Move over, islet cell loyalists. A brain-centered theory of diabetes pathogenesis has returned and is looking for cooperation.
The idea that the brain plays an important role in glucose homeostasis is not exactly new, though it has been overlooked for quite some time. In the 19th century, Claude Bernard induced diabetes in rabbits by injuring the floor of the fourth cerebral ventricle.1 The discovery of insulin in 1921, however, drew attention away from the brain-centered view of diabetes. Since then, the islet-centered view has dominated.
Recently, an international group of researchers has proposed to revive the brain-centered theory. In a review article published in the journal Nature, scientists from the US and Germany describe a brain-centered glucoregulatory system (BCGS) that helps maintain glucose homeostasis via insulin-dependent and insulin-independent mechanisms.2
Research on the BCGS
The new model proposes that the BCGS is part of a dynamic system. Islet cells still play a role, but the main point is about cooperation between islet cells and the brain. Most current research on the BCGS has focused on type 2 diabetes mellitus.
Researchers were clued into the brain’s role in glucose metabolism by observations of patients whose type 2 diabetes went into remission after bariatric surgery. Studies of genetic syndromes, such as lipodystrophy, also showed that hyperglycemia is harder to control in leptin-deficient conditions (leptin acts on the hypothalamus to control weight and hunger, and is implicated in glucose control). Animal research dating back more than 15 years also carved out a role for glucose, insulin, leptin, GLP-1 (a gut hormone that increases insulin secretion and is impaired in diabetes), and FGF19 (a gut hormone that acts on liver and fat tissues to lower blood sugar levels) in providing signals to the BCGS.
Critical to the BCGS model is a concept called “glucose effectiveness (GE).” GE describes the ability of rising blood glucose levels to lower themselves through insulin-independent mechanisms. About 50% of overall glucose lowering, the researchers suggest, happens through insulin-independent means. The mechanisms have yet to be understood, but scientists think that GE can help explain type 2 diabetes pathogenesis.
“There are islet-based components, which include insulin secretion and changes in glucagon release,” explained Michael Schwartz, first author of the paper and professor of medicine at the University of Washington, Seattle. “Then there is the insulin-independent component, the glucose effectiveness. We think that some amount of that GE is coordinated by the brain, which can increase glucose effectiveness.”
Dysfunction in the BCGS
The new model implies that one side of the system can compensate when the other side malfunctions, but not forever. Impairment on one side sets up a downward spiral of secondary injury to both sides. It takes failure on both systems for diabetes to develop.
Since the BCGS uses insulin and leptin to drive its own function, loss of these inputs affects peripheral tissues as well as the BCGS. Damage to the neurocircuits, especially the medial portion of the hypothalamus (thought to be the critical site) could also lead to impaired glucose tolerance.
BCGS and Type 1 Diabetes
According to Schwartz, uncontrolled type 1 diabetes and deficiencies in insulin and leptin (which depends on insulin) go hand in hand. Disruptions in these two major inputs would also cause dysfunction in the brain. Giving insulin back should restore functioning of the adipose tissue, the theory goes, which would result in generation of new leptin and bring the system back into balance. Animal studies seem to bear this out. Giving a large amount of leptin or infusing leptin into the brain of animals with type 1 diabetes has been shown to eliminate the need for insulin.
“The extent to which you can target the brain as a treatment for type 1 diabetes still needs to be worked out,” Schwartz emphasized. “I think it’s certainly a possibility that warrants consideration, especially seeing as how there aren’t really any other major targets left for treating type 1 diabetes.”
The Future: Remission in Type 2 Diabetes
Current limitations in insulin-based therapies exist, this new theory suggests, because they only target one side of the system. Although still theoretical, treatments targeting both the BCGS and islet-centered model could control blood sugar better, and even hold the potential for inducing remission in type 2 diabetes.
“I think the potential is there, but it’s all very early. Our paper was really the first one to put forth this concept,” Schwartz pointed out. “The main point is that the brain plays a bigger role in control of blood sugar than has previously been thought.”
Take Home Points