The weight loss revolution has a surprising new star: glucagon, a hormone that has lived in insulin’s shadow.
For nearly a century, glucagon occupied a familiar role in biology textbooks. Insulin lowered blood sugar. Glucagon raised it. But at the American Diabetes Association’s 86th Scientific Sessions, Duke University School of Medicine researcher Jonathan Campbell, PhD, made the case that glucagon may be far more than insulin’s counterweight.
In fact, it could be one of the key ingredients powering a new generation of experimental obesity drugs that are producing levels of weight loss that once seemed impossible.
During a packed presentation Saturday, Campbell, a metabolism and diabetes researcher and associate professor of medicine, challenged the traditional view of glucagon as merely a hormone that kicks in during fasting to prevent dangerously low blood sugar.
He described emerging evidence suggesting glucagon plays a central role in how the body processes nutrients, burns fat, and responds to insulin after meals.
The findings could help explain why experimental drugs such as retatrutide are delivering some of the strongest weight loss results seen to date: in addition to targeting GLP-1 and GIP, they also activate glucagon receptors to help increase energy expenditure.
“The drugs may be working so well in part because of glucagon,” said Campbell, a member of the Duke Molecular Physiology Institute who has studied glucagon for more than a decade.
Recent studies, including one that Campbell published last year, suggest glucagon can directly stimulate insulin release from the pancreas. Instead of working against insulin, it appears to support it especially after meals when the body needs to handle incoming sugar, fat, and protein.
“Rather than being the bad guy, it may be helping insulin do its job,” Campbell said.
Tackling the body’s resistance to weight loss
Perhaps most intriguing is glucagon’s potential to counter one of weight loss’s biggest biological hurdles: the body’s tendency to conserve energy as pounds drop.
As people lose weight, metabolism typically slows. The body begins burning fewer calories, making further weight loss harder and increasing the likelihood of regaining weight.
Human studies examining glucagon’s effects on calorie burning have produced mixed results. But Campbell presented new animal data suggesting glucagon receptor activation may help prevent that metabolic slowdown.
In the studies, animals receiving the experimental drug retatrutide maintained energy expenditure despite substantial weight loss.
If the same phenomenon occurs in humans, the finding could explain why retratrutide has generated unusually large and sustained weight-loss effects.
Why retatrutide is turning heads
Retatrutide belongs to a new class of drugs known as triple agonists.
Unlike earlier medications that targeted a single pathway, these compounds activate three distinct hormonal systems simultaneously:
- GLP-1, which reduces appetite and lowers blood sugar
- GIP, which appears to enhance metabolic regulation
- Glucagon, which may improve nutrient processing, liver health and energy balance.
The approach appears remarkably powerful.
According to Phase 3 diabetes results released in Lancet alongside the ADA meeting, retatrutide lowered A1C, a measure of average blood sugar, by nearly 2 percentage points, roughly comparable with the performance of tirzepatide. Tirzepatide is known as Mounjaro for diabetes management, or Zepbound for weight management and sleep apnea treatment.
The obesity results presented at the meeting were even more striking.
Participants receiving the highest doses experienced weight loss approaching 30% of body weight, surpassing the roughly 22% weight reduction seen in tirzepatide in earlier studies.
The obesity data have not yet been fully published, but researchers say the magnitude of weight loss suggests glucagon is contributing something meaningful.
Early promise for fatty liver disease
The hormone’s effects may extend to one of the fastest-growing health concerns: fatty liver disease.
Campbell presented evidence that glucagon plays a broader role in regulating how the body handles proteins, fats, and carbohydrates, particularly in the liver. That could be crucial for people with obesity and type 2 diabetes, who often also have fatty liver disease and disrupted metabolism.
Early studies suggest activating glucagon receptors can reduce liver fat, improve markers of liver injury, and potentially slow the progression of metabolic dysfunction-associated steatohepatitis, or MASH — a severe form of fatty liver disease.
Those findings remain preliminary, but they hint at a treatment approach that goes beyond weight loss alone.
Next frontier in drug development
Researchers now believe the future of obesity treatment may involve increasingly sophisticated combinations of hormones.
At ADA 2026, scientists discussed experimental therapies targeting four, five or even more metabolic pathways simultaneously.
But that focus is beginning to shift.
“Maybe we don’t need to focus on the magnitude of weight loss, but focus on the quality of weight loss,” Campbell said, that is, preserving muscle while maximizing fat reduction.
Another pressing question remains unsolved: what happens after patients reach their goal weight?
“Once someone has their blood pressure under control, they don’t stop taking their medication,” he said. “That’s not what happens. The same is true for obesity medications. People take them for life.”
Unlike blood pressure medications, obesity therapies are often expensive — costing $149 to more than $1,000 a month — and injectable, raising questions about patient burden, long-term access, and maintenance.
“The off-ramp is one of the biggest challenges,” he said following the presentation. “So, there’s going to be a lot of innovation in that space.”
Yet amid all the excitement surrounding next-generation drugs, perhaps the most surprising development is the renewed attention being paid to a hormone that spent decades hiding in plain sight.
Now Campbell and others in the field recognize it as a master regulator of metabolism that influences how the body handles nutrients.
“Once you look at it as a whole, it is now being reconsidered as a central player in metabolic health,” he said, and a potential cornerstone of the next era of treatment.