LEXINGTON, Ky. (June 2, 2021) – Research led by University of Kentucky endocrinologist and Center for Clinical & Translational Science director Dr. Philip Kern was recently highlighted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in its 2021 Recent Advances & Emerging Opportunities report. The publication conveys important accomplishments resulting from NIDDK-funded research, as well as the enormous promise this research holds for the future.
Kern’s research demonstrated for the first time that a medication called mirabegron, already FDA-approved to treat overactive bladder, improves multiple measures of glucose metabolism in people who are overweight/obese with insulin resistance by inducing beige fat formation in their white adipose fat tissue. The findings uncover a potential new mechanism for treatment of diabetes.
Brian Finlin, Ph.D., assistant professor of internal medicine/endocrinology, was first author on the resulting paper, titled “The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans” and originally published in the Journal of Clinical Investigation.
“Mirabegron is a very well-tolerated drug with very few side effects. If it does improve insulin sensitivity and secretion, as this study suggests, it could be used to prevent the onset of or even reverse diabetes,” said Kern. As it turns out, not all fat is the same. Brown fat burns calories (energy) to generate heat, as opposed to white fat, which is more abundant in the body and stores energy. Beige fat cells have similar energy-burning properties to brown fat and can be formed in white fat by cold exposure or through activation of the protein β(beta)3 adrenergic receptor (β3AR). This receptor is present in fat cells and some bladder cells and can be stimulated by mirabegron. Recent studies in mice demonstrated that beige fat cells can improve glucose metabolism, but no study before this demonstrated a link between beige fat and glucose metabolism in humans.
The research team recruited 13 people who were overweight/obese and had either prediabetes or metabolic syndrome and treated them with mirabegron at the maximal approved dose (50 mg/day) for 12 weeks. After taking mirabegron, more than half of the participants who had prediabetes prior to treatment no longer met criteria for that condition. This finding was consistent with overall improvement of glucose tolerance, a marker of how well the body handles blood glucose.
(As a result of a PET scan required by the study, one of the participants was found to have early stage thyroid cancer. She received successful treatment at UK’s Markey Cancer Center. Check out her story here.)
The researchers further examined the participants to measure the function of β cells, which produce the insulin necessary for processing glucose, and how well other tissues respond to insulin (a measure known as insulin sensitivity). The results indicated that an improvement in both measures led to the improved glucose tolerance. Typically, improved glucose tolerance in people with prediabetes or type 2 diabetes is associated with weight loss, but the participants in this study did not experience weight loss.
The researchers then looked at how mirabegron treatment affected certain molecular markers known to be present in beige fat. They saw an increase in several of these markers in white adipose tissue, indicating the formation of beige fat cells in response to the drug. These changes correlated with the improved glucose metabolism.
When the researchers examined effects of the medication on skeletal muscle, Kern was surprised to find that mirabegron induced an increase in type 1 muscle fibers (also called “slow twitch”), which could account for improvements in insulin sensitivity in muscle. Type 1 muscle fibers, which burn fat for energy, are a natural characteristic that’s difficult for a person to change outside of extreme training.
“This was surprising because neither β cells nor skeletal muscle cells have the β3AR protein, so the effects of the drug on muscle fiber must have been indirect, likely from the changes in fat tissue induced by the medication,” Kern said.
In further experiments using muscle cells in laboratory culture dishes, the research team deduced that the effects on muscle fiber type were a result of white adipose tissue “beiging” and sending out a signal to the skeletal muscle cells.
A multidisciplinary team from across UK’s campus contributed to the research, including Hasiyet Memetimin, College of Medicine; Beibei Zhu, College of Medicine; Amy Confides, College of Health Sciences; Hemendra Vekaria, College of Medicine; Dr. Riham El Khouli, assistant professor of radiology; Zachary R. Johnson, College of Medicine; Philip Westgate, Ph.D., associate professor of biostatistics in the College of Public Health and part of CCTS’ BERD core; Jianzhong Chen, Ph.D., Saha Cardiovascular Research Center; Andrew Morris, Ph.D., professor of cardiology; and Esther E Dupont-Versteegden, professor of rehabilitation sciences.
The CCTS clinical research unit, participant recruitment team, and Wellness, Health & You program also provided support, including outreach to the latter’s LGBTQ+ community.
Based on the findings of this study, Kern and team are now conducting a placebo-controlled trial using a higher dosage of mirabegron to determine if an increased dosage solicits greater improvement in glucose metabolism.
“This kind of work requires so many areas of expertise that it’s only possible through team science,” Kern said.
Funding for this research was provided by National Institutes of Health grant R01DK112282. The UK Center for Clinical and Translational Science is funded by NIH grant UL1TR001998.