Update from Section Chief John Wysolmerski, MD
After a year-long nationwide search, John Wysolmerski, MD, was appointed chief of the Section of Endocrinology & Metabolism in June 2021. Wysolmerski and section leadership have remained true to the mission of the Section of Endocrinology and Metabolism throughout the years: to improve the health and well-being of patients with endocrine and metabolic diseases by advancing scientific knowledge; by skillfully applying new knowledge to the care of patients; and by training the next generation of physician-scientists.
After Robert Sherwin, MD, retired as section chief, faculty members developed a five-year plan to expand the section’s clinical practice with these goals in mind: to better capitalize on new educational and research opportunities within the growing Yale New Haven Health System; to enhance its educational programs with a better organized curriculum and new fellowship training opportunities; and to grow and broaden its research base by recruiting new physician-scientists. As section chief, Wysolmerski has brought together a leadership team to help the section accomplish its collective goals. The leadership team members are Silvio Inzucchi, MD, who continues to serve as clinical chief; Renata Belfort de Aguiar, MD, PhD, who serves as associate chief for Diversity, Equity and Inclusion; Richard Kibbey, MD, PhD, and Jonathan Bogan, MD, who are co-associate chiefs for research; and Barbara Gulanski, MD, MPH, who serves as associate chief for education.
Section faculty focus on type 1 diabetes and complications of hypoglycemia; type 2 diabetes and insulin resistance/ obesity; and metabolic bone disease and calcium metabolism.
The section welcomed two new clinical faculty members in 2021. Anika K. Anam, MD, joined the faculty in the clinician-educator track. Anam will work with Gulanski on curriculum development for residents and medical students. Also contributing to the curriculum initiative are Brian Wojeck, MD, and Lisa Parikh, MD.
Kavya Mekala, MD, also joined the faculty in 2021. Her focus is on the development of a thyroid nodule biopsy program working with endocrine surgery and radiology. Mekala also will help to develop a secondary practice site in Stanford, Connecticut. The section also is partnering with Endocrine Associates of Connecticut to increase its coverage at Yale New Haven Hospital Saint Raphael Campus, where a new diabetes consultation service is under development. Despite the pandemic, the section’s clinical practice has seen more patients than ever before, and its faculty have been publishing papers, collecting awards, and securing grants. Here are some highlights of the faculty’s recent achievements.
Ana Louisa Perdigoto, MD, PhD, was named the winner of the 2021 Iva Dostanic, MD, PhD, Physician- Scientist Trainee Award by the Yale School of Medicine Department of Internal Medicine.
Karl L. Insogna, MD, FACP, received the 2021 Frederic C. Bartter Award, an esteemed award from the American Society for Bone and Mineral Research.
Elizabeth Jonas, MD, was nominated for her second Javits Award by the National Institute of Neurological Disorders and Stroke in recognition of her leadership and scientific contributions. She first received the Javits Award in 2013.
Kevan C. Herold, MD, the C.N.H. Long Professor of Immunobiology and of Medicine, has been named chair of Type 1 Diabetes (T1D) TrialNet, an international consortium dedicated to finding ways to prevent, delay, and slow progression of the disease.
Gerald I. Shulman, MD, PhD, was elected to a three-year term as chair of a section of the National Academy of Sciences. He will lead Section 42: Medical Physiology and Metabolism of the National Academy of Sciences (NAS) from May 1, 2022, to April 30, 2025.
Endocrinology & Metabolism and Pulmonary, Critical Care, & Sleep Medicine
Although there’s a well-documented bidirectional connection between obesity and mood- and stress-related psychiatric disorders, the molecular mechanisms altered in obesity have not been fully explained. Yale researchers investigated relationships between obesity and synaptic density using the radioligand [11C]UCB-J, which binds to synaptic glycoprotein SV2A, together with positron emission tomography (PET) in individuals with obesity with or without stress-related psychiatric disorders. Stephen Baldassarri, MD, MHS, and Ania Jastreboff, MD, PhD, and colleagues published their findings in Nature.
Endocrinology & Metabolism
In a JAMA Internal Medicine research letter, Joseph Ross, MD, MHS, and Kasia Lipska, MD, MHS, and colleagues performed a retrospective analysis of new levothyroxine prescriptions between 2008 and 2018. They found that levothyroxine was commonly prescribed for patients with mildly increased thyrotropin levels, a pattern at odds with clinical practice guidelines, as 60% had subclinical hypothyroidism and 30% normal thyroid function.
Endocrinology & Metabolism, Neuroscience and Cell Biology
Fragile X Syndrome is a devastating X-linked genetic disorder, and the most common inherited cause of intellectual disability. It has also been associated with metabolic abnormalities indicative of uncoupled oxidative phosphorylation in mitochondria. In a continuation of its study of the mitochondrial ATP synthase function, the Jonas laboratory has reported that neurons in a mouse model of Fragile X syndrome have a mitochondrial membrane leak that explains both the abnormalities in intellectual function and systemic metabolism. A key finding was that closing this ATP synthase c-subunit leak could attenuate the metabolic abnormalities and improve brain function, suggesting a novel treatment approach for the otherwise untreatable condition.
Endocrinology & Metabolism and Cell Biology
Jonathan Bogan’s laboratory is interested in the mechanisms by which insulin stimulates glucose uptake into muscle and fat after a meal. In elegant work over the years, he has identified a pathway by which cleavage of a protein called TUG results in the relocation of glucose transporters from inside the cell onto the cell surface, allowing glucose to enter muscle and fat cells. In new work published in Nature Metabolism, Bogan’s lab showed that upon insulin stimulation, a fragment of the TUG protein enters the nucleus to increase oxidate metabolism and heat production. This finding demonstrates that insulin can stimulate energy expenditure, and may explain the long-standing observation that our temperature rises after eating. Alterations in sensitivity to this process are associated with risk of developing diabetes and may also be important in the development of obesity.
Endocrinology & Metabolism and Pediatric Endocrinology
Karl L. Insogna, MD, FACP, has had a longstanding interest in disorders of phosphate wasting. Together with Thomas Carpenter, MD, in pediatrics, Insogna performed clinical studies that were instrumental in the approval of burosumab (an anti-FGF23 antibody) for the treatment of X-linked hypophosphatemic rickets, which is caused by genetic overproduction of the phosphaturic hormone FGF23. Tumor-induced osteomalacia is another disorder of renal phosphate wasting caused by the overproduction of FGF23 by a variety of tumors. In a multicenter study published in the Journal of Bone and Mineral Research, Insogna, Carpenter, and colleagues at other institutions demonstrated that burosumab is effective in raising phosphate levels, healing osteomalacia and fractures, and improving quality of life in patients with tumor-induced osteomalacia, providing the first effective medical therapy for this condition.
Endocrinology & Metabolism, Digestive Diseases, Cellular and Molecular Physiology and Pharmacology
All medical students learn that glucagon counters the actions of insulin and stimulates the liver to release glucose. In fact, glucagon is used to treat severe hypoglycemia in diabetics, and alterations in the ratio of glucagon to insulin in the portal vein are thought to lead to the increased hepatic gluconeogenesis that contributes to the development of hyperglycemia in type 2 diabetes. Despite these important observations, the molecular mechanisms by which glucagon stimulates hepatic glucose production have been poorly understood. In a paper published in Nature, Rachel Perry, PhD, Gerald Shulman, MD, PhD, and their colleagues across YSM demonstrated that glucagon stimulates hepatic glucose production primarily by stimulating intrahepatic lipolysis through the actions of the inositol triphosphate receptor 1 (INSP3R1). These important basic observations on the regulation of hepatic glucose production by glucagon have implications for the pathogenesis of diabetes; and also suggest that INSP3R1 may represent a drug target for nonalcoholic fatty liver disease and type 2 diabetes.
A Retirement and a Farewell
The academic year also saw the retirement of one of the field’s most important researchers. Gary Cline, PhD, professor (endocrinology); director, Analytical Core, Mouse Metabolic Phenotyping Center; and co-director, Clinical Metabolism Core, Yale Diabetes Research Center, retired effective July 1, 2021. Cline has been an important member of the metabolism research community at Yale and across the world. He has had longstanding partnerships with members of the Endocrine Section to develop innovative techniques combining classical and novel metabolic tracers with advanced imaging techniques. These new methods in turn, have allowed detailed study of metabolic pathways in animal models and in people. Cline's efforts have helped us better understand basic processes of carbohydrate and fat metabolism and how normal physiology becomes dysregulated in such diseases as diabetes and obesity. Ultimately, these studies will be key building blocks toward better therapies for patients, says Section Chief Wysolmerski.
The section also mourned the loss of Arthur Broadus, MD, PhD, who helped train scores of endocrinology fellows over the years and launched the careers of many junior faculty who have gone on to their own leadership positions in academic medicine, industry, and clinical practice. Of all his scientific accomplishments, Broadus was perhaps best known for solving a longstanding mystery: why patients with certain types of cancer develop dangerously elevated blood calcium levels, a syndrome known as malignancy-associated hypercalcemia. His investigations led in 1987 to the isolation from tumor samples of a new hormone named parathyroid hormone-related protein or PTHrP.
The past months encompassing the COVID-19 pandemic have been challenging for academic medicine; the Endocrine & Metabolism Section met those challenges and thrived in many ways despite the physical and social isolation that kept the faculty and staff from interacting in their usual ways. Traditionally, the community has gathered together at Friday conferences to share in the solving of Clinical Dilemmas and to learn about the latest science related to endocrinology and metabolism at Endocrine Grand Rounds. After being completely online for the last academic year, in September 2021 we marked the return of a hybrid version of these conferences that includes a small in-person masked gathering with simultaneous and interactive Zoom-casting to a wider audience. Small steps but happy progress back towards normal.
To learn more about the Section of Endocrinology & Metabolism, visit medicine.yale.edu/intmed/endocrin/.
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