Houston Daily

A researcher at the University of Houston has identified a potential new approach to managing diabetic ketoacidosis, a serious complication affecting people with diabetes. The research focuses on reducing ketone levels in diabetic patients and increasing their exercise capacity to improve health outcomes.

Diabetic ketoacidosis occurs when there is not enough insulin in the body, leading to high blood sugar and an accumulation of ketones that can make the blood acidic. This condition is life-threatening if left untreated and affects approximately 20-30% of the 830 million people worldwide living with diabetes.

Ravi K. Singh, assistant professor of pharmacology at the University of Houston College of Pharmacy, led a team that studied a muscle-specific protein isoform called MEF2Dα2. This protein is produced through alternative splicing after birth and is only present in muscles, which are significant consumers of ketone bodies when at rest.

Singh's team used CRISPR/Cas9 gene editing technology to investigate the function of MEF2Dα2. "Our findings identify a new role for the MEF2Dα2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity and systemic ketone body levels," Singh reported in EMBO reports. "It is often assumed that if ketones are produced and released in the bloodstream, they will be utilized by peripheral organs. Our work shows that the optimum utilization of ketone bodies in skeletal muscle is regulated by the muscle-specific variant of MEF2D gene, MEF2Dα2."

When researchers disabled this protein using CRISPR technology, they observed reduced expression of enzymes responsible for using ketones in muscle tissue. As a result, muscles were less able to use ketones for energy, leading to higher levels of ketones in the blood after exercise or following a high-fat ketogenic diet. The study also found that subjects lacking MEF2D⍺2 had reduced capacity for physical activity.

"A reduced utilization of ketones by skeletal muscle led to increased ketone levels in the blood after exercise and after eating a high-fat keto diet. In the future, our findings can be utilized to increase exercise capacity or reduce high ketone body levels in diabetic patients for better health outcomes," said Singh.

The research team included members from several institutions: Xuan Ji from University of Houston College of Pharmacy; Sushil Kumar, Hina Iqbal, Brittany Mis, Devanshi Dave, Suresh Kumar, Jacob Besler and Ranjan Dash from Medical College of Wisconsin; and Xiangnan Guan and Zheng Xia from Oregon Health & Science University.