Conventional wisdom says diabetes results from dysfunctional beta cells caused by autoimmune destruction or metabolic disorders. But mounting evidence suggests that the central nervous system (CNS) plays an important, and perhaps a dominant role in the pathogenesis and progression of at least some forms of diabetes. Many of these dysfunctional pathways appear to come together in the hypothalamus.
“It is known that the brain, specifically the hypothalamus, interacts with the functioning of some organs, such as the pancreas and the gut,” said Vincent Prevot, PhD, of Inserm and the University of Lille, France. “The brain talks to the organ system, and in response the organ will release a hormone—insulin, for example, or GLP-1. And the organs, and maybe muscles or other systems signal to the brain that the commands given were fully implemented and everything is fine. But we didn’t know how the brain and the periphery talk to each other.”
The problem, Dr. Prevot explained, is that insulin, GLP-1 (glucagon-like peptide-1), and other hormones are peptides and the brain sits behind the blood-brain barrier that blocks macromolecules. Hormone-mediated signaling between the brain and other tissues should not be possible, but it’s also necessary for homeostasis.
But not every structure within the brain is behind the blood-brain barrier. The median eminence of the hypothalamus was described in the 1970s as a signaling conduit between the brain and the pituitary gland, Dr. Prevot explained. It’s also a conduit for insulin, GLP-1, leptin, and possibly other hormones.
Specialized cells, tanycytes, transport these and likely other hormones from the circulation into the cerebrospinal fluid to interact with the CNS. Blocking the transport system can induce severe type 2 diabetes in mouse models.
“Diabetes may be caused by a communication breakdown between the brain and the periphery,” Dr. Prevot said. “Because of the brain dysfunction, mice no longer release insulin in response to glucose, but do not become obese. This is very similar to the East Asian type 2 diabetes we see in Korea and Japan.”
Dr. Prevot will discuss the emerging role of tanycytes in energy control during the symposium Central Nervous System Control of Systemic Metabolism on Monday, June 6. The two-hour session, which begins at 2:15 p.m. CT in Great Hall B at the convention center, will also be livestreamed for virtual meeting participants.
The session’s other presenters will explore the latest findings in gut-brain signaling in the hypothalamic detection of macronutrients, the role of the ventromedial hypothalamus in glucose disposal, and mechanisms by which repeated episodes of hypoglycemia can lead to hypoglycemia unawareness.
“Most neurons use glucose as fuel, but a subset of neurons use glucose as a signal as well,” said Sarah Stanley, MB, BCh, PhD, Associate Professor of Medicine, Endocrinology, Diabetes, and Bone Disease, and of Neuroscience at the Icahn School of Medicine at Mount Sinai. “We see many glucose-sensing neurons in the hypothalamus, which is not surprising given that the hypothalamus plays a big role in controlling blood glucose.”
There are two types of glucose-sensing neurons, Dr. Stanley continued. Glucose-excited neurons are activated by high glucose levels while glucose-inhibited neurons are activated by low glucose levels, she said.
Repeated activation of glucose-inhibited neurons by repeated episodes of hypoglycemia can result in physical changes to their mitochondria. Mitochondria in glucose-inhibited neurons elongate in response to a single episode of low glucose, but this mitochondrial response is lost after repeated activation when the cells are unable to sense hypoglycemia. In mice experiencing repeated hypoglycemia, drugs that block mitochondrial fission to maintain elongated mitochondria can restore neurons’ ability to detect low blood glucose levels.
“Neural populations play a profound role in restoring blood glucose to normal and can override peripheral organs,” Dr. Stanley said. “It looks like circuits from the central nervous system to peripheral organs can act almost as master regulators. It’s important to understand which CNS circuits regulate blood glucose and their roles. And, eventually, we may be able to harness these circuits to improve glucose control.”
The session’s two other presenters are J. Nicholas Betley, PhD, of the University of Pennsylvania, and David Olson, MD, PhD, of the University of Michigan.