More than a decade ago, researchers found that an acute complication of type 1 diabetes, diabetic ketoacidosis (DKA), can be resolved with the hormone leptin, even in the absence of insulin.
An analysis published today in The Journal of Clinical Investigation explains how leptin affects the brain and how it might be used in future therapeutics.
DKA happens when the body is unable to make insulin and begins to break down fat for fuel. This can lead to a life-threatening buildup of sugar (glucose) and ketoacids in the blood. Doctors have typically administered insulin to address the complication, authors noted.
But evidence now shows that, when insulin is insufficient, the brain plays a key role in driving DKA, according to the new analysis, based in literature and research that includes studies conducted at UW Medicine since 2011.
When the pancreas can't make 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.
Leptin helps the brain regulate appetite and body weight. Leptin is produced by your body's fat cells. The hormone is carried by the bloodstream into your brain, particularly an area called the hypothalamus . This is the part of your brain that controls when and how much you eat. Insufficient leptin leads the brain to activate circuits that mobilize energy sources, including glucose and ketones.
Schwartz and his team discovered this connection in 2011 when they first administered leptin into the brain of rats and mice with type 1 diabetes. At first, nothing happened. But four days later, they were astonished when the animals' blood glucose and ketone levels became completely normal, despite ongoing severe 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."
These responses suggested that the brain can maintain normal blood sugar levels even in the absence of insulin, Schwartz said.
At the time, the diabetes research community didn't know what to make of the discovery.
"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.
Schwartz said he will seek FDA approval to begin human trials to test whether leptin is capable of normalizing blood sugar levels in people with type 1 diabetes.
Positive results would open the door to pharmaceutical therapies for type 1 diabetes that target the brain.
"This is one of the most exciting discoveries of my career," said co-author Dr. Irl Hirsch , a UW Medicine's diabetes treatment and teaching chair and a professor of metabolism, endocrinology and nutrition at the University of Washington School of Medicine.
Hirsch said controlling blood glucose with leptin could unlock new avenues of treatment 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 noted that insulin management is a substantial burden 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.
If the brain can be convinced that fuel stores are not depleted, or if specific brain neurons that trigger the production of glucose and ketones are turned off, the body stops the reaction that leads to severe hyperglycemia and DKA.
"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."
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).
