Genetic Tools Help Identify a Cellular Culprit for Type 1 Diabetes
May 19, 2021 | Scott LaFee
By mapping its genetic underpinnings, researchers at University of California San Diego School of Medicine have identified a predictive causal role for specific cell types in type 1 diabetes, a condition that affects more than 1.6 million Americans.
The findings are published in the May 19, 2021 online issue of Nature
Type 1 diabetes is a complex autoimmune disease characterized by the impairment and loss of insulin-producing pancreatic beta cells and subsequent hyperglycemia (high blood sugar), which is damaging to the body and can cause other serious health problems, such as heart disease and vision loss. Type 1 is less common than type 2 diabetes, but its prevalence is growing. The U.S. Centers for Disease Control and Prevention projects 5 million Americans will have type 1 diabetes by 2050. Currently, there is no cure, only disease management.
The mechanisms of type 1 diabetes, including how autoimmunity is triggered, are poorly understood. Because it has a strong genetic component, numerous genome-wide association studies (GWAS) have been conducted in recent years in which researchers compare whole genomes of persons with the same disease or condition, searching for differences in the genetic code that may be associated with that disease or condition.
In the case of type 1 diabetes, identified at-risk variants have largely been found in the non-coding regions of the genome. In the Nature study, senior author Kyle Gaulton, PhD, an assistant professor in the Department of Pediatrics at UC San Diego School of Medicine, and colleagues integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas. Epigenomic mapping details how and when genes are turned on and off in cells, thus determining the production of proteins vital to specific cellular functions.
Specifically, researchers performed the largest-to-date GWAS of type 1 diabetes, analyzing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.
“By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally,” said Gaulton. Continue Reading...
UC San Diego Receives $9 Million in Grants to Pinpoint Cellular Cause of Type 1 Diabetes
August 13, 2019 | Yadira Galindo
University of California San Diego School of Medicine researchers have been awarded nearly $9 million to fund two multi-institutional research projects that use human pluripotent stem cells, CRISPR and human organoids to dissect beta cell defects and create a human cell model of type 1 diabetes aimed at identifying the elusive cellular actions leading to disease onset.
“We are using technology that, for the first time, allows us to create human conditions that mimic type 1 diabetes in a culture dish in order to understand the mechanism or genes by which beta cells are killed,” said Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine and co-principal investigator on both grants. “Our hope is that we can generate the information we need to eventually make beta cells survive in people living with type 1 diabetes.”
Two multi-year special statutory grants from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (NIH), help build on ongoing research into type 1 diabetes, an autoimmune disease that destroys pancreatic beta cells and affects more than 1 million people in the United States. Pancreatic beta 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 reduces insulin production, leading to types 1 and 2 diabetes.
A $3.8 million grant funds work co-led by Sander and Kyle Gaulton, PhD, assistant professor in the Department of Pediatrics and the Pediatrics Diabetes Research Center, to decipher the function of genes associated with genetic risk for type 1 diabetes using a high resolution reference map of pancreatic cells. Sander, Gaulton and colleagues are designing the map after receiving an NIH grant in 2018.
“A unique aspect of this project is to determine how pancreatic beta cells are affected in type 1 diabetes through a combination of both your genes and your environment,” said Gaulton, who brings expertise in genetics and genomics of diabetes into the project. “Our goal is to identify genes that protect beta cells from immune responses that occur during the development of type 1 diabetes, and which may represent novel therapeutic targets in preventing disease onset.”
After identifying genes associated with beta cell function, the team, including Prashant Mali, PhD, assistant professor in the Department of Bioengineering at UC San Diego Jacob School of Engineering, Wenxian Fu, PhD, assistant professor in the Department of Pediatrics and the Pediatrics Diabetes Research Center, and Graham McVicker, PhD, assistant professor at the Salk Institute, will use CRISPR to validate which genes are promoting cell survival and which are causing cell death.
This information can then be tested using an islet-on-a-chip (human organoid) being developed with the second $5.1 million NIH grant to study the immune attack on beta cells in the dish. Human organoids are miniaturized, 3D versions of an organ.
In this case, human induced pluripotent stem cells (hiPSC) from persons with type 1 diabetes are converted into beta cells and supporting cells in the lab to create the human islet organoid. Sander is collaborating with Karen Christman, PhD, professor in the Department of Bioengineering, Luc Teyton, MD, PhD, professor in the Department of Immunology and Microbiology at Scripps Research, Steven George, MD, PhD, professor in the Department of Bioengineering at UC Davis, and Christopher C.W. Hughes, PhD, professor in the Department of Molecular Biology and Biochemistry at UC Irvine.
At UC Irvine, the Hughes lab has created an organ chip that allows living blood vessels to provide nutrients to tissues growing in the lab.
“We are growing human islets in culture that are supported (that is, fed) by perfused human blood vessels. All organs in the body receive their nutrients through blood vessels and we are capturing this process in the lab,” said Hughes. “Under these conditions, we expect the islets to behave much more like they do in the body than if we had grown them using standard procedures, which have not changed much in the last 30 years.”
Immune cells from the blood of the same person whose hiPSC were used to induce beta cells in the human organoid will be fed into the organoid to watch the immune system response to the beta cells.
“We will activate and deactivate genes we think are involved in whether beta cells live or die. We want to know what causes the attack on beta cells because no one has been able to identify it,” said Sander, who is also director of the Pediatric Diabetes Research Center, co-director of the Center on Diabetes in the Institute of Engineering in Medicine and a member of the Sanford Stem Cell Clinical Center. “We recognize that people who are living with type 1 may still have beta cells. If we can rescue those cells we may be able to help with blood glucose management and provide a clinical improvement.”
In a multi-institutional research project, UC San Diego School of Medicine researchers have teamed up to create a human cell model of type 1 diabetes that includes a vascularized human pancreatic islet in a dish. Pictured are blood vessels in green and islets (cell nuclei) in magenta.
Macrophages Influence Both the Replication and Function of Beta Cells
January 04, 2019 --Yadira Galindo
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?
In the journal Cell Metabolism, Wenxian Fu, PhD, assistant professor of pediatrics, Jerrold Olefsky, MD, professor of medicine at UC San Diego School of Medicine, and colleagues reported distinct functions of obesity-associated inflammation in pancreatic islets. Also called islets of Langerhans, pancreatic islets are the regions of the pancreas that make and secrete hormones like insulin.
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.
Mapping the Pancreatic Islets
October 24, 2018 --Yadira Galindo
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.
"A human cell atlas of type 1 diabetes would help us understand what is happening in the pancreas, allowing us to reconstruct cell signaling networks so that we can see what leads to destruction of insulin-producing cells," said Maike Sander, MD, professor in the Departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine, director of the Pediatric Diabetes Research Center and co-principal investigator on the grant. "We have a good idea of how type 1 diabetes develops in mouse models. Mice have been cured many times, but there are substantial differences with human disease so we have to analyze human tissue."
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.
Red is Insulin-producing beta cells in pancreas.
The multi-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH), teams Sander, an expert in islet biology and diabetes, with Kyle Gaulton, PhD, assistant professor in the Department of Pediatrics and the Pediatrics Diabetes Research Center, who brings expertise in genetics and genomics of diabetes, as well as David Gorkin, PhD, and Sebastian Preissl, PhD, associate directors of the UC San Diego Center for Epigenomics, directed by Bing Ren, PhD, professor of cellular and molecular medicine. The Center for Epigenomics will provide the state-of-the-art technology needed to analyze biobank tissue from people with type 1 diabetes needed to create the cell atlas.
"The goal is to fully understand which immune cells and other cell types populate the pancreas when beta cells are destroyed," said Ren. "By generating a comprehensive map of pancreatic cells using cutting-edge epigenomic technologies, we may reveal critical interactions leading to the onset of type 1 diabetes."
Using samples from the NIH’s Network for Pancreatic Organ Donors with Diabetes (nPOD), the team is employing epigenomic technology to analyze tissue at the single cell level. The information is a critical piece needed by a consortium of diabetes experts, the NIDDK Human Islet Research Network, of which Sander is a contributing investigator, to find innovative strategies to protect or replace functional beta cell mass in people living with diabetes.
"By generating an atlas of pancreatic cells from non-diabetic and type 1 diabetic individuals, we may identify novel biomarkers of disease that can inform strategies for early intervention or treatment," said Gaulton. "Together our findings may provide key insights into the pathogenic processes of cells in the pancreatic micro-environment that lead to beta cell loss in type 1 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