Researchers at UC San Diego School of Medicine have identified new roles for specialized immune cells called macrophages that impact insulin-producing beta cell function. Targeting these immune cells could lead to the development of novel therapeutic strategies for preventing obesity-associated beta cell functional impairment.
Relative insulin insufficiency — the inability to compensate for insulin resistance — has been known and discussed for many years. This phenomenon beckons the question, why is that insulin-producing beta cells in mice and humans, who are insulin-resistant and become hyperglycemic, do not increase insulin secretion to fully compensate for resistance and keep glucose levels within a normal range?
Using animal models for human obesity and type 2 diabetes, researchers found that macrophages influence both the replication and function of beta cells and identified the signaling pathways that mediate crosstalk between macrophages and beta cells. They found that obesity increased the capacity of macrophages to "eat" more insulin granules from beta cells. This finding not only provides an explanation of beta cell functional impairment, but may also lead to potential therapies by targeting cell to cell communication between macrophages and beta cells.
Future work will evaluate whether the findings from these animal studies can be repeated in human samples and whether macrophages in human pancreatic islets play similar roles. The long-term goal is to restore beta cell function and prevent type 2 diabetes by harnessing macrophages.
The mechanism leading to development of type 1 diabetes remains a mystery, hampering the ability to find new ways to prevent, treat or even cure this condition. With a new $3.3 million grant, University of California School of Medicine researchers hope to create a high resolution reference map of pancreatic cells that will identify molecular changes that arise during type 1 diabetes.
In the United States, 1.25 million people live with type 1 diabetes, an autoimmune disease that destroys pancreatic beta cells. These cells, found in groups called islets of Langerhans, help maintain normal blood glucose levels by producing the hormone insulin — the master regulator of energy (glucose). Impairment and the loss of beta cells interrupts insulin production, leading to type 1 and 2 diabetes.
Specialized Macrophages May Play a Role in Type 1 Diabetes
December 8, 2017
Type 1 diabetes is an autoimmune disease that develops when a person’s own immune system mistakenly attacks beta cells, the body’s insulin-producing cells. Each year, an estimated 40,000 people are diagnosed with this disease in the United States. People with type 1 diabetes require life-long insulin treatment. Poor glucose management can lead to medical emergencies that result in hospitalization and early death.
In a paper recently published in the journal eLife, University of California San Diego School of Medicine researchers identified a potential role of the protein complement receptor of immunoglobulin family (CRIg) in type 1 diabetes. In mouse models, the expression of CRIg on tissue resident macrophages — specialized immune cells that play a variety of roles including the initiation and resolution of inflammation — resulted in the formation of a protective barrier surrounding pancreatic islets. These barriers protect insulin-producing beta cells from immune attack.
CRIg+ macrophages (red) block the invasion of pathogenic cells (blue) into the islets of Langerhans during the development of autoimmune type 1 diabetes.
“These findings reveal a novel mechanism by which tissue-resident macrophages regulate T cell activities,” said Wenxian Fu, PhD, senior author and assistant professor in the Department of Pediatrics. “CRIg is a molecular link between environmental cues and adaptive immunity that regulates tissue inflammation and immune tolerance.”
Fu and team demonstrated that gut microbiota instruct macrophages to express CRIg, which potently blocks the devastating autoimmunity effects in type 1 diabetes. Targeting CRIg could have clinical implications if it could be used to develop new and more effective therapies for this disease, said Fu.
Macrophages expressing CRIg are amply present in other gastrointestinal organs, including the liver and intestines in both humans and mice. Reduced levels of these macrophages could be associated with exacerbated tissue inflammation in multiple inflammatory conditions. Therefore, identifying what signals induce or suppress the expression of CRIg in tissue-resident macrophages is important to better understand how these macrophages sense environmental signals and in turn orchestrate the activities of T cells.
Pathways Leading to Beta Cell Division Identified, May Aid Diabetes Treatment
May 2, 2017 -- by Yadira Galindo
Pancreatic beta cells help maintain normal blood glucose levels by producing the hormone insulin — the master regulator of energy (glucose). Impairment and the loss of beta cells interrupts insulin production, leading to type 1 and 2 diabetes. Using single-cell RNA sequencing, researchers at University of California San Diego School of Medicine have, for the first time, mapped out pathways that regulate beta cell growth that could be exploited to trick them to regenerate.
The findings are published in the May 2 issue of the journal Cell Metabolism.
“If we can find a drug that makes beta cells grow, it could improve blood sugar levels in people with diabetes,” said Maike Sander, MD, professor in the Department of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine. “These people often have residual beta cells but not enough to maintain normal blood glucose levels.”
Researchers at UC San Diego School of Medicine identified pathways that regulate pancreatic beta cell (pictured in green) growth. These cells help maintain normal blood glucose levels by producing the hormone insulin.
The body generates beta cells in utero and they continue to regenerate after birth, but as people age, cell regeneration diminishes. The predominant way to grow new beta cells is through cell division, but beta cells capable of dividing are rare, compromising less than 1 percent of all beta cells. Scientists have been investigating molecular pathways that govern beta cell growth in hopes of finding new therapies that would help people regain blood glucose control after the onset of diabetes.
“No one has been able to do this analysis because the 1 percent or less of beta cells that are dividing are masked by the 99 percent of beta cells that are not dividing,” said Sander. “This in-depth characterization of individual beta cells in different proliferative states was enabled by newer technology. It provides a better picture of what sends beta cells into cell division and clues we can use to try to develop drugs to stimulate certain pathways.”
Whether stimulating beta cells to grow will result in therapeutic interventions for diabetes is still to be seen, but this new information opens the door to find out, said Sander.
Co-authors include: Chun Zeng, Francesca Mulas, Yinghui Sui, Tiffany Guan, Yuliang Tan, Fenfen Liu, Wen Jin, Andrea C. Carrano, and Gene W. Yeo, UC San Diego; Nathanael Miller, and Orian S. Shirihai, UC Los Angeles; and Mark O. Huising, UC Davis.
This research was funded, in part, by the National Institutes of Health (DK068471, DK078803) and an Iacocca Family Foundation fellowship.
Type 1 Diabetes Symposium: Combining Medicine & Engineering
On January 19, 2017, the UC San Diego Pediatric Diabetes Research Center (PDRC) and the Institute of Engineering in Medicine (IEM) hosted a full day symposium entitled "Type 1 Diabetes: New Technologies and Therapeutics". There were more than 180 registrants from as far as Munich, and expert speakers from around the country and from here in San Diego. The meeting was unusual, in that it convened experts with engineering perspectives on diabetes therapy, alongside experts pursuing biological research and treatment approaches.
"I have received numerous comments from attendees about how much they enjoyed hearing about both engineering- and medicine-based approaches to diabetes therapies" says Dr. Maike Sander, Director of the Pediatric Diabetes Research Center.
The symposium started with a keynote presentation by Carla Greenbaum, M.D. from the Benaroya Research Institute in Seattle. Dr. Greenbaum is the coordinator of multiple clinical trials for type 1 diabetes, and she set the stage for the symposium by providing an overview of what is known about disease progression and clinical challenges.
The first session focused on recent developments in the generation of an artificial pancreas, a version of which has recently been approved by the FDA and entering clinical use. This session included talks from: Edward Damiano, Ph.D. from Boston University, on insulin and glucagon control with the artificial pancreas; Dr. Francis Doyle, Ph.D., from Harvard, on the design of algorithms to control the artificial pancreas; David Gough, Ph.D., from UC San Diego, on a new generation of fully implanted, long-term glucose sensors that need only infrequent recalibration; and Howard Zisser, M.D., from UC Santa Barbara, who gave a clinical perspective, history, and overview of artificial pancreas applications.
The program then turned to potential stem cell therapies, aspects of which are still at the level of applied research and far from routine use in the clinic, but hold substantial promise. Jeremy Pettus, M.D., from UC San Diego, described the recent clinical trial with stem-cell derived islets encapsulated devices under way here in San Diego. Clark Colton, Ph.D., from MIT, reviewed progress on developing methods for supplying the necessary oxygen to implanted islet cell devices. Duc S. Dong, Ph.D., from the Sanford Burnham Presbys Medical Discovery Institute, spoke about generating replacement beta cells in vivo by conversion of cell lineages.
The final session focused on pancreatic regeneration, an exciting possibly curative approach, which is still in early preclinical stages. Teresa Rodriguez-Calvo, DVM, PH.D., of the La Jolla Institute for Allergy and Immunology, spoke about approaches to increase proinsulin production and preserve beta cells, followed by Neal Devaraj, Ph.D., UC San Diego, who spoke about the creation of markers for imaging of beta cells. Maike Sander, M.D. of UC San Diego, then described novel pathways for expanding beta cell mass, and Bryan Laffitte, Ph.D., of the Novartis Research Foundation, spoke about pharmaceutical approaches for stimulating beta cell proliferation.
Overall, the speakers covered a broad range of topics all tied together by their potential for application to diabetes therapy. It was consensus that the environment in La Jolla with UC San Diego, neighboring research institutes, and local biotechnology and pharma companies provides a fertile ground for interdisciplinary research, innovation, and clinical translation. The meeting was supported by a conference grant from JDRF and sponsorships from San Diego companies including Dexcom, GlySens, and Novo Nordisk, IEM and the PDRC.
The NIH Awards PDRC Researchers, Drs. Maike Sander, and Kyle Gaulton, and UCSD Colleagues $3.3 Million to Link T1D to its Genetic Origins
October 24, 2016 -- “We know there is a genetic component to type 1 diabetes,” said Sander, director of the Pediatric Diabetes Research Center. “Some people have bad genetics leading them to be more prone to develop this disease. The key is to study the human condition and human cells to understand type 1 diabetes from the genes up.”
Sander and colleagues were awarded $3.3 million to link type 1 diabetes to its genetic origins. Previous studies have identified heritable risk factors, but the complexity of the disease allows for many different genetic variants among people with diabetes. This research will focus on identifying where the genetic risks are expressed, what variants are associated with them and what cellular processes are regulated. To do this, the team proposes to combine the latest computational methods, high-throughput molecular assays and human pluripotent stem cells-based cell models.
“No one has done this before,” said Sander. “We want to identify new therapeutic targets for the prevention and treatment of type 1 diabetes by mapping out the mechanisms by which this disease begins. This is an approach that requires collaboration between researchers from multiple disciplines.” Read more
JDRF Funds PDRC Researcher to Investigate Early Biomarkers in Type 1 Diabetes
May 2016 -- JDRF has selected PDRC researcher, Dr. Ulupi Jhala, to receive an innovative grant to investigate early blood borne biomarkers associated with autoimmune destruction of beta cells in type 1 diabetes (T1D). Currently there are no known biomarkers that can be used to predict the development of T1D. In fact, by the time T1D is diagnosed, widespread beta cell destruction has already occurred, greatly diminishing the body’s ability to produce insulin and resulting in a near total dependence on the external administration of insulin. Preserving even a small capacity for making insulin could mean the difference between life and death.
Dr. Jhala has developed an innovative model to replicate early events of beta cell destruction in a petri dish. During the course of destruction, beta cells release a class of highly stable and highly specific biomarkers which makes them easier to identify.
“This type of biomarkers”, says Dr Jhala,
“is already being used to successfully detect pregnancy and prostate cancer.”
By identifying a set of biomarkers that are the first to be shed from the surface of a dying beta cell, Dr. Jhala’s research offers the potential for developing highly effective, routine and inexpensive diagnostic screenings for pre-symptomatic people at risk for T1D.
PDRC Researchers Receive Grant From The Helmsley Charitable Trust to Identify Drugs for Stimulating Beta Cell Regeneration
April 2016 -- Professor Maike Sander, M.D., Director of the Pediatric Diabetes Research Center has been awarded a two-year grant from the Helmsley Charitable Trust to validate a new pharmacological target for stimulating beta cell regeneration. Preserving even a small fraction of beta cells and hence insulin production has huge benefits for patients with type 1 diabetes. Drugs that could increase beta cell numbers would have a tremendous clinical impact on type 1 diabetes.
The Sander laboratory recently identified a novel protein that controls the replication of human beta cells and thus could be a drug target to safely expand beta cells in patients with diabetes. With support by the Helmsley Charitable Trust, the team will partner with GNF-Novartis in San Diego to develop and test drugs for targeting this protein. They will transplant human beta cells into mice and determine whether injecting mice with the drug will stimulate expansion of the transplanted cells.
"Having pharmaceutical companies next door to UC San Diego is a huge advantage for moving new discoveries into the clinic" says Dr. Sander.
Researchers are hopeful that this work will translate into a new treatment for type 1 diabetes.
Dr. Kyle J. Gaulton Joins the PDRC
December 2015 -- The UC San Diego Pediatric Diabetes Research Center (PDRC) is pleased to welcome new faculty member, Kyle Gaulton, PhD. Dr. Gaulton comes from the Department of Genetics at Stanford University and will join the PDRC in January 2016.
Dr. Gaulton studies how genetic risk contributes to T1D and will work closely with scientists and clinicians at the Rady Pediatric Genomics and Systems Medicine Institute. His research will help identify novel strategies for preserving beta cells in patients at risk for T1D.
"Open" Stem Cell Chromosomes Reveal New Possibilities for Diabetes
April 2, 2015 -- Researchers map chromosomal changes that must take place before stem cells can be used to produce pancreatic and liver cells
Stem cells hold great promise for treating a number of diseases, in part because they have the unique ability to differentiate, specializing into any one of the hundreds of cell types that comprise the human body. Harnessing this potential, though, is difficult. In some cases, it takes up to seven carefully orchestrated steps of adding certain growth factors at specific times to coax stem cells into the desired cell type. Even then, cells of the intestine, liver and pancreas are notoriously difficult to produce from stem cells. Writing in Cell Stem Cell April 2, researchers at University of California, San Diego School of Medicine have discovered why. Read more