New Study Reveals Insulin’s Key Role in Brain Health, Link between Diabetes and Alzheimer’s Disease

Brain Insulin Signaling Impact on Diabetes and Neurological Disorders

BOSTON, MA — A new study from Joslin Diabetes Center explores the role of insulin signaling in the brain’s immune cells, and how it may mediate the relationship between type 2 diabetes and Alzheimer’s disease (AD), as well as contribute to the onset and progression of AD. The findings, published in Proceedings of the National Academy of Sciences, could help identify potential targets to treat diabetes patients with AD.

“Type 2 diabetes, obesity, and metabolic syndrome are major causes of illness and death worldwide, and insulin resistance, especially brain insulin resistance, features prominently in all these conditions,” said lead author Wenqiang Chen, PhD, instructor of Medicine at Joslin Diabetes Center, a neuroscientist whose research focuses on the intersection of insulin signaling in the brain and its implications for diabetes and brain health. “A growing body of evidence links insulin resistance with increased risks of brain disorders, including AD and depression, but exactly how brain insulin resistance links to these diseases remains incompletely understood.”

To better understand insulin’s role in the brain, Chen and colleagues in the lab of Ronald Kahn, MD, Section Head of Integrative Physiology and Metabolism, created a mouse model in which they could "turn off" insulin receptors in certain brain cells. These “knockout mice,” called MG-IRKO mice, gave the scientists a precise tool to study how specific brain cells behave without insulin’s influence.

The Joslin investigators looked specifically at microglia—the brain’s resident immune cells. They act as the brain’s cleanup crew, removing waste, responding to injury, and helping to regulate inflammation. Most importantly in the context of Alzheimer’s, they help clear away amyloid-beta (Aβ), a sticky protein that can build up to form the damaging plaques in the brain that are a hallmark of neurodegenerative disease.

Their findings were striking:

• Mice without insulin signaling in microglia showed depressive-like behaviors and altered social interaction
• When these mice were crossed with a widely used Alzheimer’s disease model, the resultant mice—carrying both insulin resistance and AD risk genes—developed more severe disease
• In the team’s cellular model of microglia lacking insulin receptors, the cells shifted to a less efficient way of producing energy and became less effective at clearing amyloid-beta.

“Our findings point to the importance of understanding a cell type specific regulation of insulin action and insulin resistance in brain homeostasis and disease pathogenesis,” said senior author Kahn, who is also Joslin’s Chief Academic Officer and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. “These insights will help identify the cellular and molecular mechanisms underlying the link between Type 2 diabetes and brain disorders, thus bringing the potential for better therapeutics for patients with these comorbid conditions.”

Co-authors included Xiangyu Liua and Vitor Rosetto Munoza of Joslin Diabetes Center. This work was supported by the National Institutes of Health (grant R01 DK031036 and in part by NIH training grant T32 DK007260). Dr. Chen conducted this work in part as a recipient of the Steno North American Fellowship (grant NNF23OC0087108) awarded by the Novo Nordisk Foundation — a transatlantic research program fostering collaboration between Joslin Diabetes Center and Steno Diabetes Center Copenhagen.

The authors declare no competing interest.

About Joslin Diabetes Center

Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Part of Beth Israel Lahey Health, Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is affiliated with Harvard Medical School and one of only 18 NIH-designated Diabetes Research Centers in the United States.