Rush Researchers Find Possible Cause of Diabetes Related to Muscular Disorder

Malignant hyperthermia susceptibility is an inherited condition that causes a person’s body heat to increase uncontrollably during surgery or strenuous exercise, especially if it is done in the heat. While rare, the episodes of malignant hyperthermia can have devastating results, including brain damage, cardiac arrest, internal bleeding, organ failure and death.

Researchers at Rush University Medical Center now have found that malignant hyperthermia susceptibility also causes problems with glucose metabolism within muscle, leading to elevated blood sugar. The results of their study were published in the June 9 issue of eLife.

Malignant hyperthermia susceptibility is a severe reaction, usually triggered by anesthesia. An uncontrolled increase in muscle calcium causes a sustained contracture and increase in oxidative metabolism — a chemical process in which oxygen is used to make energy from carbohydrates or sugars. In turn, this greatly increases body temperature. If left untreated, the episode can result in death.

“Most people aren’t aware that they have the condition until they have an incident, which usually happens during a procedure or surgery,” said Eduardo Ríos, Lic, a professor in the Department of Physiology and Biophysics and director of the Section of Cellular Signaling at Rush Medical College, who coauthored the study.

“Before a serious reaction happens, some people go to a doctor because they had overheating or cramps or pain in the muscles. In others, the condition can manifest as hypersensitivity to statins, which are used to lower cholesterol levels,” Ríos said. “Sometimes a family member has an incident during a procedure, and that prompts other family members to be tested for this condition.”

To study the disorder, Rush entered into a collaboration with the malignant hyperthermia investigation unit at Toronto General Hospital, University Health System in Canada, where 560 participants had already enrolled over a 14-year period. Approximately 40% of them had elevated fasting blood sugar, more than double the expected amount in the age-matched general population.

Since the collaboration started, muscle biopsies (obtained from new participants by an incision through the skin to allow a sample of tissue to be cut) were sent to Rush, where they were studied in detail in Rios’ lab. A total of 170 patients were studied in the Rush lab, of which 40 completed the diabetes mechanism study.

“We found something unexpected — molecules that deal with the metabolism of glucose were modified in the patient. Muscle is a main consumer of glucose. We know that when the consumption of sugar is limited, we get diabetes,” said Eshwar Tammineni, PhD, an author of the study and research fellow in the Department of Physiology and Biophysics.

Muscle has two functions: to control movement and to store and consume glucose (a simple sugar) to fuel movement. Muscle cells have stores of calcium inside them, which signal the muscle to contract.

Changes in calcium levels enhance the use of glucose that fuel these contractions. However, variations in calcium have also been linked to diabetes, and it’s been unclear when and how these signals become harmful.

When muscles are resting, the concentration of calcium is very low. When performing an action, an order from the brain sends an electrical signal to the muscle.

That signal in the muscle cell is translated and triggers the sacs of calcium within the muscle to release the calcium. The sacs have channels (proteins) that are capable of passing calcium through them, but normally they’re closed. When the electrical signal arrives, it commands those channels to open to allow the calcium’s passage into the muscle, which makes the muscle move.

The researchers found that enzymes that help convert glycogen (the main storage form of glucose) to glucose are more active in patients with MHS, and found in different locations inside muscle cells, while the enzymes that change glucose into glycogen are less active. As a result, glucose is converted into glycogen for storage more slowly, while glycogen was converted to glucose faster.

In these patients who have malignant hyperthermia susceptibility, the channels do not stay closed, and they leak. Although it’s not enough of a leak to make the muscle contract, it causes other problems such as an alteration in glucose and glycogen balance that leads to hyperglycemia and diabetes in the long term. 

“We aren’t sure why this happens,” said Ríos. “Either the channel (protein or molecule) that allows calcium to pass through has a mutation, or other proteins are connected to that channel.”

“In the lab we found the explanation for the change in glucose consumption,” Ríos said. “The enzymes that store glucose as glycogen were inhibited by the elevated calcium, while the opposite occurred to those that convert glycogen to glucose. This is an important finding.

“Primarily malignant hyperthermia susceptibility is a calcium disease because the calcium channels are leaking. We think secondarily the leak of calcium causes the issues with glucose metabolism.”

Currently the prevalence of malignant hyperthermia susceptibility is unknown. Since most do not know they have the condition, it may be underestimated. Anywhere between 1 in 200 and 1 in 5000 people have the disorder.

These findings suggest that MHS may start decades before developing diabetes and blood sugar levels in these patients should be regularly monitored. Future studies should investigate whether drugs that block calcium from leaking may help prevent high blood sugar in patients with MHS or other conditions that cause a similar calcium leak.