Gastric inhibitory polypeptide (GIP) is best known as a gut hormone with broad effects on appetite, satiety, obesity, and insulin secretion. But GIP, an incretin receptor that has become an important target in type 2 diabetes treatment, is also expressed in the brain, where its effects are still largely a mystery.
“We were trying to screen for different actors in the brain that can promote leptin resistance—a hallmark of obesity—in obesity and type 2 diabetes and happened to find GIP receptors in the brain as a potential candidate,” said Makoto Fukuda, PhD, Assistant Professor of Pediatrics and Nutrition, Baylor College of Medicine. “We all knew that GIP receptors are expressed in many tissues, especially in the pancreas and fat, but the role of GIP receptors in the brain was totally new to us and to the field.”
Dr. Fukuda will open this year’s ADA Diabetes Symposium—New Turf for the Other Incretin—GIP Signaling in the Brain and Effects on Food Intake and Energy Balance, which will begin at 8:00 a.m. ET Sunday, June 27. He will discuss the growing body of evidence regarding interactions between GIP and leptin in the brain that regulate, and sometimes dysregulate, energy homeostasis and the pathways that can lead to obesity and type 2 diabetes.
GIP in the brain can activate multiple pathways that promote obesity, inflammation, and type 2 diabetes through changes in adipose tissue, the gut, pancreas, and other systems, Dr. Fukuda explained. It is possible that the positive clinical effects of GIP stem, at least in part, from previously unrecognized effects on neural pathways that link the brain, adipose tissue, and the gut. Detailing these pathways and their molecular mechanisms will likely offer new therapeutic targets to treat obesity and type 2 diabetes.
There is a good chance at least one approved diabetes agent is already working in the brain.
“We have just one effective weight loss drug on the market, the glucagon-like peptide-1 (GLP-1) analogue semaglutide, and it is currently unknown how it works,” said Tune H. Pers, PhD, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, Denmark. “It is very possible that it works through GLP-1 receptors in the hindbrain. Also, there are dual GIP and GLP-1 receptor agonists in clinical trials which potentially act, at least in part, through the hindbrain.”
Dr. Pers is using single-cell sequencing and spatial transcriptomics to map GLP-1 and GIP receptors in the hindbrain to better understand their activity. Afferent signaling from the gut enters the brain through the dorsal vagal complex situated in the lower part of the brainstem and the hindbrain. The blood-brain barrier is less tight in that area compared to most other parts of the brain, he explained. A more permeable barrier may make it possible to target structures such as the dorsal vagal complex and cell types in the hindbrain without directly affecting too many other parts of the brain.
“The signaling networks that we are trying to characterize are, to a large extent, new to all of us,” Dr. Pers said. “Until quite recently, we didn’t even know exactly which hindbrain cell types express GIP and GLP-1 receptors. This entire symposium is the latest information on one of the newest and most promising areas of diabetes research.”
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