Brain neurons are responsible for day-to-day control of blood sugar

The brain controls the release of glucose in a wide range of stressful circumstances, including fasting and low blood sugar levels.

However, less attention has been paid to its role in day-to-day situations.

In a study published in Molecular Metabolism, University of Michigan researchers have shown that a specific population of neurons in the hypothalamus help the brain maintain blood glucose levels under routine circumstances.

Over the past five decades, researchers have shown that dysfunction of the nervous system can lead to fluctuations in blood glucose levels, especially in patients with diabetes.

Some of these neurons are in the ventromedial nucleus of the hypothalamus, a region of the brain that controls hunger, fear, temperature regulation and sexual activity.

“Most studies have shown that this region is involved in raising blood sugar during emergencies,” said Alison Affinati, M.D., Ph.D., assistant professor of internal medicine and member of Caswell Diabetes Institute.

“We wanted to understand whether it is also important in controlling blood sugar during day-to-day activities because that’s when diabetes develops.”

The group focused on VMH^Cckbr neurons, which contain a protein called the cholecystokinin b receptor.

They used mouse models in which these neurons were inactivated.

By monitoring the blood glucose levels, the researchers found that VMH^Cckbr neurons play an important role in maintaining glucose during normal activities, including the early part of the fasting period between the last meal of the day and waking up in the morning.

“In the first four hours after you go to bed, these neurons ensure that you have enough glucose so that you don't become hypoglycemic overnight,” Affinati said.

To do so, the neurons direct the body to burn fat through a process called lipolysis.

In the first four hours after you go to bed, these neurons ensure that you have enough glucose so that you don't become hypoglycemic overnight."

-Alison Affinati, M.D., Ph.D.

The fats are broken down to produce glycerol, which is used to make sugar.

When the group activated the VMH^Cckbr neurons in mice, the animals had increased glycerol levels in their bodies.

These findings could explain what happens in patients with prediabetes, since they show an increase in lipolysis during the night.

The researchers believe that in these patients, the VMH^Cckbr neurons could be overactive, contributing to higher blood sugar.

These nerve cells, however, only controlled lipolysis, which raises the possibility that other cells might be controlling glucose levels through different mechanisms.

“Our studies show that the control of glucose is not an on-or-off switch as previously thought,” Affinati said.

“Different populations of neurons work together, and everything gets turned on in an emergency. However, under routine conditions, it allows for subtle changes.”

The team is working to understand how all the neurons in the ventromedial nucleus co-ordinate their functions to regulate sugar levels during different conditions, including fasting, feeding and stress.

They are also interested in understanding how the brain and nervous system together affect the body’s control of sugar, especially in the liver and pancreas.

The work was carried out by a team of U-M researchers at the Caswell Diabetes Institute who focus on the neuronal control of metabolism—the roles played by the brain and nervous system in metabolic control and disease.

Additional authors: Jiaao Su, Abdullah Hashsham, Nandan Kodur, Carla Burton, Amanda Mancuso, Anjan Singer, Jennifer Wloszek, Abigail J. Tomlinson, Warren T. Yacawych, Jonathan N. Flak, Kenneth T. Lewis, Lily R. Oles, Hiroyuki Mori, Nadejda Bozadjieva-Kramer, Adina F. Turcu, Ormond A. MacDougald and Martin G. Myers.

Funding/disclosures: Research support was provided by the Michigan Diabetes Research Center (NIH grant P30 DK020572), the Mouse Metabolic Phenotyping Center — Live (U2CDK135066) Physiology Phenotyping Core, the Michigan Nutrition and Obesity Center Adipose Tissue Core (P30 DK089503); Department of Veterans Affairs (IK2BX005715); the Warren Alpert Foundation; Endocrine Fellows Foundation; Marilyn H. Vincent Foundation and Novo Nordisk. This work was also supported in part by NIH grant K08 DK1297226.

Tech transfer(s)/Conflict(s) of interest: Myers reports a relationship with AstraZeneca Pharmaceuticals LP, Eli Lilly and Company and Novo Nordisk Inc. MacDougald reports a relationship with Regeneron Pharmaceuticals Inc, CombiGene AB and Rejuvenate Biomed.

Michigan Research Core(s): Mouse Metabolic Phenotyping Center — Live Physiology Phenotyping Core and the Michigan Nutrition and Obesity Center Adipose Tissue Core.

Paper cited: “Control of physiologic glucose homeostasis via hypothalamic modulation of gluconeogenic substrate availability,” Molecular Metabolism. DOI: 10.1016/j.molmet.2025.102216

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