An Enzyme’s Protective Role

Long-running study leads to potential therapeutic target for people with type 1 diabetes

Young woman outdoors with backpack wearing a glucose monitor
Image: Courtney Hale / E+ Getty Images

 

Nearly two million Americans have type 1 diabetes, in which the body does not produce enough insulin to effectively manage blood sugar, leading to high blood sugar levels, or hyperglycemia. Persistent hyperglycemia puts people with diabetes at increased risk for heart disease, nerve damage, loss of sight, kidney disease, and premature death. Controlling blood sugar through the use of insulin can prevent and delay these complications of diabetes.

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Now, scientists at Harvard Medical School and Joslin Diabetes Center, led by George King, HMS professor of medicine and chief scientific officer at Joslin, have shed new light on how hyperglycemia contributes to kidney disease, and they have uncovered a potential therapeutic target. Their work, published in the Journal of Clinical Investigation, rests on a unique, long-running observational study of more than 1,000 people living with type 1 diabetes known as the Medalist Study.

Since 2003, King and colleagues have been studying people living with the disease for 50 years or more. The Medalist project has revealed surprising details about this remarkable cohort of participants. For example, as many as 30 percent of people with diabetes experience kidney disease, but just 13 percent of Medalists do. People involved in this study are called Medalists because they have all received a medal from Joslin to acknowledge their success in managing diabetes for a half century or longer.

Prior studies of Medalists by King revealed that individuals who were protected from diabetic kidney disease showed elevated levels of glucose-metabolizing enzymes compared with people with diabetes who developed diabetic kidney disease. King and colleagues suspected these enzymes, such as pyruvate kinase M2 (PKM2), may play a protective role, neutralizing some of the damage hyperglycemia typically causes to the kidney.

“There is intense interest in identifying the mechanisms underlying the toxic effects of hyperglycemia,” said King, who is also section head of vascular cell biology at Joslin. “We have demonstrated at the molecular level that activation of PKM2 can increase an important protective factor for the kidney called vascular endothelial growth factor to normalize and maintain kidney function to prevent the dysfunction induced by chronic diabetes.”

Inspired by their previous findings, King and colleagues, including first author Jialin Fu, HMS research fellow in medicine at Joslin, used mice genetically engineered to overproduce PKM2 to uncover its role in protecting the kidney from the effects of diabetes. After seven months, the researchers compared the kidneys of the engineered mice to those of wild type, or nonengineered, mice with and without induced diabetes. The mice engineered to produce high levels of PKM2 demonstrated healthier kidneys than their wild type counterparts with diabetes.

“In this experiment, we made the surprising finding that overexpression of one enzyme in a subset of kidney cells can normalize kidney function and metabolism, even after seven months of elevated blood sugar levels,” said Fu. “These improvements of metabolism could benefit diabetic kidney disease, even in the presence of systemic inflammation, a common feature of diabetes.”

Specifically, the scientists demonstrated that the overexpression of PKM2 prevented multiple pathological changes to the cells of the kidney’s filtration system frequently seen in diabetes. The enzyme’s action preserved cell function and prevented disease progression. While further research is necessary, the findings support PKM2 as a potential therapeutic target for the prevention of diabetes-related kidney disease. The results also suggest that monitoring PKM2 levels in the blood could also serve as a biomarker, allowing physicians to keep tabs on and predict the progression of diabetic kidney disease in patients with diabetes.

This work was supported by the National Institutes of Health (5P30-DK-036836, R01-DK-053105), National Institute of Diabetes and Digestive and Kidney Diseases (1DP3-DK-094333-01), Mary K. Iacocca Research Fellowship Award, American Diabetes Association (ADA) Scientific Sessions Young Investigator Award, Hiroo Kaneda Fellowship from Sunstar Foundation, American Diabetes Association (9-18-CVD1-005); ADA Mentor-Based Postdoctoral Fellowship Award.

The authors have no conflicts of interest to disclose.

Adapted from a Joslin news release.