Endocrinology, Diabetes, Nutrition, and Weight Management

Shalender Bhasin, MD Section Chief

Endocrinology, Diabetes, and Nutrition

Research Activities
Fiscal Year 2002 continued to be very productive for the Section of Endocrinology, Diabetes, Nutrition, and Weight Managment. Section faculty excelled in obtaining extramural research grant support and in publishing original basic and clinical research studies, chapters, and reviews. Extramural funds for FY2002 totaled more than $5.6 million in direct costs and $1.4 million in indirect costs.

In the Vitamin D, Skin, and Bone Research Laboratory, Michael Holick, M.D., Ph.D., program director for the General Clinical Research Center (GCRC), and Professor of Medicine, and Aram Chobanian, M.D., Dean and Provost of Boston University Medical Campus, and principal investigator, were recently awarded a five-year renewal for GCRC funding. Dr. Holick and his team of researchers continue to be leaders in the field of osteoporosis, metabolic bone disease, and psoriasis and hair research.

To better understand how 1,25-dihydroxyvitamin D3 is produced in non-renal tissues such as the prostate and skin, researchers cloned the promoter region of the enzyme’s gene and are evaluating it for its regulatory sequences. In addition, the team has identified an alternative spliced variant of the mRNA. This variant gives rise to the expression of a 1-hydroxylase that is larger in size compared with the renal 1-ahydroxylase. Studies are underway to determine its function and gene regulation.

Researchers in the Vitamin D lab also determined that the fat content in milk is not required for vitamin D to be bioavailable. A double-blind study revealed that vitamin D-fortified orange juice raised blood levels of 25(OH)D more than 100% compared with subjects who drank the same amount of orange juice that was not fortified with vitamin D.

In addition, researchers have investigated the prevalence of vitamin D deficiency in healthy young adults aged eighteen to thirty-two. At the end of winter, 32% were found to be vitamin D deficient. Another study evaluated the effect of exposing a patient with Crohn’s disease to ultraviolet radiation in a tanning bed. It was determined to be the only effective method to correct her vitamin D deficiency.

Plasmid gene constructs using the 25-hydroxyvitamin D-1?-hydroxylase (1-OHase) were made and successfully transfected into cultured human skin cells and several prostate cancer cell lines. The introduction of the 1-OHase gene into prostate cancer cells resulted in a marked increase in the expression of 1-OHase in the mitochondria. These cells increased their capacity to produce 1,25-dihydroxyvitamin D3, which down-regulated cell growth. Research is underway to develop a new gene therapy approach for treating prostate cancer.

The 1-OHase plasmid construct was topically applied to mouse skin and it was demonstrated that the gene was expressed in vivo. This offers a gene therapy approach for treating hyperproliferative skin disorders such as psoriasis and skin cancer. The expression of the 1-OHase was identified in normal human colon tissue and human colon cancer tissue. This observation provides additional evidence that the production of 1.25-dihydroxyvitamin D3 by the breast, colon, and prostate may be important for regulation of cellular proliferation and cancer prevention.

Researchers successfully formulated the receptor agonist of parathyroid hormone related peptide, PTH (1-34), in a liposomal cream (Novasome A®). A pilot clinical trial was initiated to evaluate the safety and efficacy of topical administration of PTH (1-34) for the treatment of psoriasis. The pilot study’s results suggest that PTH (1-34) is both safe and effective for treating psoriasis, and offers a novel approach for treating this skin disease. Studies were initiated on the evaluation of PTH (1-34) and PTH (7-34) for preventing and treating chemotherapy-induced alopecia. C57 BL6 mice that received cyclophosphamide and were pretreated with PTH (7-34) were able to preserve their hair to a greater extent than the placebo-treated mice were. PTH (1-34) was effective in accelerating hair regrowth in mice that received cyclophosphamide.

Because the skin is an important source of vitamin D, a human skin equivalent and a liposomal model have been developed to mimic the photoproduction of vitamin D in human skin. Using these models systems, researchers demonstrated that during exposure to solar simulated-sunlight, a unique membrane-associated mechanism stabilizes the previtamin D3 in a cis,cis-conformation and results in its rapid conversion to vitamin D3. It has now been demonstrated that human skin also produces several photoproducts including tachysterol and lumisterol, which may have important biologic functions in the skin. Research is underway to further evaluate this.

Rahul Ray, Ph.D., Associate Professor of Medicine, continues to study structure-activity of binding proteins and nuclear transcriptional factors related to the vitamin D endocrine system: protein crystallography; molecular modeling; biochemical and mutational studies; gene regulation; molecular targeting of steroid hormone receptors for selective delivery of toxins to cancer cells; development of anti-cancer agents, small molecules and proteins; and identification and characterization of breast cancer-specific antigens.

In the Diabetes Research Unit, which is under the direction of Neil Ruderman, M.D., D.Phil., Professor of Medicine, investigators continue to explore the notion that impaired oxidation of fatty acids, leading to an increase in their esterification, is a major cause of the insulin resistance that predisposes people to Type 2 diabetes, coronary heart disease, and obesity. Their recent work has focused on malonyl CoA, a molecule that inhibits fatty acid oxidation, and the enzyme AMP-activated protein kinase, which, among its other effects, regulates malonyl CoA metabolism.

Studies by Asish Saha, Ph.D., Assistant Professor of Medicine, and co-workers have helped to elucidate the enzymes controlling malonyl CoA levels in muscle. They have observed that the AMP-activated protein kinase, which is activated in muscle during exercise, both causes a decrease in malonyl CoA levels and increases insulin sensitivity. More recent work has established the possibility that AMPK may also be a target molecule for obesity therapy.

In parallel investigations, Yasuo Ido, M.D., Ph.D., head of the vascular disease and diabetes group, and Assistant Professor of Medicine, has demonstrated that the same malonyl CoA regulatory mechanisms that the group has delineated in skeletal muscle operate in human arterial endothelial cells. Dr. Ido has shown that sustained hyperglycemia causes increases in malonyl CoA, insulin resistance, and programmed cell death (apoptosis) in these cells. In addition, activation of AMPK by the drug AICAR or by molecular biological means prevents these events from occurring. Dr. Ido has found evidence that free fatty acids, as well as glucose, may contribute to vascular damage in diabetes and that here, too, AMPK activation can exert a protective effect. In recent studies, he has shown that AMPK’s protective effect may be related to its ability to decrease oxidative stress and NFB-mediated gene expression.

Zhijun Luo, M.D., Ph.D., head of the molecular biology and signal transduction group, and Assistant Professor of Medicine, has carried out seminal studies describing a novel mechanism by which insulin-signaling complexes move around in a cell. He has demonstrated that an intracellular protein, referred to as 14-3-3, plays a key role in the movement of signaling complexes containing insulin receptor substrate (IRS) and PI 3-kinase. Dr. Luo has also shown that it is likely involved in the mechanism by which insulin action in cells is down-regulated.

In the Thyroid Research Unit, Joshua Safer, M.D., Assistant Professor of Medicine, has continued studying the characterization of thyroid hormone action on skin with molecular, cell culture, and in vivo models, and the identification and clinical evaluation of individuals with isolated central resistance to thyroid hormone. Molecular analysis of thyroid hormone receptor mutations associated with thyroid hormone resistance is being pursued.

Lewis Braverman, M.D., Chief of the Section and Professor of Medicine, and Sam Pino continue to direct the Iodine Research Laboratory. This lab provides state-of-the-art analysis of iodine in urine, serum, biological tissues, and food samples to researchers and health care providers on a local, regional, and international level. A sensitive assay for measurement of urinary and serum perchlorate has been established as part of a large clinical study to evaluate the effects of low-dose perchlorate on thyroid function, since very low quantities of this anion have been detected as a contaminant in groundwater in several western states and on Cape Cod, Mass.

Dr. Braverman continues to collaborate on studies related to amiodarone; iodine excess and deficiency on thyroid function; the clinical use of recombinant human TSH; and the relationship between hypothyroidism, folic acid deficiency, elevated serum concentrations of homocysteine, and serum lipid fractions.

Within the Thyroid Research Unit, Stephanie Lee, M.D., Ph.D., Associate Professor of Medicine, continues her studies on the regulation of TRH gene expression in endocrine and non-endocrine cells utilizing state-of-the-art molecular biology techniques including adenovious – mediated gene transfer in intact mice and microchimerism of presumed fetal origin in thyroid glands from women.

In the Center for Nutrition and Weight Management, Peter Wilson, M.D., Professor of Medicine, is studying populations with a focus on metabolic and cardiovascular epidemiology. His scientific work during 2001-2002 has targeted risk factors for cardiovascular disease and diabetes, largely within the context of the Framingham Heart Study. Publications he has contributed to have included areas related to nutritional, lipid, and other risk factors for the occurrence of cardiovascular diseases and stroke, diabetes, and a metabolic syndrome.

Bench research being done by Nawfal Istfan, M.D., Ph.D., Associate Professor of Medicine, in his National Institutes of Health (NIH)-funded laboratory focuses on the mechanisms of S-phase prolongation by fish oil. His main objective is to test the hypothesis that omega-3 fatty acids alter the nuclear structure of mammalian cells in a manner that lengthens DNA replication time. The proposed mechanism involves the complex process of organization of replication foci at specific DNA sites.

Caroline Apovian, M.D., Director of the Center for Nutrition and Weight Management, and Associate Professor of Medicine, has been engaged in clinical studies related to various dietary and drug effects on weight reduction. These studies include weight loss in subjects on a VLCD and sibutramine versus placebo; a prospective study of risk factors for heart disease in subjects pre- and post-gastric bypass surgery; an investigation of an MCT oil-based liquid diet and the effects on weight loss; endothelial function in obese subjects on a weight-loss program; hypocaloric-hyperprotein enteral nutrition versus relative normocaloric enteral nutrition in critically ill medical patients; interventions to enhance adherence to obesity guidelines by providing four-hour workshops on obesity treatment to primary care physicians with patient chart follow-up; and a randomized, controlled study to examine the relationship between changes in plasma GIP levels and other gastrointestinal peptides following gastric bypass surgery in obese patients.

Also in the Center for Nutrition and Weight Management, Thomas Moore, M.D., Professor of Medicine, is testing a web-based nutrition (the DASH diet) and exercise education program, offered to the employees of EMC Corp. The program will run from February 2002 until February 2003. Outcomes to date include change in self-reported blood pressure, self-reported dietary pattern, and self-reported body weight.

Boston Medical Center (BMC) is a site for an NIH-funded, multi-center randomized trial designed to determine the efficacy of coronary revascularization, combined with aggressive medical therapy, versus aggressive medical therapy alone in Type 2 diabetic patients with stable CAD. It is also investigating the efficacy of a strategy of providing insulin or insulin secretagogues versus insulin sensitizers in the management of hyperglycemia. Susana Ebner, M.D., Assistant Professor of Medicine, and Michele Leaf, N.P., are co-investigators in this study and are closely involved with the diabetes component.

Clinical Activities
The consolidated clinic that integrates Endocrinology, Diabetes, Nutrition and Weight Management in newly renovated space on Preston 2 has been completed, and the move from the Doctor’s Office Building occurred in September 2001. The Section now has a state-of-the-art, 4,500-square-foot clinic permitting “one-stop shopping”: spacious examining rooms; a thyroid ultrasound and biopsy room; bone densitometry; a patient education and conference room; phlebotomy room; and rooms for dietary and diabetes-teaching dieticians and nurses.

The Center for Weight Management and Nutrition includes physicians, dieticians, nurse practitioners, and an exercise specialist. The Center provides medical consultation in the area of obesity; nutritional disorders; gastric bypass surgery (R. Armour Forse, M.D., Ph.D., Laslo Nando Tauber Professor of Surgery, and Vice Chairman of Surgery); lipid disorders (Dr. Wilson); and diabetes (Elliot Sternthal, M.D., Clinical Director of Diabetes Services, and Assistant Professor of Medicine).

Dr. Apovian serves as the co-principal investigator with George Blackburn, M.D., for the New England Division of the National Collaborative Center for Obesity Research and Education (CORE). This organization is dedicated to educating primary care providers with workshops designed to improve the identification and treatment of obesity.

The Section continues to provide outstanding clinical service in the diagnosis and management of bone disease and calcium disorders under the direction of Dr. Holick and Alan Malabanan, M.D., Assistant Professor of Medicine. State-of-the-art bone density evaluations are now carried out in the clinic on demand, a service currently not available elsewhere in greater Boston. Free bone density screenings were again carried out at BMC. Dr. Malabanan provides professional interpretation of bone densities carried out by a mobile unit available at affiliated community health centers.

Drs. Braverman, Lee, and Safer offer BMC and the greater Boston community nationally and internationally recognized expertise in diseases of the thyroid. In the new clinic, thyroid ultrasounds are available on site to further assess thyroid size and nodularity, and to assist in carrying out fine-needle aspiration biopsies of thyroid nodules.

The diabetes clinical service has greatly expanded under the direction of Dr. Elliot Sternthal. Patricia Hanrahan BSN, MSN, CNP, CDE, has established an insulin pump service at BMC. Inpatient diabetes management guidelines for surgical and medical patients have been established, and the Section’s American Diabetes Association (ADA)-accredited Clinical Diabetes Education Program continues to flourish. The diabetes service is now working with BMC’s high-risk prenatal group in managing pregnant women with diabetes.

Robert Levin, M.D., Associate Professor of Medicine, and James Melby, M.D., Professor of Medicine, have continued to provide superb endocrine care in general endocrinology, Paget’s disease, and adrenal and pituitary disorders. Dr. Thomas Moore brings to the Section expertise in endocrine hypertension and general endocrinology.

Section faculty have expanded clinical activities to other sites. Members are participating in clinics at the East Boston Neighborhood Health Center, the Brockton VA Hospital, the Bedford VA Hospital, and Harvard-Vanguard clinics, as well as consulting in nutrition at the Jewish Memorial Hospital.

The Section’s fellowship program is very successful and has attracted outstanding fellows who have been active in clinical and research activities. The Section has received a three-year outstanding approval of its fellowship program with no citations. Credit goes to Dr. Malabanan, program director.

The Section has continued to receive excellent reviews for its participation in the second-year medical school “Biology of Disease” course. In addition, the Section continues to attract fourth-year medical students and Medicine and Family Practice residents for a one-month clinical elective in Endocrinology. Many faculty members have presented endocrine conferences to colleagues in Primary Care, Obstetrics and Gynecology, and Internal Medicine. Section faculty attend on the general medical wards and on the endocrine consult service, as well as participate in morning report for the medical residents.

Weekly Endocrine grand rounds — including outstanding national leaders presenting seminars and discussing cases, research seminars by faculty, and fellows’ case reports — have been extremely well attended. The Section has weekly fellow conferences with faculty participation and a journal club, as well as a weekly fellow board review luncheon conference. Section fellows participate in a Friday afternoon continuity clinic supervised by a faculty member.

Major Accomplishments
During FY2002, a total of sixty-three articles were published in peer-reviewed journals; forty-six abstracts were presented; one book was edited; nineteen editorials and reviews were published; and eight book chapters were written.

In addition, Section faculty have lectured at an extraordinary number of national and international medical schools and conferences, and national and international meetings. Members have also served on NIH review committees; national and international specialty organization committees; and editorial boards of specialty journals.

Dr. Braverman received the Distinguished Clinician Award from the American College of Endocrinology in 2002. He was the First Oppenheimer Lecturer at the University of Minnesota School of Medicine in 2001. Dr. Braverman is editor of Current Opinion in Endocrinology and Diabetes and serves on the editorial boards of the Polish Journal of Endocrinology, Revista Medica de Chile, and the Journal of Endocrinologia Iranica. He was named a “Top Doc” by Boston Magazine for 2002 in Endocrinology and Metabolism.

Dr. Apovian received the Dean’s Report Award in 2002. She was named a leader in women’s health at Boston University in the Annual Dean’s Report for Boston University. In 2001, Dr. Apovian received the Physician Nutrition Specialist Salary Support Award from the American Society of Clinical Nutrition.

Dr. Holick is on the editorial boards of the Journal of Nutritional Biochemistry, Photodermatology, Photoimmunology, and Photomedicine, and Proceedings of the Society for Experimental Biology and Medicine. He serves as an associate editor on the Journal of Investigative Dermatology.

Dr. Lee was selected for a Top Doctors Award by Consumer’s Guide to Top Doctors for 2002 by a national peer-review survey in which participants were asked to name the best clinical practitioners in each specialty. Boston Magazine also named her a “Top Doc” for 2002 in Endocrinology and Metabolism.

Dr. Levin received the Medical School Teaching Award at Boston University School of Medicine’s June 2002 Commencement.

Dr. Ruderman was named the 2001 Izenstein Visiting Professor at Baystate Medical Center and Tufts Medical School. In addition, the Juvenile Diabetes Association designated BMC a Diabetes Complication Center under the direction of Dr. Ruderman and his colleagues.

Dr. Sternthal is co-editor of Current Opinion in Endocrinology and Diabetes.