Researchers at the Diabetes Institute of the University of Washington and the University of Copenhagen have implicated the brain in the ability of intracranial injections of fibroblast growth factor 1 (FGF1) to restore blood sugar control to diabetic animals for long periods of time.

Their studies appeared in the Sept. 7, 2020, online issues of Nature Communications and Nature Metabolism.

Type 2 diabetes, once it is insulin-dependent, is a constant struggle.

“Patients with diabetes are normally asked to monitor their blood sugar once or many times per day,” Michael Schwartz told BioWorld. And based on the results, they need to inject drugs, typically also multiple times per day.

And those injections “don’t achieve a specific target – they don’t know what the blood sugar level is that you are trying to achieve. You try to calibrate… usually with mixed effects.”

The current strategy is effective for 50% or fewer of patients, and those patients represent 10% of the population of the U.S.

But that state of affairs may not be inevitable.

A few years ago, Schwartz, who is a professor of medicine at the University of Washington School of Medicine and co-director of the UW Medicine Diabetes Institute, and his colleagues discovered that “the brain basically has the ability to make diabetes go away,” he said, at least as far as the lack of control over blood sugar levels is concerned.

In 2016, Jarred Scarlett, who was then a postdoctoral fellow in Schwartz’ laboratory at the University of Washington, discovered that a single intracranial injection of fibroblast growth factor 1 (FGF1) could reverse hyperglycemia in diabetic rats for weeks to months.

The finding was helped along by good instincts as well as good luck. There had been work by Schwartz and others showing that peripheral administration of FGF family members had a variety of beneficial effects on metabolism – such a variety, in fact, that Schwartz began to suspect they were being centrally orchestrated by the brain.

Scarlett administered FGF1 directly into the brain of hyperglycemic diabetic rats and showed that within six hours of treatment, their blood sugar levels decreased.

Schwartz suggested that Scarlett do further testing on the animals a week later, expecting the effect to quickly disappear.

But after a week, Scarlett found that the animals’ blood sugar levels had fallen further, to within the normal range.

“And I said, ‘Well, that can’t be,’” Schwartz recounted. “And he said, ‘Well, it is.’”

But how?

Those experiments first revealed “the ability of the brain to reset the level of blood sugar into the normal range, in an animal that previously had diabetes,” Schwartz said. “The brain can establish what the defended level of blood sugar is going to be. And it can change that from abnormal to normal. Until recently it had been thought that only the pancreas can do that.”

Initially, the reports were met with “a lot of skepticism,” Schwartz said, though as his team published follow-up studies on potential mechanisms, some of that skepticism has dissipated, though certainly, he added, “you can still be skeptical [about] how it works.”

In the studies now published in Nature Metabolism and Nature Communications, the team reported several facets of that mechanism.

In studies reported in the Nature Communications paper, the team used single-cell RNA sequencing to demonstrate that glial cells were most strongly affected by FGF1 injections. Those injections appeared to increase the interaction between astrocytes, a type of glial cell, and neurons participating in the melanocortin signaling system, which is important for the regulation of feeding.

They also showed that perineuronal nets, which are extracellular matrix structures that help cells cluster, were damaged in diabetic mice and restored by FGF1 injections. When the team co-administered enzymes that degraded perineuronal nets with FGF1, the animals no longer went into remission from the treatment.

It is possible that the perineuronal nets affected the interaction between glia and neurons and, ultimately, melanocortin signaling.

Schwartz said that beyond the specifics of how specifically FGF1 achieves its effects, the findings suggest new ways of thinking about what causes diabetes, and how to approach its treatment.

“It opens up a whole new area for understanding how glucose control is achieved in the body,” he said.

One possibility is that the part of the hypothalamus that is involved in brain control of blood sugar (the median eminence of the arcuate nucleus) is a circumventricular organ, a part of the brain that is less strictly shielded by the blood-brain barrier than other anatomical sites.

“The reason that that’s important, in part, is that in order for the brain to control blood sugar, it has to sense blood sugar,” Schwartz said. In fact, it is possible that blood sugar is out of control in type 2 diabetes due to a failure of that sensing mechanism, and that FGF1 injections restore proper sensing abilities – which would explain why blood sugar levels don’t just decrease after treatment, but homeostasis is restored.

But the increased interaction with the periphery means that it may also be able to achieve central effects with peripherally administered drugs, he added: “The idea that you could target the brain with biologicals is not too far-fetched.”

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