Diabetes drug metformin may help reduce toxic acid levels associated with MSUD -
Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the malfunctioning of an enzyme that breaks three essential amino acids: leucine, isoleucine and valine. Without treatment, infants die from toxic accumulation of keto acids resulting in the weeks following the birth. Those who are diagnosed early can live a normal life, but are forced to eat a controlled diet based on a formula. The only proven treatment for the disease, which is characterized by smelling urine is a liver transplant. Publication in Scientific Reports , researchers at the Buck Institute show that the diabetes drug metformin reduced widely used toxic acid levels associated with MSUD in both skin cells from MSUD patients and the mouse. The discovery offers the possibility of a new treatment for a disorder identified 1 180 000 births.
lead author and Buck faculty Arvind Ramanathan, PhD, says metformin reduces toxicity levels ketoisocaproic acid (KIC) in patients derived fibroblasts from 20 to 50 percent and reduced levels significantly KIC in skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path in a clinical trial and we hope that the doctors who treat MSUD patients will start to push in this direction," he said. "There is a clear need for new interventions."
Ramanathan, who specializes in metabolomics, came to MUSD discovery as he studied various compounds and enzymes that impact in the context of aging. The work could provide a mechanistic explanation for the success of metformin in diabetes control and possibly extend healthspan in animals and humans. The research also highlights the similarities between rare pediatric disease and normal aging - and shows how the study may inform the other
The researchers studied enzyme BCKDH, which is defective in MSUD and activity decreases with normal aging also declined .. Ramanathan said BCKDH is involved in obesity and diabetes; he believes he can be involved in a number of other conditions related to age well. Ramanathan also studied an enzyme upstream from BCKDH - called CTAB. He says in MSUD, CTAB converts leucine, isoleucine and valine in toxic ketones in the mitochondria of skeletal muscle -resulting in muscle weakness and atrophy associated with MUSD. "We believe that the same process may be underway with the age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with CTAB and in our treatment of MSUD mice with metformin significantly reduces the accumulation of toxic acid in skeletal muscle."
"This is an excellent example of how aging research can have a significant impact on people at any age and work also highlights the value of the study of drugs already approved by the FDA "said Brian Kennedy, PhD, co-lead author and Chief Buck Institute direction. "In this case, we hope that our discovery will help people with MUSD. We expect to build on these ideas to advance our research to extend the healthy years of life for us all."
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