More than a decade ago, researchers discovered that diabetic ketosidosis (DKA), an acute complication of type 1 diabetes, can be broken down by 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 it will be used in future treatments.
DKA occurs when the body is unable to produce insulin and begins to break down fat for fuel. This can lead to a life-threatening accumulation of sugar (glucose) and ketosides in the blood. Doctors usually administer insulin to address complications, the authors noted.
However, the evidence shows that insufficient insulin is, the brain plays an important role in driving DKA, based on new analyses based on literature and research, including studies conducted in UW medicine since 2011.
When the pancreas can't make insulin, “the brain receives the message that the body is out of fuel. Even if it doesn't, this information is partially transmitted by low blood levels of hormone leptin,” said Dr. Michael Schwartz, a professor of medicine.
Leptin helps the brain regulate appetite and weight. Leptin is produced by fat cells in your body. Hormones are transported by blood flow to the brain, particularly the area known as the hypothalamus. This is part of the brain that controls when and how much you eat. When leptin is insufficient, the brain activates circuits that recruit energy sources such as glucose and ketones.
Schwartz and his team discovered the link in 2011 when they first administered leptin to the brains of rats and mice with type 1 diabetes. At first nothing happened. However, four days later, they were surprised when the animal's blood sugar and ketone levels became completely normal despite ongoing severe insulin deficiency.
“I think the most surprising thing is that not only did my blood sugar levels not fall, but my levels have dropped,” he said. “If you tried to get them to stand up, they're back. If you tried to lower them, they're back.”
These responses suggested that the brain could maintain normal blood glucose levels even in the absence of insulin, Schwartz said.
At the time, the diabetes research community had no idea what to do with the findings.
I understand much better the findings that the scientific community largely ignored when first reported in 2011. ”
Dr. Michael Schwartz, Professor of Medicine, Department of Metabolicism, Endocrinology, Nutrition, University of Washington School of Medicine
Schwartz said he would seek approval from the FDA to begin human trials to test whether leptin can normalize blood glucose levels in patients with type 1 diabetes.
Positive results will open the door to pharmaceutical therapy for type 1 diabetes, targeting the brain.
“This has been one of the most exciting discoveries of my career,” said IRL Hirsch, PhD, UW Medicine's Diabetes Treatment and Education Chair and Professor of Metabolism, Endocrinology and Nutrition at Washington University School of Medicine.
Hirsch said controlling blood glucose with leptin can unlock new measures of treatment for patients.
“Don't get me wrong. Discovering insulin 104 years ago was one of the biggest discoveries of the last century,” said Hirsch, who had suffered from type 1 diabetes since childhood. “But this is the next step. This might be a better way.”
Schwartz noted that insulin management is a huge burden for patients and their families.
“If we can treat type 1 diabetes without daily insulin injections or blood glucose monitoring, patients will say that is the biggest thing ever,” he added.
If the brain is sure that the fuel storehouse is not depleted, or when certain brain neurons that cause glucose and ketone production are turned off, the body will stop the responses leading to severe hyperglycemia and DKA.
“This new framework challenges traditional wisdom regarding insulin deficiency as the sole cause of diabetic ketosidosis, which has been widely accepted for decades,” Schwartz said. “It shows that the brain plays a powerful role in the origins of uncontrolled diabetes, indicating that it may hold the key to new treatments.”
Funding for this study was supported by the National Institutes of Health (Grants DK083042, DK101997, DP2DK128802, DK089056, DK124238 and S10OD036208). NIH-NIDDK is the Center for Nutritional Obesity Research (NORC P30DK035816), Diabetes Research Center (DRC P30DK017047) and the University of Washington Diabetes, Obesity and Metabolic Training Grant (T32 DK007247); Department of Defense Peer-Reviewed Medical Research Program (W81XWH-20-1-0250).
sauce:
Washington University School of Medicine
Journal Reference:
Mirzadeh, Z., et al. (2025). Unexpected role of the brain in the pathogenesis of diabetic ketosidosis. Journal of clinical research. doi.org/10.1172/jci196357.
