Researchers at the Massachusetts General Hospital (MGH) have discovered that a gene used by the tiny worm C. elegans to regulate how much it eats, how fat it becomes and how long it lives is strikingly similar to the gene for the human insulin receptor. In the August 15 issue of Science, the team led by Gary Ruvkun, PhD, announced their surprising discovery, implying that insulin-like control of metabolism is very ancient. The finding also suggests that human counterparts of other worm genes that interact with this insulin-like signal may be defective in diabetes, an insight that could lead to new therapies for the disease. In addition, the discovery that the worm's form of insulin regulates its lifespan suggests that human aging may be intimately connected to how food is metabolized.
Ruvkun and his colleagues -- postdoctoral fellow Koutarou Kimura, PhD, graduate student Heidi Tissenbaum, and technician Yanxia Liu -- identified and cloned the gene daf-2, which regulates whether C. elegans lives a short, lean life focused on reproduction or a long, fat life focused on energy storage and survival. They discovered that daf-2 has important structural similarities to genes coding for insulin receptor proteins in humans and other mammals. They also found that, as with the human insulin receptor, the worm gene regulates metabolism: worms with a defective gene shift their metabolism towards storage of fat rather than burning energy for fast reproduction. In fact a mutation identical to one that the MGH team found in the worm gene has been observed in the same location on the insulin receptor gene of an obese human patient with an atypical form of diabetes.
Last year, another team from the Ruvkun lab showed that the gene age-1, which acts together with daf-2, also controls worm lifespan and matches a human gene.
"The match between daf-2 and the human insulin receptor is striking," says Ruvkun, "because it brings together what we thought were two separate jigsaw puzzles into one that is much more complete. Both research fields -- the insulin-based system for control of human metabolism and the genetic pathways that control worm metabolism -- are well studied. But the newly discovered similarities between daf-2 and the human insulin receptor may help to solve outstanding mysteries about how human insulin regulates metabolism and why this regulation fails in diabetes, which affects about 5 percent of the general population."
Ruvkun expects that more of these worm genes will match human genes being identified in the human genome project and will prove to serve precisely the same roles in metabolic control. For example, Shoshanna Gottlieb, PhD, a former member of the Ruvkun lab now at the University of Pennsylvania, and Ruvkun have identified a gene that allows worms to survive normally in the absence of their insulin signals. The human equivalent of such a gene may be important in the development of therapies for diabetes.
The insulin-like signaling in worms also controls the animals' entry into a state of hibernation when food is limited or other environmental extremes exist. In this hibernating state, worms store up fat and can survive much longer than their normal 10-day lifespan. Ruvkun believes that the association of longevity genes with hibernation is not unique to worms.
He says, "Many animals hibernate, some for extended periods of time, and the genes that allow animals to survive longer periods of metabolic shutdown may help them withstand tough periods of drought or cold in which food supplies are scarce. While humans don't hibernate, there have been reports that very-low-calorie diets cause dramatic increases in longevity in some mammals. The increase in worm lifespan associated with this hibernation state may be very similar to the increase in mammalian longevity caused by reduced food intake.
"In fact," Ruvkun continues, "the same mutations that allow people to survive famines might underlie the prevalence of diabetes in certain populations. For example, almost half of the Pima Indians in Arizona, who have high levels of obesity, develop diabetes. What was once a beneficial mutation, allowing people to store enough fat to survive and reproduce, could now be a cause of disease when food is plentiful." The Ruvkun team also expects that variations in the human counterparts of other genes in the worm's insulin-like pathway may be responsible for the variations in diabetes prevalence among several human populations.
The Massachusetts General Hospital, established in 1811, is the oldest and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with a 1996 research budget of $197 million and major research centers in the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital (BWH) to form Partners HealthCare System, Inc., which now also includes the North Shore Health System.
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Journal
Science