Molecular Link between Obesity and Type 2 Diabetes Reveals Potential Therapy

Inflammatory molecule LTB4 promotes insulin resistance in obese mice and blocking the LTB4 receptor prevents and reverses type 2 diabetes in this model —

Obesity causes inflammation, which can in turn lead to type 2 diabetes. What isn’t well established is how inflammation causes diabetes — or what we can do to stop it. Researchers at University of California, San Diego School of Medicine have discovered that the inflammatory molecule LTB4 promotes insulin resistance, a first step in developing type 2 diabetes. What’s more, the team found that genetically removing the cell receptor that responds to LTB4, or blocking it with a drug, improves insulin sensitivity in obese mice. The study is published Feb. 23 by Nature Medicine. … Read the full story from the UC San Diego Newsroom


Dr. Jerrold OlefskyStudy senior author Jerrold M. Olefsky, MD, is professor of medicine in the Division of Endocrinology and Metabolism and associate dean for scientific affairs for the University of California, San Diego, School of Medicine.

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The Connection Between Oxygen and Diabetes

A lack of O2 in fat cells triggers inflammation and insulin resistance in obesity:

Researchers at the University of California, San Diego School of Medicine have, for the first time, described the sequence of early cellular responses to a high-fat diet, one that can result in obesity-induced insulin resistance and diabetes. The findings, published in the June 5 issue of Cell, also suggest potential molecular targets for preventing or reversing the process.

Dr. Jerrold Olefsky“We’ve described the etiology of obesity-related diabetes. We’ve pinpointed the steps, the way the whole thing happens,” said Jerrold M. Olefsky, MD (left), associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego. “The research is in mice, but the evidence suggests that the processes are comparable in humans and these findings are important to not just understanding how diabetes begins, but how better to treat and prevent it … Read the full story from the UC San Diego Newsroom

A New Protein Target for Controlling Diabetes

Researchers at the University of California, San Diego School of Medicine have identified a previously unknown biological mechanism involved in the regulation of pancreatic islet beta cells, whose role is to produce and release insulin. The discovery suggests a new therapeutic target for treating dysfunctional beta cells and type 2 diabetes, a disease affecting more than 25 million Americans. … Read the full story from the UCSD Newsroom


Dr. Jerrold OlefskyPrincipal Investigator Jerrold M. Olefsky, MD, is Associate Dean for Scientific Affairs and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism.

Study report coauthors from the Department of Medicine are Hui Dong, PhD, associate professor of medicine in the Division of Gastroenterology; and Yun Sok Lee, Hidetaka Morinaga, and William Lagakos in the Division of Endocrinology and Metabolism.

Citation for the report: Yun Sok Lee, Hidetaka Morinaga, Jane J. Kim, William Lagakos, Susan Taylor, Malik Keshwani, Guy Perkins, Hui Dong, Ayse G. Kayali, Ian R. Sweet, Jerrold Olefsky. The Fractalkine/CX3CR1 System Regulates β Cell Function and Insulin Secretion. Cell – 11 April 2013 (Vol. 153, Issue 2, pp. 413-425)  |  Read the report summary

Other Recent UCSD News Stories about Dr. Olefsky’s Work

Knocking Out Key Protein in Mice Boosts Insulin Sensitivity

By knocking out a key regulatory protein, scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity in lab mice, an achievement that opens a new door for drug development and the treatment of diabetes…. Read the full story from the UCSD Newsroom

Dr. Jerrold Olefsky

Senior author of the study is Jerrold M. Olefsky, MD, pictured above. Dr. Olefsky is Associate Dean for Scientific Affairs, UC San Diego Health Sciences, and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism.  | Read the summary of the study report in Cell

Dr. Seth Field Elected to the American Society for Clinical Investigation

Dr. Seth FieldSeth J. Field, MD, PhD, Associate Professor of Medicine in the Division of Endocrinology and Metabolism, has been elected to the American Society for Clinical Investigation (ASCI).

ASCI membership is a distinction that recognizes the nation’s most outstanding physician-scientists.

“Seth is a highly innovative biomedical researcher, a caring clinician, and a teacher who devotes himself to mentoring learners at all levels,” said Wolfgang Dillmann, MD, Professor and Interim Chair of the Department of Medicine, who supported Dr. Field’s nomination. “He embodies the ideals of the ASCI.”

“It has been a pleasure to watch Seth’s career take off and succeed at UCSD,” said Jerrold M. Olefsky, MD, who proposed Dr. Field’s nomination. “He’s an outstanding and incisive scientist who still manages to be an exceptional clinician and teacher.”

Dr. Olefsky is Associate Dean for Scientific Affairs and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism.

Dr. Field has earned international recognition and major extramural funding for his original research. His investigations focus on the metabolism and signaling pathways of phosphoinositides, a group of lipid signaling molecules implicated in the pathophysiology of a range of human diseases.  |  Visit his laboratory website

“His findings,” said Dr. Dillmann, “have catalyzed a major paradigm shift in our understanding of the export of proteins from the cell.”

In 2009, Dr. Field and coworkers discovered that the Golgi protein GOLPH3 binds to phosphatidylinositol-4-phosphate in the trans-Golgi membranes and connects the Golgi to F-actin via binding the unconventional myosin MYO18A. The resulting tensile force plays an important role in the secretory pathway by drawing vesicles and tubules from the Golgi. In the process, the Golgi apparatus acquires its characteristic stretched and flattened shape.

Dr. Field and colleagues reported the finding in the journal Cell in October 2009. The discovery, announced in a UC San Diego press release, earned worldwide attention.  |  Read the report in Cell (free full text)

Now, in one of many subsequent studies, Dr. Field is examining how GOLPH3 may function to cause cancer and whether there are potential therapeutic targets in the GOLPH3 pathway. GOLPH3 has been identified as a cancer gene commonly associated with human cancers, including breast cancer.

This work is supported by a 5-year, $3.8 million Era of Hope Scholar Award for Breast Cancer Research he received last year from the US Army Medical Research and Materiel Command.

Dr. Field collaborated with Judith A. Varner, PhD, and coworkers in the tumor inflammation studies reported in the June 14, 2011, issue of the journal Cancer Cell. They have identified a single point at which myeloid cells are triggered to enter cancer cells and promote tumor growth: the PI-3 kinase-gamma enzyme. The report, pinpointing what may be an important new therapeutic target for cancer treatments, was highlighted in a mini-review in the same journal.  |  Read the report in Cancer Cell (free full text)

Dr. Field has also collaborated with Dr. Ronald Evans and coworkers in the Gene Expression Laboratory at the Salk Institute for Biological Studies in defining a novel negative feedback pathway for insulin signaling. The results identify a new target area for the development of insulin-sensitizing drugs.

In 2008, Dr. Field was honored with an NIH Director’s New Innovator Award, a five-year, $ 2.3-million research grant. Recipients of the NIH Director’s New Innovator Award are selected for the exceptional creativity and potential impact of their research.

In an earlier honor that brought major funding, the Burroughs Wellcome Fund granted Dr. Field a Career Award in the Biomedical Sciences in 2004. The five-year, $500,000 career awards are given to support outstanding postdoctoral researchers in their transition from advanced training to academic faculty service. The funding supported Dr. Field’s project, “Comprehensive analysis of phosphoinositide function.”

An active teacher in the Department of Medicine’s education programs, Dr. Field is also a member of the teaching and research faculty of the UC San Diego Biomedical Sciences Graduate Program. In addition, he is an investigator in the Cancer Biology program at the UC San Diego Moores Cancer Center.

Dr. Field received his MD degree from Harvard Medical School and his PhD in Genetics in the laboratory of Michael E. Greenberg, PhD, at Harvard. After his internship and residency in internal medicine at the Hospital of the University of Pennsylvania, he completed his fellowship in endocrinology at the Massachusetts General Hospital.

He returned to Harvard for his postdoctoral research training in cell biology and systems biology in the laboratory of Lewis C. Cantley, PhD. In 2005, he joined the UC San Diego Department of Medicine faculty as an assistant professor in the Division of Endocrinology and Metabolism.

Dr. Field and the other honorees for 2011, including Dr. Maike Sander from UC San Diego’s Department of Pediatrics, were introduced April 16 at the annual joint meeting of the ASCI and the Association of American Physicians in Chicago.

With the addition of Dr. Field, the ASCI now includes 63 current members of the faculty of the Department of Medicine.

Endocrinology Researchers Uncover New Hope for Treating Type 2 Diabetes

Dr. Jerrold OlefskyDr. Jerrold M. Olefsky and colleagues have reported a discovery that suggests a new way to treat obesity-related insulin resistance and Type 2 diabetes.

In a laboratory study, they found that insulin resistance could be reversed by lowering the amount of adipose tissue macrophages (ATMs) in tissue.

ATMs normally help fight infection, but in obesity they accumulate in fat tissue and can become triggers for inflammation. The inflammation is a factor in the development of insulin resistance and Type 2 diabetes.

Jerrold M. Olefsky, M.D., is Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism and Associate Dean for Scientific Affairs. Co-leader of the study is Jaap Neels, Ph.D., a former UCSD colleague.


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Health Sciences Communications


Their Division of Endocrinology and Metabolism coauthors are researchers David Patsouris, Ph.D., Ping-Ping Li, and Divya Thapar.

The report is published in the October 8 issue of the journal Cell Metabolism. The full citation:

Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008 Oct;8(4):301-309. Read the article abstract

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