Diabetes Forecast

What’s Happening in the Brain During Hypoglycemia Unawareness?

Janice Hwang, MD, MHS
Anthony DeCarlo/Yale School of Medicine

Janice Hwang, MD, MHS

Endocrinologist at the Yale School of Medicine


American Diabetes Association Research Funding
Clinical Translational Research

One of the most unpleasant, fearsome consequences of diabetes is hypoglycemia. It’s what happens when your blood glucose drops dangerously low. Symptoms usually include dizziness, shakiness, sweating, and intense feelings of hunger. “It’s scary, and it feels terrible,” says Yale School of Medicine endocrinologist Janice Hwang, MD, MHS.

As frightening as the symptoms of hypoglycemia can be, they are, in fact, a defense mechanism. They’re the body’s way of calling for help, prompting an immediate reaction: Get food, fast.

Yet after frequent hypoglycemic episodes, some people—particularly those with type 1 diabetes—develop what doctors call hypoglycemia unawareness. That’s when blood glucose levels drop but there are no symptoms to provide a warning. “That could put you in harm’s way because the body’s lost its defense mechanisms to tell you to act,” Hwang says.

She wanted to know more about the causes of hypoglycemia unawareness—specifically, if the brains of people with hypoglycemia unawareness reacted differently to low blood glucose than those of people still sensitive to the body’s signals. Ultimately, her goal was to see if hypoglycemia unawareness could be reversed so people could regain their warning systems.

With the help of a grant from the American Diabetes Association, Hwang set up an experiment using functional magnetic resonance imaging and spectroscopy (fMRI/MRS), which monitors brain activity in real time. She put people with type 1 diabetes and a history of hypoglycemia unawareness on an IV drip of insulin and dextrose, a sugar the body converts into glucose. By adjusting the levels of sugar they were getting through the IV, she was able to artificially induce mild hypoglycemia and see what happened in their brains when their blood glucose got low.

When she compared their brain scans to scans of healthy individuals and to those of people with type 1 diabetes still sensitive to lows, the differences were obvious. “Frequent hypoglycemia and variable blood sugar can influence how blood glucose gets into the brain and is sensed,” Hwang says.

In hypoglycemia-sensitive brains, regions connected to cravings and the brain’s planning and control centers lit up in response to a drop in blood glucose levels. That makes sense: The priorities in a blood glucose crisis should be wanting carbohydrate and figuring out how to get it.

In people with hypoglycemia unawareness, on the other hand, “virtually no places in the brain light up,” Hwang says. “When we expose them to moderate lows, people with hypoglycemia unawareness have very minimal changes in the brain.”

Hypoglycemia unawareness is a short-term problem that often comes with long-term consequences. With no way to know when blood glucose is dipping dangerously low, hypoglycemia-unaware people can be reluctant to keep their blood glucose levels tightly managed. With higher blood glucose levels, they run a greater risk of complications such as retinopathy and cardiovascular disease later on. Study after study has shown that tight glucose management is the best way to prevent long-term complications of diabetes. “If we could restore hypoglycemia awareness, it would go a long way to improving adherence,” says Hwang. “A big limiting factor to tight control is fear of hypoglycemia.”

What’s still unclear is whether hypoglycemia unawareness is reversible. Hwang hopes that knowing more about how hypoglycemia unawareness works will help researchers develop ways to turn it around.

Her next step is to set up experiments to investigate the current theory that sustained periods without hypoglycemic episodes can reboot the brain’s hypoglycemia sensors. To do so, her team has started a clinical trial to put patients with hypoglycemia unawareness on new insulin delivery systems that combine continuous glucose monitors (CGMs) and insulin pumps, minimizing or preventing hypoglycemic episodes and variability of blood glucose levels. After a few months, she will test their brains again to see if they light up the way they should.

In the meantime, she says, it’s important for patients to have open conversations with their health care teams about hypoglycemia. “Doctors spend so much time getting A1C down, they don’t spend enough time addressing people’s fears of hypoglycemia,” she says. “And that’s the root cause of a lot of patients’ problems with adherence.”

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