A heart-shaped pancreatic islet in a zebrafish larva. Image credit: Mullapudi et al. (CC BY 4.0)
Diabetes is a disease that affects the ability of the body to control the level of sugar in the blood. Individuals with diabetes are unable to make a hormone called insulin – which normally stimulates certain cells to absorb sugar from the blood – or their cells are less able to respond to this hormone. Most treatments for diabetes involve replacing the lost insulin or boosting the hormone’s activity in the body. However, these treatments can also cause individuals to gain weight or become more resistant to insulin, making it harder to control blood sugar levels.
In addition to insulin, several other factors regulate the levels of sugar in the blood and some of them may operate independently of insulin. However, little is known about such factors because it is impractical to carry out large-scale screens to identify drugs that target them in humans or mice, which are often used as experimental models for human biology.
To overcome this challenge, Mullapudi et al. turned to another animal known as the zebrafish and generated mutant fish that lack insulin. The mutant zebrafish had similar problems with regulating sugar levels as those observed in humans and mice with diabetes. This observation suggests that insulin is just as important in zebrafish as it is in humans and other mammals.
The mutant zebrafish did not survive into adulthood, and so Mullapudi et al. transplanted healthy tissue into the zebrafish to allow them to produce enough insulin to survive. These adult zebrafish produced many offspring that still carried the insulin mutation. Mullapudi et al. used these mutant offspring to screen over 2,000 drugs for their ability to decrease blood sugar levels in the absence of insulin. The screen identified three promising candidate drugs, including a molecule that interferes with a receptor for a signal known as androgen.
These findings will help researchers investigate new ways to treat diabetes. In the future, the screening approach developed by Mullapudi et al. could be adapted to search for new drugs to treat other human metabolic conditions.
