UCSF has a long history at the forefront of diabetes research, and today, basic science and clinical research teams are continuing to lead the charge in the fight to advance scientific understanding, treatment options and ultimately a cure for the disease.
The UCSF Diabetes Center unites research, clinical care and education in a comprehensive program dedicated to all forms of diabetes, a disorder that develops when the body’s immune system disrupts the way insulin regulates blood sugar. The most common forms of the disease are type 1 and type 2.
In type 1 diabetes, which is often diagnosed in children, the immune system destroys the pancreatic beta cells that make insulin. In type 2, impaired use of insulin in the body is coupled with reduced production of insulin in the pancreas. Type 2, which is linked to obesity, is far more prevalent, and is affecting increasing numbers of people.
Jeffrey Bluestone, PhD, UCSF executive vice chancellor and provost, spoke at the 10th anniversary celebration of the comprehensive UCSF Diabetes Center in 2010.
“What we have learned in the last decade and a half is absolutely amazing,” says Matthias Hebrok, PhD, director of the Diabetes Center. He ticks off a list of some of the accomplishments that contribute to the body of knowledge important for developing new therapies: learning how to generate beta cells; defining the master gene that controls autoimmune T cells; and creating a roadmap for deriving beta cells from human stem cells with the goal of then transplanting these new cells into patients.
“We are clearly moving toward a rational strategy of developing beta cells,” Hebrok says. A good supply of beta cells, and a good method for getting them into the bodies of patients with diabetes, would be a major step forward. But the problem of the immune system’s rejecting those cells must also be addressed, and much of the research efforts is focused there as well.
“The cure will have to do both,” Hebrok says. “It will have to create more beta cells, and it will have to block the immune system from destroying them.”
Type 1 diabetes is an autoimmune disease in which the immune system, instead of doing its intended job, turns against the body. Researchers continue to discover genes that may serve as critical markers in the development of immune disorders, and many of the most significant discoveries in understanding the disease mechanisms were made in the labs of the UCSF Metabolic Research Unit, established in 1949, and the UCSF Hormone Research Institute, established in 1956.
Supporting UCSF’s clinical research is the Immune Tolerance Network (ITN), an international consortium of more than 1,000 of the world's leading scientific researchers and clinical specialists who focus on testing new therapies for autoimmune diseases such as type 1 diabetes. Jeffrey Bluestone, PhD, an immunobiologist who is UCSF executive vice chancellor and provost, co-founded ITN.
Bluestone is a prominent leader in research to modify the response of key immune molecules in order to reduce harmful autoimmune attacks and boost the immune system’s protective capacity. Clinical trials sponsored by both ITN and the National Institutes of Health are now testing these strategies in type 1 diabetes patients and organ transplant recipients.
UCSF developed the method now in use at many clinical research sites to isolate and transplant insulin-secreting pancreatic beta cells into patients as a treatment for type 1 diabetes. Active research also is underway at UCSF to prod embryonic and adult stem cells into developing into beta cells, which thereby could provide an unlimited supply of these precious insulin-producing factories.
Patients with diabetes are at high risk for developing a number of complications, including destruction of kidney function, which had a direct impact on Bluestone and his family. “My father and mother both had diabetes,” Bluestone says. “My father ended up needing a kidney transplant and I ended up donating my kidney. And I realized at that moment that we need to do something about this disease. My aspiration from the very beginning was that we would put together a team that would be among the world leaders in trying to pull this off, and I think we have.”
UCSF research projects are tackling many aspects of diabetes, and they include:
Matthias Hebrok, PhD, director of the Diabetes Center
- Isolating pancreatic islets: Peter Stock, MD, PhD, and Andrew Posselt, MD, PhD, head the UCSF solid organ pancreas transplant program and pancreatic islet cell program. This work is supported by a state-of-the-art facility at UCSF to isolate pancreatic islets. “When you think of stem cell therapy, this is one that makes total sense,” says Stock, referring to strategic UCSF research efforts to develop stem cells as sources of pancreatic islets, which would then be transplanted into patients. “If we could get more and better beta cells and then transplant these without any rejection problems, we’d have a cure for diabetes.”
- Identifying the mechanisms that regulate development and regeneration of pancreatic beta cells: Michael German, MD — whose mentor, former UCSF Hormone Research Institute director William Rutter, PhD, led the team that cloned the human insulin gene and thereby helped make it possible to create synthetic insulin – has pioneered efforts to create a new source of insulin-producing beta cells. German, who is clinical director of the UCSF Diabetes Center, led a team focusing on a previously unexamined gene known as Rfx6. The researchers found the absence of this gene causes a complete absence of insulin, a vital insight for beta cell development and insulin production that may lead to new drugs. Another study led by German made a surprising discovery: The cause of diabetes during pregnancy is regulated by the neurotransmitter serotonin, which is influenced by the amount of protein in the mother’s diet early in her pregnancy. A research group headed by Diabetes Center Director Hebrok is studying signals that regulate the development of insulin-producing beta cells during embryogenesis (the process of embryo formation). His group also is exploring the signals that control the regeneration of beta cells in adult animals to test whether expansion of existing beta cells poses a possible alternative for treatment of diabetic patients. In earlier research, German and Hebrok created a roadmap for deriving beta cells from human stem cells.
- Controlling autoimmune cells: Mark S. Anderson, MD, PhD, defined a master gene — named the AIRE gene because it is an autoimmune regulator — that controls autoimmune T cells. An endocrinologist, Anderson sees great hope in the recent discovery that the AIRE gene — long thought to be produced only in the thymus gland — is also produced in another cell outside the thymus. “We’re looking for ways to exploit that cell to turn off diabetes,” he says.
- Leptin and insulin resistance: Allison Xu, PhD, leads a lab at UCSF studying the way neural pathways in the brain affect people’s diets and ultimately their insulin production. Xu wants to tackle the biological causes of obesity, which is one of the leading causes of type 2 diabetes, the most common and fastest-growing form of diabetes. Her work follows on that of her colleague Christian Vaisse, MD, PhD, who discovered the defective genes that can cause obesity and type 2 diabetes. Xu says obesity is a result of a complex mix of genetics and environment, and she is focusing on the hormone leptin, which is produced in the body’s fatty tissues and regulates diet. In an age of “food overabundance,” Xu says, the hormone has not adjusted, and instead, some obese people have developed a leptin resistance. She sees this in lab mice that become obese and develop leptin resistance when placed on a high-fat diet. According to Xu, successful disruption of the signal pathways involved in leptin resistance could help people lose weight and possibly defeat type 2 diabetes. “Leptin resistance and insulin resistance almost always go hand in hand,” she says. “We think they share a common pathway, but there could be some differences. We need to do more basic research.”
- Role of fat tissue in diabetes: Arriving in May 2011 from Harvard, Shingo Kajimura, PhD, will continue studies on the role of brown fat tissue and white fat tissue in diabetes, which Hebrok says is becoming more important as diabetes research expands into studying obesity. Kajimura will be part of the research group based in the new Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research building on the Parnassus campus.
- Fatty acids and the immune system: UCSF clinical fellow Suneil Koliwad, MD, is studying how different fatty acids can affect the activation stage of macrophages, which are cells that work in the immune system. Koliwad’s research may ultimately help prevent a common complication of obesity, since chronic inflammation is linked to insulin resistance and diabetes. Koliwad currently is based at the J. David Gladstone Institutes, an independent, nonprofit biomedical research foundation affiliated with UCSF and adjacent to its Mission Bay campus, and will join the Diabetes Center as a faculty member in early 2011.
- Stem cells as a source of insulin-secreting cells: In its continuing quest to translate discoveries from labs to patients, UCSF has partnered with ViaCyte, a preclinical therapeutic company based in San Diego that is focused on diabetes. ViaCyte received a $20 million Disease Team Award from the California Institute for Regenerative Medicine, of which a UCSF team led by Bluestone received $2.8 million. The grant will enable stem cell researchers to work on developing an alternative to insulin injections by producing cells – similar to the cells that the immune system has destroyed – that secrete insulin in patients.