Clinical Programs
(Metabolic Bone Diseases Program |Neuroendocrine Diseases Program |
Diabetes Mellitus and Obesity |
Weight Control Center )
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Metabolic Bone Diseases Program
John P. Bilezikian, Professor of Medicine and Pharmacology and Chief of the Division, is director of the Metabolic Bone Diseases Program in the Division. Dr. Bilezikian’s basic research interests are directed to mechanisms by which hormones control biochemical features of bone cell function. His recent work has focused upon the parathyroid hormone (PTH) molecule, a key regulator of calcium homeostasis. The emergence of PTH as an anabolic therapy for osteoporosis has heightened the need to understand better how and under what circumstances PTH is an anabolic agent. With several bone cell culture models, he has gained insight into what portions of the PTH molecule and under what conditions they signal the cell to be operative in the anabolic or catabolic mode. He has also contributed to basic understanding of the potent vascular properties of PTH in circulatory beds such the coronary arterial system. He has recently initiated a study of the basic cellular effects of the bisphosphonates in an effort to understand how similar molecules can demonstrate different properties of clinical relevance.
Dr. Bilezikian’s clinical studies in Primary Hyperparathyroidism (PHPT) have, in large measure, redefined this disease in the developed world. With support from NIDDK, now in its 20th year, Dr. Bilezikian oversees a large number of key projects subsumed under this project including the largest prospective natural history study that has ever been conducted in this disease. This work is being conducted closely with Dr. Shonni Silverberg, Professor of Clinical Medicine. Examples of some of the areas that he and his associates are studying include: densitometric mechanisms of bone involvement; the use of modern analytical approaches to assess bone structure such as microCT, back scattered quantitative electron microscopy, and infrared analysis. With these new tools, his group is defining more completely and rather uniquely the remodeling unit in PHPT. Appreciating that PHPT involves the cortical and cancellous skeleton in different ways, he is applying new densitometric approaches to evaluate these 2 major bone compartments, with the ultimate goal being to determine site-specific fracture incidence in this disease. He and Dr. Silverberg have recently described another modern presentation of PHPT in which patients have elevated PTH levels in the absence of hypercalcemia or any cause for a secondary elevation in PTH. Their work has extended to an active program in which pharmacological alternatives are being studied, such as the bisphosphonates, SERMS, and calcimimetics. A particularly severe form of PHPT, parathyroid cancer, is focused on the calcimimetics. Neurocognitive elements of PHPT, an entity that has long been elusive to investigators, is being studied for the first time with quantitative tools in a controlled setting. Many of the aforementioned studies are being studied together with Dr. Mishaela Rubin, Instructor in Medicine. Drs. Silverberg, Bilezikian and Rubin are studying different biochemical forms of PTH secreted by adenomatous parathyroid glands in patients with PHPT, and histological and descriptive studies of patients with a new histologic type of PHPT are also ongoing. With Dr. David Dempster, Professor of Clinical Pathology and Director of Bone Research at Helen Hayes Hospital, and Dr. Elizabeth Shane, Professor of Clinical Medicine, the group has characterized the histomorphometric features of PHPT. Drs. Bilezikian and Silverberg were major participants in the Workshop on the Management of Asymptomatic Primary Hyperparathyroidism that was held at the NIH in 2002. The study of primary hyperparathyroidism includes many other members of the Division: Dr. Thomas Jacobs, Professor of Clinical Medicine, Dr. Ethel Siris, Madeline Stabile Professor of Clinical Medicine, Dr. Robert Lindsay, Professor of Clinical Medicine and Chair, Department of Medicine at Helen Hayes Hospital, Dr. Felicia Cosman, Associate Professor of Clinical Medicine. Other members of the Division who are actively involved in the PHPT project are Dr. Elizabeth Shane, and Dr. David Dempster, The activities of some of these investigators in other research areas are listed below. In addition to his studies in PHPT, Dr. Bilezikian heads an investigation of osteoporosis in men in collaboration with Dr. Etah Kurland (Assistant Professor of Medicine and recipient of an NIH K23 Award), with Dr. Silverberg, in Chinese Americans and, with other collaborators, several major clinical trials in postmenopausal osteoporosis. Noteworthy among these is the PaTH study in which he serves as principal investigator for the Columbia site. This study that is exploring the potential usefulness of combination antiresorptive and PTH therapy in osteoporosis received the award as the most outstanding abstract of the 2003 meeting of the American Society of Bone and Mineral Research. The paper was just published in New England Journal of Medicine (Sept 25, 2003).
Dr. Silverberg is involved in several ongoing projects in other areas of mineral metabolism. She is heading an investigation of the effects of tamoxifen withdrawal on the bones of postmenopausal women with breast cancer. In addition, she is studying the effects of bariatric surgery on indices of mineral metabolism in the morbidly obese patient.
Dr. Shane is Associate Program Director of the Irving Center for Clinical Research. Her primary research interests are in secondary forms of osteoporosis such as steroid induced osteoporosis, transplantation osteoporosis, bone loss due to medications and disorders of the gastrointestinal tract, such as inflammatory bowel disease and celiac disease. Her pioneering work in secondary causes of osteoporosis is highlighted by her description of organ transplant-related bone loss and more recently the investigation of effective therapeutic approaches to this problem. Dr. Shane’s definitive study of the therapy of cardiac transplantation-associated bone loss was just accepted for publication in the New England Journal of Medicine.
Dr. Ethel Siris is principal investigator of National Osteoporosis Risk Assessment (NORA), a longitudinal study of osteoporosis risk factors and outcomes that enrolled over 200,000 postmenopausal women. She is examining fracture outcomes in women with osteoporosis and osteopenia. Another project in NORA is examining fracture outcomes in non-Caucasian women. Dr. Siris directs studies related to the SERM, raloxifene, in which bone density, fracture, and non-skeletal endpoints such as breast cancer are being evaluated. Dr. Siris is the Director of the Toni Stabile Osteoporosis Center in the Division.
Dr. Carolyn Becker, Associate Clinical Professor of Medicine, and Associate Director of the Toni Stabile Osteoporosis Center is one of our most accomplished teachers. Her research is focused upon the potential utility of teriparatide [PTH(1-34)] to accelerate fracture healing in individuals who have sustained an osteoporotic fragility fracture. This study, in which she is the principal investigator, is likely to provide even more information about the potential utility of this new treatment for osteoporosis. Dr. Becker is a member of the Subspecialty Examination Board for Endocrinology, Diabetes and Metabolism of the ABIM and was recently elected Vice President of the Endocrine Society.
Neuroendocrine Diseases Program
The Neuroendocrine Unit is headed by Dr. Sharon Wardlaw (Professor of Medicine). One of her NIH-funded research projects focuses on the melanocortin neuropeptide system which plays a key role in regulating appetite and body weight and is an important target for leptin in the hypothalamus. Studies center on the regulation of proopiomelanocortin (POMC) and the POMC-derived peptides, α-MSH, γ-MSH and ß-EP, together with the newly discovered agouti related protein (AGRP) that is synthesized in the hypothalamus and is a potent antagonist of the MSH peptides. α-MSH inhibits feeding and AGRP is an orexigenic peptide that antagonizes the actions of α-MSH at specific melanocortin receptors. Ongoing studies are examining the regulation of POMC and AGRP gene expression, peptide processing and peptide release in the rat hypothalamus by both leptin and insulin as well as interactions between the POMC and AGRP neurons themselves which both express melanocortin receptors. The role of leptin in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis is also being studied. The HPA axis plays a key role in energy homeostasis and is intricately related to the obesity syndromes in leptin deficient animals. Transgenic mice that overexpress α-MSH and γ-MSH have also been developed to further understand the role that these neuropeptides play in modulating feeding behavior, metabolic and endocrine responses. These mice have a lean phenotype, enhanced insulin sensitivity and alterations in the HPA axis. Recently obtained AGRP knockout mice will be studied in parallel and crossed with the MSH transgenic mice. Future studies will focus on the modulation of peripheral insulin sensitivity and the HPA axis by the hypothalamic melanocortin system. Another of Dr. Wardlaw’s NIH-funded projects focuses on inflammatory cytokines and mechanisms of HPA activation and on the modulation of cytokine and HPA responses to inflammation by leptin and the melanocortin system. There is evidence that leptin, which plays a key role in regulating energy homeostasis, can also modulate the inflammatory response.
a-MSH is synthesized in the hypothalamus and in the periphery and can be regulated by leptin. a-MSH has potent anti-inflammatory properties and can antagonize many of the actions of the inflammatory cytokines. Little is known, however, about the role of the endogenous melanocortin system, consisting of a-MSH, the melanocortin receptors, and the MSH antagonist, AGRP, in modulating cytokine and neuroendocrine responses. This project is examining the role of leptin, a-MSH and AGRP in modulating pro-inflammatory (IL-1ß, IL-6, TNF-α ) and anti-inflammatory cytokine (IL-1ra and IL-10) responses to endotoxin and IL-1ß in the rhesus monkey. Major goals are to determine the physiological roles that α-MSH and AGRP play both centrally and peripherally in modulating the HPA response to an inflammatory challenge and to determine if the effects of leptin on the HPA axis are mediated in part by α-MSH. A rodent model will be used to examine the effects of endotoxin on POMC and AGRP gene expression in the hypothalamus and the effects of leptin on IL-1ß-stimulated CRH release from the hypothalamus in vitro. Mice that overexpress α-MSH and agouti protein will also be utilized to study the role of the melanocortin system and of leptin in modulating cytokine and neuroendocrine responses to endotoxin. Dr. Wardlaw is a member of the Endocrinology Study Section.
The Neuroendocrine Unit also conducts an active program of clinical research. Dr. Pamela Freda (Assistant Professor of Medicine) has become one of the major national leaders in the study of acromegaly. Following upon her K23 Award, Dr. Freda has just been awarded an RO1 grant to study new approaches to evaluation and treatment of acromegaly. Studies to be conducted as part of this grant are both large and long-term clinical projects that will also utilize the Neuroendocrine laboratory. One of Dr. Freda’s recent papers in press in the Journal of Clinical Endocrinology and Metabolism has been selected to be highlighted with editorial commentary. Dr. Judith Korner’s administrative home is in this unit although she works closely with the basic and clinical investigators in the Diabetes unit. She is heading the development of our obesity center. In addition to the basic studies reviewed above, Dr. Korner’s work can be summarized in three separate areas:
a) to determine the effect of weight loss on fasting and postprandial concentrations of hormones (ghrelin, PYY) that are involved in
the regulation of energy homeostasis. Different weight loss methods will be analyzed including bariatric surgery (gastric banding, gastric
bypass, partial gastrectomy with biliopancreatic diversion) and implantable gastric stimulation;
b) to determine the effects of leptin administration in obese individuals who have lost 10% of their initial body weight. Changes in HPA axis and
gastrointestinal hormones will be analyzed;
c) to assess the efficacy of melanocortin agonists for the treatment of hypothalamic obesity. Dr. Korner has been invited to write several
editorials in 2003 in the New England Journal of Medicine and in the Journal of Clinical Investigation. In addition to the NIH K23 Award,
Dr. Korner is the recipient of an Irving Assistant Professorship.
Diabetes Mellitus and Obesity
The research program in diabetes mellitus and obesity is headed by Drs. Robin Goland (Associate Professor of Clinical Medicine) and Rudy Leibel (Professor of Medicine and Pediatrics). They are Co-Directors of the Naomi Berrie Diabetes Center. The research programs of the Division dovetail with the research program of the Center. They cover a wide-range of clinical and basic research. Dr. Goland is studying the clinical expression of gestational diabetes and of Type 2 diabetes in young adults. She is leading a number of projects including the evaluation and comparison of strategies for enhancing minority patient inclusion in diabetes clinical research protocols. Dr. Goland is a co-investigator of the ACCORD trial, an NIH-supported project to prevent cardiovascular disease in diabetes. Dr. Goland is an investigator in IDEATEL (Informatics, telemedicine and education demonstration project) in which the effectiveness of telemedicine in the delivery of diabetes education is being tested. All 300 patients being studied at the Columbia site are Hispanic or African-American patients. Dr. Goland’s studies include clinical trials such as the NIH-sponsored project, TRIGR (Trial to reduce autoimmunity in genetically at risk); and ADOPT (A Diabetes Outcome Progression Trial) in which insulin sensitizers are being studied to preserve β-cell function. Dr. Goland is collaborating with Dr. Kevan Herold (see below) in Trial net, a NIDDK sponsored study, using a novel immunotherapeutic approach to prevent onset of type 1 diabetes. She is testing in the DREAM trial (Diabetes Reduction Assessment with Ramipril and Rosiglitizone) whether treatment with an ACE-inhibitor or thiazolidinedione prevents the development of Type 2 Diabetes Mellitus in adult patients with impaired glucose tolerance. An initiative in oral health in diabetes has been launched with a P50 grant to study periodontal disease in diabetic children. In addition to serving as Co-Director of the Berrie Center, Dr. Leibel heads the Center on Medical Genetics and shares responsibility with the Columbia Genome Center for its microarray facility. Current research activities include efforts to identify genes (and relevant allelic variants) related to obesity and/or type 2 diabetes in mice and humans. His laboratory has particular interest in the molecular physiology of energy homeostasis and glucose/insulin metabolism. An expert in the use of naturally occurring and transgenic rodent models to identify candidate molecules, Dr. Leibel and his associates are vetting these candidates in large numbers of human subjects using high throughput methods (DHPLC, pyrosequencing, fluorescence-based SNP detection). Following his pioneering work in cloning of the mouse Lepob (leptin) and leptin receptor Lepr genes, Dr. Leibel is currently engaged in studies of the molecular physiology of leptin in humans. In collaboration with Dr. Sharon Wardlaw (Professor of Medicine) and Dr. Judith Korner (Assistant Professor of Medicine and recipient of an NIH KO8 Award), his team is investigating the role of the POMC gene and the Agouti Related Peptide (AGRP) gene in the obesity of the Koletsky rat. He is also heading studies on the long-term consequences of weight reduction in obese and non-obese human subjects on energy homeostasis, including skeletal muscle physiology. Dr. Leibel is investigating pancreatic beta cell function in pre-obese rodents segregating for single gene obesity mutations (ob or db). Specific mouse strains are particularly susceptible (C57BLK/J) or resistant (C57BL/6J) to diabetogenic effects of obesity. Dr. Ann-Marie Brillantes (Instructor in Medicine and recipient of an NIH KO8 Award) is continuing her work with Dr. Leibel to examine expression in pancreatic islets of genes that mediate islet neogenesis and beta cell apoptosis.
Dr. Domenico Accili (Professor of Medicine) is conducting a cutting-edge research program on the genetics and pathogenesis of insulin resistance and its role in type 2 diabetes. He is utilizing transgenesis, targeted mutagenesis in embryonic stem cells and gene transfer techniques. Current interests include the role of the forkhead transcription factor Foxo1 in insulin action, and especially in linking peripheral insulin action and b-cell function. His laboratory is also examining the role of different tissues in insulin action and insulin resistance. To examine the paradox that impairment of insulin action in skeletal muscle can not account completely for the metabolic derangements in type 2 diabetes, he is using tissue-specific rescue of insulin receptor knockout mice by transgenesis and conditional knock-ins. Dr. Accili received the 2003 award from the American Diabetes Association for Excellence in Research, one of the most prestigious awards in the field of endocrinology. Dr. Accili is the principal investigator of the NIH Diabetes and Endocrinology Research Center (DERC) grant that was just awarded. Columbia is the recipient of one of only 13 grants in the United States.
Dr. Kevan Herold (Associate Professor of Medicine) is studying mechanisms of autoimmune diabetes and developing novel therapeutic approaches. His pioneering studies suggest that a non-Fc receptor binding humanized anti-CD3 monoclonal antibody (hOKT3g1(Ala-Ala) prevents the immune mediated destruction of insulin producing cells in early onset Type 1 disease. In addition to pursuing this important observation, Dr. Herold is considering other mechanisms of disease regulation, such as inducing tolerance to autoimmunity. This approach could help to reestablish insulin secretion of new b cells. These basic studies are complemented by clinical trials of anti-CD3 antibody in patients with new onset Type 1 diabetes and in those at risk. Dr. Herold is heavily involved in a new initiative to develop an NIH-funded Islet Transplantation Program at Columbia University. He is a member of the Immunology Study Section. |
Weight Control Center
The Weight Control Center specializes in assisting patients with their weight loss goals to achieve improved health. Our physicians are board certified endocrinologists specializing in the area of bariatric medicine. In addition to offering successful weight loss strategies, we also assess the presence of weight related health risks, such as insulin resistance, diabetes, polycystic ovarian syndrome (PCOS), high blood pressure, elevated cholesterol, and obstructive sleep apnea. Weight loss may potentially help decrease the risk of developing these conditions or help improve them. At the WCC, we understand that achieving long term weight loss can be a difficult, complex process that requires a multifaceted and individualized approach. We will work with you to develop a comprehensive plan that addresses: |
- Nutrition
- Physical Activity
- Behavioral Modification (such as stress management, problem-solving strategies, and changing unhealthy eating habits)
- Medications
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Judith Korner, MD, PhD, Director, Weight Control Center
Dr. Korner is the founder and director of the Weight Control Center at Columbia University Medical Center. She has extensive experience assisting patients lose weight. With post-graduate training at Columbia University, she is a renowned expert in the science and treatment of weight management. She is the author of multiple research papers, review articles, and textbook chapters, and heads several research studies investigating the hormonal aspects of weight control as well as changes that occur with weight loss surgery. She is also a national media resource who has appeared on CNN World News and NBC’s Today Show.
Michelle Lee, MD
Dr. Lee has joined the Weight Control Center as a staff physician after completing post-graduate training at Yale University and Columbia University. She is a board certified endocrinologist whose research interests lie in the hormonal regulation of body weight. |
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