The ancient Chinese philosophy of Taoism emphasizes a harmony of opposing forces. Light counterbalances darkness. Action counterbalances inaction.

Similarly, blood-sugar raising hormones such as glucagon counterbalance the blood- sugar lowering hormone insulin. Disrupting this delicate equilibrium can lead to diabetes, a disease that affects about 29 million people in the U.S. and costs an estimated $245 billion each year.

Focused mainly on insulin, diabetes researchers haven’t yet fully explored the contributions of its opposing hormones, says Wei Roc Song, a postdoctoral researcher at Harvard Medical School, and that may leave out a significant part of the picture.

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Now, using a new fruit fly model of Type 2 diabetes, Song and colleagues have found that a chronic high-calorie diet can lead to high blood sugar simply by boosting the gut hormone activin-beta, which in turn stimulates activity of the fly version of glucagon—without affecting insulin.

The findings, published in Cell Metabolism, provide a deeper understanding of how diabetes can arise from a high-calorie diet and support existing efforts to manipulate the body’s response to glucagon as a potential alternative to insulin for managing diabetes.

“We know what glucagon does in the body, but we haven’t known the exact mechanism by which it contributes to diabetes,” said Song, who is first author of the study. “Our work may explain why diabetes patients frequently have high glucagon levels and enhanced glucagon responses.”

“This study is a striking example of the relevance of the fruit fly to unravel fundamental mechanisms involved in hormonal regulation and physiology,” said Norbert Perrimon, James Stillman Professor of Developmental Biology at HMS and senior author of the study.

The work also reveals that endocrine cells in the midgut—at least, the midguts of flies—can make activin-beta, which up until now researchers thought was produced only in the brain and peripheral nerves.

Sugar spike

In a healthy body, when sugar floods the bloodstream, as happens after a meal, the pancreas releases insulin to sweep the extra sugar into the liver and muscles for storage or into other cells to be used for immediate energy. On the flip side, when blood sugar is low, the pancreas releases glucagon, which triggers the liver and muscles to release some of their energy cache.

In Type 2 diabetes, the body stops responding well to insulin, leaving too much sugar in the bloodstream. Yet many diabetes patients also have abnormally high glucagon activity in their livers. Song and other members of the Perrimon lab, together with collaborators from Beth Israel Deaconess Medical Center and the University of Minnesota, set out to understand why. 

The researchers began with a well-established model system for studying human metabolism: fruit flies. They fed the flies high-sugar diets and watched what happened.

Adipokinetic hormone (AKH) activity, the fly equivalent of mammalian glucagon, spiked in an organ called the fat body, the fly equivalent of the human liver and fat tissue. The fat body obeyed the AKH hormonal signal and released glucose into the bloodstream. The flies developed high blood sugar, insulin resistance and obesity, all similar to what happens in Type 2 diabetes.