Beyond Insulin: Regulating Blood Sugar

Scientists have known since 1854 that the brain contributes to the regulation of glucose in the body. That’s when French physiologist Claude Bernard punctured the floor of the fourth cerebral ventricle of a rabbit, causing blood glucose to rise dramatically in the animal.

The brain’s role in the disease was overshadowed in 1921, however, by the discovery of insulin, which is released by the islet of Langerhans in the pancreas. After a meal, the islets release insulin, which ushers glucose from the blood stream into the body’s cells for immediate use in the production of energy, or into the liver and fat cells for storage. When people develop diabetes, they can regulate their blood sugar levels by injecting insulin.

That has been the story ever since–diabetes is a disease caused by inadequate insulin, often accompanied by cellular resistance to insulin’s action. Either way, the symptoms can be controlled by increased insulin.

Michael W. Schwartz, however, has been investigating how the brain plays a role in regulating glucose metabolism, and the insights he and his colleagues have produced may lead to new methods of controlling diabetes.

“What we have discovered, in mice at least, is that there is a direct pathway and an indirect pathway that can control glucose metabolism,” said Schwartz, director of the Diabetes and Obesity Center of Excellence at the University of Washington in Seattle. “When you’re fasting, the liver is a glucose producing machine. When you’re feeding, it becomes a glucose uptake machine. This appears to be regulated in animals even when the ability of insulin to act on liver has been disrupted. We’re still trying to figure out how that works, but I believe the brain is mediating this indirect control pathway.”

Schwartz and his colleague Gregory Morton started studying this phenomenon four years ago using rats with uncontrolled diabetes caused by the drug streptozotocin, which destroys the insulin-secreting cells in the pancreas.

“What caught our attention and changed the way we think about this was that when we took away insulin from these animals with streptozotocin, the animals also become severely deficient in another hormone, leptin,” he said. “Leptin is made by fat cells, and when you take away insulin, fat cells are stimulated to mobilize all their fat stores. They can’t store fat anymore. As a result, fat cells stop making leptin, and the rats became leptin deficient.”

So how much of the uncontrolled diabetes in the rats was caused by insulin deficiency, and how much was caused by a deficiency of leptin? Since leptin, a hormone produced by fat cells, acts on the brain to suppress hunger, Schwartz and his colleagues redid the experiment, infusing leptin directly into the brains of the rats instead of injecting it into their bodies.

“What was shocking to us was the way that blood sugar, over a couple of days, dropped to completely normal levels,” Schwartz said. “We looked to see if we had somehow rescued the defect in insulin secretion induced by streptozotocin, but there was no evidence of that. The animals were just as insulin deficient whether they got leptin or not. That led us to conclusion that brain, under the influence of leptin, has the ability to normalize elevated blood sugar in diabetic animals. That forced me to rethink my original understanding of how glucose homeostasis is achieved.”

In a paper published in the Journal of Clinical Investigation in November 2013, Schwartz, Morton, and their colleagues reported that the gut-derived hormone known as fibroblast growth factor 19, or FGF19, dramatically improved glucose tolerance in mutant mice that produce no leptin, which are used as a model of type II diabetes. Because of their leptin deficiency the mice overeat and become massively obese, and develop high blood sugar. Within two hours after injecting leptin directly into the brains of these mice, their glucose levels dropped significantly, even though FGF19 exerted no effect on either insulin secretion or sensitivity.

“The finding that the brain has the inherent ability to lower blood glucose levels via such a mechanism opens new potential avenues for diabetes drug discovery,” the authors said.

At the recent Society for Neuroscience annual meeting in Washington, DC, Schwartz presented his recent findings on “the brain-centered glucoregulatory system” as part of a symposium on “Exercise, Energy Intake, and the Brain.” The symposium emphasized the positive effects of regular aerobic exercise and moderate food intake, including intermittent fasting, on brain function, presumably because they contribute to insulin sensitivity and overall glucose metabolism.

Henriette van Praag, of the National Institute on Aging, described her research showing that mice that exercise display better memory function. She attributes this to AMP-activated protein kinase (AMPK), which is produced by muscles and finds its way to the brain, where it promotes the functional integration of new neurons in the hippocampus.

Monika Fleshner, at the University of Colorado-Boulder, discussed how regular physical activity increases resistance to the negative consequences of stress on mind and body by changing the brain’s stress-responsive neurocircuitry.

And Mark Mattson, chief of the Laboratory of Neurosciences at the NIA’s Intramural Research Program, discussed his extensive research showing that intermittent fasting promotes brain function and health.

Schwartz presented data on how the brain contributes to efficient energy metabolism – a vital function for overall health. He pointed out, for example, that exercise can help prevent inflammation of the hypothalamus, which is associated with both leptin and insulin resistance. Exercise also enhances the signaling of BDNF (brain-derived neurotrophic factor), which can enhance the action of insulin and reduce glucose in peripheral tissues, including the liver. Up to 50 percent of glucose regulation may be governed by the brain independent of the action of insulin, Schwartz suspects.

“There’s a lot of untapped potential for the brain to be a target of glucose lowering in metabolic diseases,” Schwartz said. “Most treatments for diabetes now revolve around insulin – either insulin itself or drugs that either stimulate insulin secretion or increase insulin sensitivity – but we’re nearing the limits of what can be achieved with those drugs.”

Another clue to the brain’s role in regulating glucose metabolism comes from bariatric surgery, which exerts profound effects on blood sugar that appear to be at least partly independent of weight loss.

“Bariatric surgery has very impressive glucose-lowering effects, and can more or less induce remission in patients with type 2 diabetes,” Schwartz said. “Clearly there’s a role for losing weight, which improves glucose metabolism, but there’s also evidence of a weight-independent effect.”

Schwartz suspects that the indirect pathway to glucose homeostasis that involves the brain makes a significant contribution to the effects of bariatric surgery that appear to be independent of weight loss.

“No one knows how this works, but we have reason to believe that bariatric surgery affects brain mechanisms,” he said, “and we’re gearing up to study that in a serious way.”