Vignettes highlighting research supported by the NIDDK over the past year that have opened new avenues for research and have the potential to profoundly affect our understanding of human health and disease.
Adult Pancreas Cells Reprogrammed to Insulin-producing Beta Cells
New research has taken a step closer to cell replacement therapy for diabetes. Scientists made an exciting discovery that some adult cells in the mouse pancreas, called exocrine cells, can be reprogrammed to become insulin-producing beta cells. Beta cells are at the center of the development of both type 1 and type 2 diabetes, and researchers are vigorously trying to find ways to replace damaged or destroyed beta cells in people with diabetes.
One way to approach this difficult task is to reprogram different adult cell types into beta cells. The pancreas is made up of many different cell types, of which exocrine cells are the most plentiful. To identify factors to reprogram exocrine cells, they focused on proteins called transcription factors, which regulate whether genes are turned on or off. Although over 1,100 transcription factors are known to be important in pancreatic development, the scientists limited their experiments to testing nine transcription factors of key importance, based on knowledge from earlier research on pancreatic development from embryonic to adult stages.
Using a genetically-engineered virus, they delivered a mix of the nine factors into pancreases of mice. By removing one factor at a time from the mix, the researchers identified a combination of just three transcription factors that reprogrammed some of the exocrine cells into beta cells. The newly-formed beta cells produced enough insulin to decrease high blood glucose levels in diabetic mice. This “reprogramming” appeared to occur directly from the exocrine cell type to the beta cell type, and the procedure did not require the addition of stem cells. If the same type of approach works in humans, this discovery could have a dramatic impact on the ability to increase beta cell mass in people with diabetes. While much work remains to be done before this becomes a safe and effective therapy, this adult cell reprogramming is a major step forward and serves as a model for other applications of regenerative medicine.
Zhou Q, Brown J, Kanarek A, Rajagopal J, and Melton DA: In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455: 627-632, 2008.
Back to Top
Consortium Identifies Six More Genetic Variants Affecting Likelihood of Type 2 Diabetes
Type 2 diabetes, by far the most common form of diabetes mellitus, is caused by a complex interaction of genes and the environment. Diabetes is much more common in some ethnic groups than in others, suggesting that genes may explain these health disparities. Type 2 diabetes is also strongly associated with obesity, but most of the genetic components identified so far are unrelated to factors influencing obesity. Indeed, most obese people do not develop diabetes, and some people with normal body weight do. Understanding the reasons why one person develops the disease and another does not is a critical research priority. However, until recently, there has been little definitive information about the genetic variants that predispose or protect a person from type 2 diabetes. In the last 2 years, three independent genome-wide association studies have employed powerful new genomic tools to identify 10 common genetic variants, each of which has a modest effect on the probability of a person developing type 2 diabetes.
Because a large sample size is required to uncover genetic variants that have relatively small effects, researchers from the three previous genome-wide association studies formed a consortium to combine their data to potentially identify additional type 2 diabetes genes. They also confirmed their results in samples from several other studies. The larger effective sample size—which combined genetic data from more than 70,000 people—provided the statistical power to identify 6 more common variants associated with an effect on the likelihood of developing type 2 diabetes, raising the known total to 16 genes. In the case of all of the new genes, and most of those previously identified, the precise genetic changes that influence the development of diabetes remain unknown—only their genetic neighborhood has been identified for certain. None of the new genetic variants were previously known to be associated with type 2 diabetes. Interestingly, the new gene that was most strongly associated with risk for type 2 diabetes was previously found also to be associated with prostate cancer.
When each genetic region found to influence development of type 2 diabetes has been carefully investigated, the precise genetic changes that exert these effects will be identified. Study of these genes should lead to greater biological understanding of the development of this serious disease, and may lead to new and better diagnostics and personalized treatments. Because the new genetic regions had not previously been associated with type 2 diabetes, this research opens up novel avenues for investigation of underlying causes of the disease. Furthermore, recent analysis of data from the NIDDK’s landmark Diabetes Prevention Program clinical trial confirmed that a particular gene variant increases risk for type 2 diabetes in people participating in the trial. However, even the participants at highest genetic risk benefited from healthy lifestyle changes shown to prevent or delay development of type 2 diabetes. This result was very encouraging because, despite a person’s genetic risk, lifestyle change could still reduce risk for developing type 2 diabetes.
Zeggini E, Scott LJ, Saxena R, and Voight BF, for the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium: Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40: 638-645, 2008.
Back to Top
Gut Microbes Protect Against Type 1 Diabetes in Mice
Research in mice has found that the trillions of bacteria and other microbes that live in the gut can blunt the immune system attack that causes type 1 diabetes. The discovery may shed light on rising rates of type 1 diabetes in developed countries. Scientists don’t know exactly what triggers the body’s immune attack on beta cells in type 1 diabetes. During the past decades, researchers saw clues in the observed increased incidence of type 1 diabetes in developed countries. The scientists suspected that changes in the environment, including the microbes that live in our bodies, may be influencing the disease. Supporting this idea, previous studies found that the incidence of type 1 diabetes in mice susceptible to this disease can be affected by microbes in their environment. The researchers set out to further explore the possible connection between type 1 diabetes and microbes.
Receptors on certain immune cells recognize molecular patterns that mark the surface of microbes. These immune cells signal through a protein called MyD88 to launch an immune system response. When researchers disrupted the gene for MyD88 in a mouse model of type 1 diabetes, the mice no longer developed the disease. While the researchers confirmed that immune activation in the MyD88-deficient mice was suppressed in pancreatic lymph nodes, it was not eliminated. Thus, type 1 diabetes prevention was likely more than simply a matter of turning off part of the immune system. The researchers therefore raised the mice in a germ-free environment. These same mice developed type 1 diabetes when raised in this type of environment, showing that the disease is not dependent solely on the MyD88 pathway. The researchers next gave the germ-free mice a defined mix of “friendly” gut bacteria and found that the incidence of diabetes was significantly reduced. These experiments show that a complex interaction between the immune system and bacteria in the gut may help to lower the risk of developing type 1 diabetes. The widespread use of antibiotics and more aggressive cleanliness of modern society can alter the mix of microbes living in our body. This research suggests that an unintended consequence of this environmental change is an increased risk of autoimmune diseases like type 1 diabetes. The idea opens avenues for further exploration and hints at the possibility of developing bacteria-based treatments for people with autoimmune diseases.
Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, and Chervonsky AV: Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455: 1109-1113, 2008.
Reprinted, in a slightly modified form, from NIH Research Matters; original article by Harrison Wein, Ph.D., published on September 29, 2008.
Back to Top
Bacterial Interaction with Gastric Stem Cells Related to Stomach Cancer Development
NIDDK-sponsored research has yielded insights into how the bacterial species Helicobacter pylori evolves and interacts with stem cells in the human stomach, contributing to disease progression to conditions such as cancer. H. pylori is the major cause of peptic ulcers, which affect a large number of individuals in the U.S. Most of those who become infected with this bacterium develop an inflammation of the stomach known as gastritis. However, in a small subset of individuals, gastritis progresses to a more severe form called chronic atrophic gastritis, in which some stomach cell types are destroyed. This condition may progress further to a type of stomach cancer known as gastric adenocarcinoma. Little is known about the role that H. pylori plays in these disease progressions; however, the bacteria are known to interact with the outer surface of epithelial cells that line the stomach and to establish themselves within gastric stem cells.
To explore the impact of interactions between H. pylori and gastric cells on disease progression, researchers engaged in a multi-species series of studies based largely on genomic techniques. Starting in the clinical realm, they analyzed samples taken originally for a population-based endoscopy study in Sweden. They focused their attention on samples collected from the stomach of one participant who developed gastric adenocarcinoma over the course of 4 years after an initial diagnosis of chronic atrophic gastritis. From these samples, they isolated H. pylori present before and after cancer development, and compared their genomes. They found that a single strain of H. pylori persisted throughout disease progression, but that several characteristics of the bacteria had changed over time. To study this disease-related H. pylori strain further, they switched to two experimental models: a mouse model of chronic atrophic gastritis, and a gastric stem cell culture model in which they could compare the direct effects of infection by the H. pylori specimens. Using these models, they were able to identify unique characteristics of the H. pylori present before and after stomach cancer development, including a gene turned on only in the cancer-associated bacteria that could serve as a biomarker for bacterial adaptation and stomach cancer. The cancer-associated H. pylori was also found to be better adapted to life inside the gastric stem cells, where it could influence cancer development. At the same time, the experiments also revealed changes in the mouse stomach stem cells. For example, the cancer-associated form of the bacteria affected mouse genes related to tumor development, among other genes. This study provides insights into how H. pylori interacts with stomach stem cells to influence disease progression that can culminate in stomach cancer. This new knowledge enhances understanding of the host-microbe interactions that contribute to these gastric diseases, and how this information might be used to predict risk of disease development and progression.
Giannakis M, Chen SL, Karam SM, Engstrand L, and Gordon JI: Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells. Proc Natl Acad Sci USA 105: 4358-4363, 2008.
Back to Top
Building Brown Fat with BMP-7
A new discovery in fat cell research may point the way to new therapeutic options for obesity. In mammals, not all fat, or adipose tissue, is the same. White adipose tissue stores extra calories as fat for later use and is the tissue associated with obesity, while brown adipose tissue, or brown fat, actually burns fat to generate heat, keeping an animal warm and slim. Until recently, it was thought that in humans, only newborns had brown fat, but new findings suggest that adults actually retain some as well. In a recent study, researchers sought out factors that determine the generation of brown fat from precursor cells. Working with laboratory-grown fat precursor cells from mice, they found that treatment with a molecule called bone morphogenetic protein 7, or BMP-7, is sufficient to drive precursor brown fat cells to develop into active brown fat cells. BMP-7 treatment suppressed cellular factors that normally inhibit brown fat cell development and induced production of key molecules that drive brown fat cell maturation—including UCP1, a signature protein found in brown fat cells that is essential for generating heat. Precursor brown fat cells treated with BMP-7 also increased by five-fold the number of their mitochondria, the cellular powerhouses that enable them to burn fat. In contrast, precursor white fat cells from mice were not affected by BMP-7 treatment. Demonstrating that BMP-7 is important to brown fat tissue development in animals, the researchers found that mice genetically engineered to have no BMP-7 had very little brown fat and produced little or no UCP1 protein as compared with normal, BMP-7-producing siblings. Increasing the amount of BMP-7 in mice had the opposite effect. The researchers found that administering extra BMP-7 to mice via a genetically engineered virus not only increased their brown fat mass, but also significantly increased whole body energy expenditure and basal body temperature—leading to a significant reduction in weight gain when compared with control mice. Although these experiments were all performed with mouse cells and in mice, now that brown fat has been found in humans, the findings suggest that BMP-7 may prove to be a therapeutic target to help counteract obesity in humans in the future.
Tseng Y-H, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, and Kahn CR: New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454: 1000-1004, 2008.
Back to Top
New Insights into a Common Form of Kidney Disease
Two recent reports describe the development of new research tools and advances in our knowledge of the mechanisms underlying IgA nephropathy (IgAN). IgAN is a relatively common form of kidney disease arising from the accumulation of IgA—an antibody the body uses to fight infections—in the kidneys. The cause of IgAN is unknown, although there is evidence that it runs in families. Over time, IgA deposits can damage the kidneys, and in severe cases patients require dialysis or a kidney transplant to live.
In most patients with IgAN, the sugar molecules that are normally attached to the IgA antibodies are aberrantly-formed, and this is thought to lead to IgA accumulation in the kidneys. Basic research on IgAN has been hampered by a dearth of experimental models. To advance research progress, scientists recently used a blood sample from a patient with IgAN to establish IgA-producing cells that can be grown in the laboratory. By analyzing these cells, they identified the specific step in the biologic pathway at which the addition of sugar molecules to the IgA antibodies goes awry. Such studies may identify new targets for future therapies. In a second study, researchers measured aberrant IgA levels in patients with IgAN, their relatives, and other volunteers as controls. High levels of aberrant IgA were detected in blood from patients with IgAN compared to controls. Somewhat surprisingly, approximately half of the family members of IgAN patients had elevated levels of the aberrant IgA but did not display symptoms of IgAN. The study suggested that the defect in sugar addition to IgA antibodies is an inherited trait, but that additional factors—either genetic or environmental—are required for kidney disease to develop. The study also showed clustering of abnormal IgA within some of the families, a result that suggested that there may be different subtypes of IgAN.
The new cultured cell line will facilitate future studies of the mechanism of the disease, may identify new targets for therapy, and could help scientists test possible approaches to treatment. The discovery that IgAN arises at least in part due to a genetic component helps scientists understand how the disease is transmitted, and the observation that some people with elevated abnormal IgA do not display symptoms suggests that additional, unknown factors may be contributing to the disease. These and future studies may allow physicians to predict which at-risk patients are likely to develop IgAN, and to personalize treatment depending on an individual’s disease subtype.
Gharavi AG, Moldoveanu Z, Wyatt RJ, Barker CV, Woodford SY, Lifton RP, Mestecky J, Novak J, and Julian BA: Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol 19: 1008-1014, 2008.
Suzuki H, Moldoveanu Z, Hall S, Brown R, Vu HL, Novak L, Julian BA, Tomana M, Wyatt RJ, Edberg JC, Alarcón GS, Kimberly RP, Tomino Y, Mestecky J, and Novak J: IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest 118: 629-639, 2008.
Back to Top
Genetic Cause Identified for Iron Deficiency in Individuals Unresponsive to Oral Iron Supplementation
A recent study implicates mutations of the gene TMPRSS6 as causing a particular form of iron deficiency anemia. TMPRSS6 encodes a cell membrane-bound protein produced in the liver that controls levels of a critically important iron-regulatory protein called hepcidin. In the U.S., most people with iron deficiency are easily treated with oral iron therapy; however there exists a small subset of children who don’t respond to oral iron therapy—a condition termed iron-refractory iron-deficiency anemia (IRIDA). Investigators identified five families in which IRIDA was present in siblings. Because the siblings’ parents did not have iron deficiency, the scientists thought that each parent may have one mutant and one normal copy of the causative gene, and that perhaps the children inherited only mutant copies of the gene, resulting in the disorder. Once identified as a likely candidate gene for this form of iron deficiency, analysis of this gene derived from the five families revealed several different types of genetic mutations.
Although not fully understood, mutations in the TMPRSS6 protein cause the body to over-produce hepcidin. Hepcidin controls iron concentrations in the body by regulating the recycling of iron from old red blood cells, and also by controlling intestinal iron absorption. The over-production of hepcidin effectively shuts down absorption of dietary iron from the intestine and traps the body’s existing iron within the cells (called macrophages) that attempt to recycle it, thereby limiting the availability of iron to be used for new red blood cell production. These findings demonstrate the importance of TMPRSS6 to normal iron regulation in humans. Additionally, this study raises the possibility that delivery of functional TMPRSS6 into patients with IRIDA may reduce hepcidin levels and timely improve iron absorption from the intestine and release of iron from internal iron stores. Because other iron metabolism disorders are also associated with abnormal hepcidin levels, the development of strategies to modulate TMPRSS6 activity could potentially have even broader clinical implications in the future.
Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, and Fleming MD: Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40: 569-571, 2008.
Back to Top
