When people have things in common and cross paths regularly, they often form bonds and become friends. If this were true in the world of biology, then diabetes and mitochondrial disease could become besties.
Mitochondria are organelles that sense and control cells’ energy balance. Certain defects in the way the mitochondria work may lead to diabetes, and the ways our bodies adapt to high blood sugars share many features with the ways our bodies respond to mitochondrial disease.
Exploring these intersections is essential because there are no approved treatments for mitochondrial diseases, which occur in one out of 5,000 people. And any parallels with disorders of energy imbalance, such as diabetes and obesity, could point the way to repurposing drug therapies already on the market for those conditions.
Shana McCormack, MD, a physician-scientist at The Children’s Hospital of Philadelphia, investigates potential common pathways of mitochondrial dysfunction in patients with diabetes and patients with genetic mitochondrial disorders. She combines her knowledge of cellular biology with her insights from treating children in the division of Endocrinology and Diabetes and in the Healthy Weight Program at CHOP.
Dr. McCormack made an important observation that children and adolescents with insulin resistance, a factor related to the development of type 2 diabetes, have worse skeletal muscle mitochondria function. A possible explanation is that disrupted mitochondria may not effectively process nutrients and cause decreased insulin action. Without enough insulin, the body cannot move blood sugar (glucose) into the cells. High levels of sugar remain in the bloodstream instead of getting used by muscles.
This leads to a chicken and egg question: “Which problem came first?” Dr. McCormack asked. “Did they develop obesity and insulin resistance, and then their mitochondria got sick? Or are these kids whose mitochondria wasn’t working well to begin with, and that’s why they developed these other problems?”
Dr. McCormack began thinking about her patients who have genetic mutations that cause their mitochondria not to work well. Are individuals who start off with a mitochondrial defect able to balance their blood glucose levels efficiently? With all these intriguing questions and not enough answers in the scientific literature, Dr. McCormack and her study team have launched several research projects.
MRI Assessment of Muscle Mitochondria Function
The first one is a magnetic resonance imaging (MRI) study of muscle mitochondrial function. A MRI is a noninvasive test that uses a magnetic field and pulses of radio wave energy to produce pictures of body organs and structures. Radiologists at the University of Pennsylvania’s Center for Magnetic Resonance and Optical Imaging have developed a new technique called in vivo OXPHOS quantitation by MRI that gives researchers like Dr. McCormack excellent anatomic resolution in the estimation of muscle mitochondrial function.
“In order to test a lot of these hypotheses that sick mitochondria contribute to endocrine disease, and to study the relationship between mitochondrial dysfunction and problems with the way the body handles glucose and predisposes to diabetes, we have to have a good measure of muscle mitochondrial impairment,” Dr. McCormack said. “So our first task was to ask, ‘Does this new technique pick up differences in mitochondrial function in individuals with mitochondrial disease the way we might expect that it does?’ And we’ve had very promising results so far.”
The researchers are expanding the pilot study to include more participants with a wider range of genetic mitochondrial disorders and also to see how children respond to the MRI assessment. Once the study team builds enough evidence to demonstrate that this is a reliable metric of muscle mitochondrial function, it could be used beyond research purposes to potentially improve the diagnostic process and follow how a patient is doing over a course of treatment.
Glycemic Index and Mitochondrial Disease
In a separate study, Dr. McCormack and her study team are looking at how foods’ tendency to raise blood sugar, or glycemic index, relates to mitochondrial disease. Some sources of carbohydrate such as lentils have a low glycemic index and do not raise the blood sugar much when eaten; however, other forms such as soda and juices have a high glycemic index and can elevate the blood sugar quickly. Some people with diabetes pay careful attention to foods’ glycemic index as a nutritional way to manage their disease.
“For patients with mitochondrial disease, for whom we know there is a tendency to develop diabetes more often, there is very little evidence about what those individuals should be eating,” Dr. McCormack said.
She designed a double-blind placebo-controlled crossover study in which participants with mitochondrial disease will arrive on two separate days to consume two different test shakes. The shakes are designed to look and taste similar, and they have an identical amount of carbohydrate, protein, and fat, but they do not have the same glycemic index.
“We would expect that for people with mitochondrial diseases to see a very pronounced rise in blood sugar with a higher glycemic index food because the muscles’ mitochondria don’t work as well,” Dr. McCormack said. “This might suggest that those individuals make food choices guided in part by the food’s glycemic indices.”
Also, a big glycemic excursion that quickly goes up and then comes down may not be optimal for brain metabolism. Dr. McCormack often hears from patients with mitochondrial disease that they feel foggy after consuming high-glycemic meals. So study participants will take attention and working memory tests that allow researchers to measure their cognitive capacity and see if there are any correlates to patients’ reports.
Molecular Mechanisms Underlying Glucose Processing
Both the MRI and glycemic index studies will help to inform the cellular biology work that Dr. McCormack is performing as part of a research career development award that she recently received from the National Institutes of Health, under the mentorship of Marni Falk, MD, and the guidance of Douglas Wallace, PhD, both of CHOP’s Center for Mitochondrial and Epigenomic Medicine. In the lab, Dr. McCormack will take a detailed look at cells derived from patients with genetic mitochondrial diseases to learn what molecular mechanisms might underlie the differences in how they process glucose in comparison with healthy individuals.
“CHOP is an awesome place to be doing all of this work because of its expertise in each of these areas,” Dr. McCormack said. “And we take care of so many awesome patients and families who volunteer to participate in research and really want to be able to move the care forward.”