research is adolescent polycystic ovarian syndrome. Dr. Klein shares laboratory space with Dr. Jeffrey Chang in reproductive endocrinology, and hopes to increase collaboration using his expertise and her patient population.

Maja Marinkovic, MD is the local principal investigator studying treatment of children with IGF-1 deficiency and maintains clinical database of patients with IGF-1 deficiency treated with Increlex.

Anthony Montgomery, PhD has focused on methods to improve the ex vivo expansion of insulin-producing beta cells for transplantation. Dr. Montgomery has shown that interactions between beta cells and their extracellular environment induce cultured beta cells to transition into a defunct mesenchymal phenotype. Importantly, Dr. Montgomery has identified small compound inhibitors that prevent this process and subsequently preserve the native phenotype and function of beta cells in culture. In collaboration with Dr. Alberto Hayek, Dr. Montgomery is also developing novel approaches to increase the yield and function of insulin producing beta cells from both human embryonic stem cells and pancreatic progenitor populations. This work is focused on the use of small compound inhibitors of select non-receptor tyrosine kinases and upon the manipulation of the extracellular matrix environment.

Ron Newfield, MD has developed and is maintaining a comprehensive database of endocrinology and diabetes patients seen at Rady Children’s Hospital-San Diego. He also has a type 1 diabetes-specific retrospective study to assess weight gain and glycemic response to insulin as well as evaluating other conditions at presentation. The database and diabetes-specific protocols have already enabled publication of manuscripts and abstracts, and will remain a valuable source for future research in pediatric diabetes and endocrinology. Dr. Newfield is involved in clinical trials of growth hormone treatment in children with idiopathic short stature, a study to assess QOL in children with short stature, and pharmokinetic and efficacy studies of lipid-lowering medications. The clinical trial, related to the immunomodulation of type 1 diabetes mellitus in recently diagnosed children and adolescents, by way of a vaccination with an islet-cell antigen, was terminated due to lack of efficacy in an equivalent study in Europe. The site at Rady Children’s Hospital has tested over 500 subjects that are relatives of patients with type 1 diabetes for their risk of developing the disease as well, as part of TrialNet, a multicenter network in the US and abroad. Dr Newfield has 2 industry-based studies with subjects already enrolled, and 2 more to begin enrolling, to study new therapies in children and adolescents with type 2 diabetes. He also initiated a study in collaboration with Quest Diagnostics, to retrospectively evaluate thyroid tissue from pediatric thyroid cancer surgical specimens, and assess the frequency of different mutation classes, and genotype vs. phenotype correlations.

Susan Phillips, MD translational research is focused on improving our understanding of the development of metabolic diseases such as diabetes and fatty liver disease in human obesity. Obesity is recognized to increase the risk of developing type 2 diabetes, yet only about 20% of obese subjects have diabetes. To better understand the factors that contribute to the development of diabetes in the obese, Dr. Phillips has developed methods to study the hormonal activity of freshly isolated human fat tissue and cells over prolonged periods of time. Using this culture technique Dr. Phillips has worked to better understand the regulation of the insulin sensitizing in the obese are associated with reductions in the production of adiponectin by visceral (central) fat cells and that these fat cells are poorly responsive to currently available therapeutics. The cellular mechanisms responsible for synthesis and secretion of adiponectin are poorly understood. In recently published work Dr. Phillips reported that cellular obesity, hypertrophy, appears to contribute significantly to the low circulating levels of adiponectin in the obese. Ongoing studies are directed towards the identification of regulatory mechanisms that link cell size to adiponectin production. The ultimate goal of this work is to identify key regulatory steps in adiponectin synthesis and secretion for targeted therapeutic intervention to prevent obesity-related metabolic disease.

Maike Sander, MD conducts research into developing strategies for a cell-based therapy for diabetes mellitus. The successful production of insulin-producing beta-cells requires a thorough understanding of the molecular networks that direct the normal development of these cells, as well as the identification of an appropriate convertible cell type, such as embryonic stem cells or adult progenitor cells. The main objective of Dr. Sander’s current research is to identify strategies for producing functional insulin-producing beta cells from pluripotent stem cells in vitro. To track changes in gene expression and chromatin state during beta cell differentiation, the Sander laboratory recently published the first epigenetic map of human embryonic stem cells during their progression to Beta cells. The goal is to use this knowledge to identify factors that can induce beta cell differentiation in vitro.

Jianhua Shao, MD, PhD is studying obesity and obesity-induced insulin resistance. His laboratory currently is working on three main projects: 1) Transcriptional regulation of adiponectin gene expression. The main goal of this study is to elucidate the underlying mechanisms that suppress adiponectin gene expression during the development of obesity 2) Adipocytokines and lipid metabolism. The objective of this study is to identify the regulatory effects of adiponectin on FFA and triglyceride metabolism in skeletal muscle and adipose tissue and 3) Macrophage infiltration and adipogenesis. Conditional gene knockout and macrophage-specific ablation approaches are employed to investigate the developmental role of macrophages in excessive energy intake-induced adipogenesis and angiogenesis. 4) Maternal obesity and offspring adiposity, which study how maternal overnutrition alters intrauterine metabolic environment and through which programs offspring adiposity. In addition, a series of preliminary studies are carrying out for a new project, which aims at brown adipocyte