A growing body of research suggests the brain plays a central role in diabetic ketoacidosis, opening the possibility of treating type 1 diabetes in an entirely new way.
More than 10 years ago, scientists made an unexpected discovery about a life-threatening complication of type 1 diabetes. They found that diabetic ketoacidosis (DKA) could be reversed using the hormone leptin, even when insulin was not present.
Diabetic ketoacidosis (DKA) is one of the most dangerous emergencies linked to type 1 diabetes. When the body cannot make insulin, it cannot use sugar for energy in the usual way. Instead, it shifts into fat burning, which can send sugar (glucose) and ketoacids climbing to deadly levels in the bloodstream.
A new analysis published in The Journal of Clinical Investigation takes a closer look at how leptin acts on the brain and why this pathway could eventually shape new treatments.
DKA develops when the body cannot produce insulin and begins breaking down fat for energy instead. As fat is metabolized, levels of sugar (glucose) and ketoacids rise in the bloodstream. Without treatment, this buildup can become life threatening. Traditionally, doctors have relied on insulin therapy to correct the condition, the authors noted.
The new report argues that insulin deficiency is only part of the story. Drawing on years of research, including studies conducted at UW Medicine since 2011, the analysis concludes that the brain plays a central role in triggering DKA when insulin levels fall too low.
When the pancreas stops producing insulin, “the brain gets the message that the body is out of fuel, even if it’s not. This information is being communicated in part by a low blood level of the hormone leptin,” said senior author Dr. Michael Schwartz, professor of medicine, Division of Metabolism, Endocrinology and Nutrition at the University of Washington School of Medicine.
How Leptin Signals the Brain
Leptin is a hormone made by fat cells that helps regulate appetite and body weight. After being released into the bloodstream, it travels to the brain, especially to a region known as the hypothalamus. This area controls hunger and energy balance.
When leptin levels drop, the brain responds as if the body is running out of fuel. It activates neural pathways that increase the production of energy sources, including glucose and ketones. In people with little or no insulin, that response can worsen high blood sugar and accelerate DKA.
Schwartz and his colleagues uncovered this link in 2011. They injected leptin directly into the brains of rats and mice with type 1 diabetes. At first, there was no visible change. After four days, however, the animals’ blood glucose and ketone levels returned to normal, despite severe ongoing insulin deficiency.
“I think the most amazing thing is that the blood sugars just didn’t come down, but that the levels stayed down,” he said. “If you tried to get them to rise, they came back down. If you tried to lower them, they came back up.”
The results suggested that the brain, under certain conditions, can keep blood sugar in a normal range even without insulin, Schwartz said.
From Skepticism to New Interest
When the findings were first reported, many diabetes researchers were unsure how to interpret them.
“We now have a much better understanding of a finding that was largely ignored by the scientific community when it was first reported in 2011,” Schwartz said.
He now plans to seek FDA approval to launch clinical trials to determine whether leptin can safely normalize blood sugar levels in people with type 1 diabetes.
A Potential Shift in Diabetes Treatment
If human studies confirm the earlier results, treatments that target the brain could become a new strategy for managing type 1 diabetes.
“This is one of the most exciting discoveries of my career,” said co-author Dr. Irl Hirsch, a UW Medicine diabetes treatment and teaching chair and professor of metabolism, endocrinology, and nutrition at the University of Washington School of Medicine.
Hirsch said that using leptin to control blood glucose could create new options for patients.
“Don’t get me wrong, discovering insulin 104 years ago is one of the greatest discoveries of the last century,” said Hirsch, who has had type 1 diabetes since childhood. “But this, this is the next step. This might be a better way.”
Schwartz emphasized that managing insulin is a daily challenge for patients and their families.
“I think if you could treat type 1 diabetes without daily insulin injections and blood sugar monitoring, patients would say that is the greatest thing ever,” he added.
According to the researchers, if the brain can be reassured that the body’s fuel supply is adequate, or if specific neurons that drive glucose and ketone production can be silenced, the chain reaction that leads to severe hyperglycemia and DKA may be stopped.
“This new framework challenges that conventional wisdom about insulin deficiency as the sole cause of diabetic ketoacidosis that has been widely accepted for decades,” said Schwartz. “It shows that the brain plays a powerful role in the genesis of uncontrolled diabetes — and may hold the key to new treatments.”
Reference: “An unexpected role for the brain in the pathogenesis of diabetic ketoacidosis” by Zaman Mirzadeh, Gregory J. Morton, Irl B. Hirsch and Michael W. Schwartz, 1 August 2025, The Journal of Clinical Investigation.
DOI: 10.1172/JCI196357
Funding for this research was supported by National Institutes of Health (grants DK083042, DK101997, DP2DK128802, DK089056, DK124238 and S10OD036208); the NIH-NIDDK funded Nutrition Obesity Research Center (NORC P30DK035816), Diabetes Research Center (DRC P30DK017047) and the Diabetes, Obesity and Metabolism Training Grant (T32 DK007247) at the University of Washington; and the Department of Defense Peer-Reviewed Medical Research Program (W81XWH-20-1-0250).
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