Researchers at the Massachusetts General Hospital (MGH) have announced an important new insight into how the lack of insulin causes diabetes. The research team, led by Gary Ruvkun, PhD, reports in the journal Nature their discovery -- based on molecular genetic analysis in the worm C. elegans -- of previously unsuspected human genes that may be misregulated or defective in diabetics. These genes represent new candidates for the underlying cause of diabetes and define novel targets for new diabetes therapies.
Two months ago, the Ruvkun lab reported that a gene equivalent to the human insulin receptor gene regulates the metabolism of worms. The match between the worm and human insulin receptors suggested that the detailed genetic analyses of worm metabolic control could be applied to human metabolic diseases such as diabetes. In the October 30 issue of Nature, the Ruvkun team announces the first new insight into the mechanism of diabetic disease to emerge from the discovery that worms use an insulin-like signal to control their metabolism.
The team -- which also includes first author Scott Ogg, PhD, Suzanne Paradis, Shoshanna Gottlieb, PhD, Garth Patterson, PhD, Linda Lee, and Heidi Tissenbaum, PhD -- discovered that insulin may control metabolism via inactivation of a second gene, daf-16. The researchers found that, although insulin normally is required to regulate metabolism in the worm C. elegans, as in humans, the animal no longer needs insulin if it also carries a mutation in daf-16. This gene encodes a DNA-binding protein that passes along insulin signals within the cell to control the production of enzymes that metabolize sugars and fats. The team proposes that in the absence of insulin, the DAF-16 protein becomes unregulated, and that its runaway activity may be the key cause of metabolic disease in diabetes. In support of this model, the research team shows that metabolic defects in worms with defective insulin signaling are "cured" by the inactivation of the daf-16 gene.
Thus C. elegans insulin genetics yield the surprising result that these animals can live quite well without their version of insulin, if they also carry an inactive or less active daf-16 gene. The team also reports that humans carry two daf-16 equivalent genes that may similarly pass along insulin signals.
Neither of these human genes had been previously suspected to be involved in insulin control of metabolism. The researchers suggest that these human daf-16 equivalents may be defective in some diabetics and that drugs which inactivate the human daf-16 gene or its product may be therapeutic in diabetes.
The Nature paper also shows that another metabolism-regulating hormone, encoded by the gene daf-7, conspires with insulin to regulate C. elegans metabolism and suggests that the human equivalents of the other genes in this parallel signaling pathway may also be defective in diabetics. Another team from the Ruvkun lab -- including Patterson, Allison Koweek, Arthur Wong, and Yanxia Liu -- published this month a related paper in the journal Genes and Development, reporting that inactivation of another DNA-binding protein, encoded by the gene daf-3, "cures" the metabolic defects caused by lack of the daf-7 hormonal signal. Ruvkun and his team propose that the DAF-16 and DAF-3 DNA-binding proteins integrate the insulin-like and daf-7 endocrine hormonal signals to control metabolic gene expression in the worm. They suggest that human equivalents of these genes may define previously unsuspected hormones and signaling pathways that conspire with insulin to control metabolism.
The knowledge of the exact identity of these key worm genes that act together with worm insulin could speed discovery of the molecular causes of and therapies for diabetes. A major effort has been underway to identify human genes that might be the cause of diabetes, but the fact that many genes are involved makes the effort difficult and expensive. Ruvkun and his colleagues are now beginning to search diabetic patients for mutations in the human genes that are the closest relatives of these worm genes.
"Our discovery that animals do not need insulin signals if they also carry an inactive daf-16 gene was completely unexpected," says Ruvkun, "and points the way for the development of an entirely new class of anti-diabetes drugs that could target human equivalents of these worm genes." For example, worms that carry the human equivalent of daf-16 could be used to screen for drugs that inactivate the human DAF-16 protein, allowing the animals to grow rather than to arrest in an immature state, as they do when this human protein functions in the worm. If the researchers' hypothesis is correct, such drugs may treat both type 1 or juvenile-onset diabetes, in which no insulin is produced, and type 2 or adult-onset diabetes, in which insulin responses are abnormal.
The Nature paper also suggests that human genes equivalent to the worm gene daf-7 may define an injectable diabetes therapy analogous to insulin. Ruvkun and his colleagues suggest that, if defects in the production of the human version of daf-7 underlie the lack of insulin response in obese people -- who are at increased risk for developing type 2 diabetes -- injection of this human hormone could be a diabetes and obesity therapy. Ruvkun cautions that this theory is unproved in humans and that drug development is a long and complex process.
"Although there still are a lot of questions to answer, we believe that our research reveals important new insights into the causes of diabetes and suggests novel avenues for its treatment," Ruvkun says.