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DRC Director's Report - March 2019

Brian T. O’Neill, MD, PhD, assistant professor in the Division of Endocrinology in the Department of Internal Medicine and member of the FOEDRC recently published in the journal Diabetes the discovery that FoxO  proteins, which are transcription factors  that regulate DNA, are the critical regulators of diabetes-related muscle atrophy.

While considerable attention has focused on the effects of diabetes on the heart, eyes, kidneys and nerves, diabetes also has a considerable impact on muscle strength and the maintenance of muscle mass. Previous studies have shown that, compared to non-diabetic individuals, patients with diabetes lose muscle strength faster during aging and/or during bed rest after a surgery. 

This loss of muscle strength leads to slower recovery from illness, disability and potentially even death. But there are no specific treatments for these conditions because the reasons for this muscle atrophy in diabetes were not previously known. Using mouse models of type 1 diabetes, Dr. O’Neill and colleagues discovered that decreased insulin signaling in muscle leads to dramatic increases in protein degradation (or breakdown), which results in muscle atrophy and weakness. 

The study proves that FoxO transcription factors, which can be directly modulated by insulin signaling in muscle, are critical drivers of protein degradation pathways by increasing genes responsible for protein breakdown. Furthermore, these same genes for protein breakdown were increased 140% to 330% in muscle biopsies from human patients with type 1 diabetes after 8 hours of withdrawal of insulin from these volunteers. 

The results demonstrate that muscle atrophy in response to insulin-deficient diabetes is mediated by FoxO-driven protein degradation and blocking this pathway may provide protection from this complication of diabetes. Ongoing work in the O’Neill lab is focused on how insulin signaling in muscle can coordinate muscle growth with energy production in the mitochondria of muscle. This recent publication in Diabetes, along with previous publications from Dr. O’Neill identify FoxOs as potential therapeutic targets to help prevent muscle loss in patients with either type 1 or type 2 diabetes during periods of illness or during aging.

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