Hanaoka800640An ongoing study examining whether insulin resistance contributes to muscle weakness and physical impairment may lead to new interventions for people with rheumatoid arthritis (RA).

Principal investigator Beatriz Hanaoka, MD, a rheumatologist at The Ohio State University Wexner Medical Center, is leading a clinical trial to determine whether treatment with the insulin-sensitizer drug pioglitazone improves skeletal muscle function. Her findings could help people with RA become more active, which is a key to maintaining functional independence.

RA linked with muscle weakness, insulin resistance

Previous research has established that the systemic inflammation associated with RA affects muscles as well as joints. Nearly two-thirds of RA patients suffer from loss of skeletal muscle mass, which causes weakness and subsequent disability  but scientists aren’t sure why.

“Even when their disease is well-controlled, RA patients often have abnormalities in body composition such as lower muscle mass and excess abdominal fat,” says Dr. Hanaoka, whose research is funded by a five-year, K23 award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“Current RA treatments help preserve joint function but can’t reverse muscle dysfunction, which means many patients still have poor mobility.”

Research has also shown that low skeletal muscle density is often accompanied by lipid accumulation, which reduces insulin sensitivity and muscle strength. To that end, Dr. Hanaoka suggests that increased lipid content in skeletal muscle contributes to insulin resistance  a common problem in people with RA  which may impair skeletal muscle homeostasis and function.

She also proposes that pioglitazone, a drug used to treat type 2 diabetes, will decrease this lipotoxicity  potentially improving muscle function by restoring the anabolic effects of insulin and calming inflammation.

Getting to the root cause of impairment

To test her hypothesis, Dr. Hanaoka is enrolling patients in a double-blind, placebo-controlled trial comparing RA patients with insulin resistance to non-RA controls. After measuring participants’ physical function, body composition, disease activity and skeletal muscle strength, she and her team will evaluate the effects of pioglitazone versus a placebo. They aim to confirm whether the experimental group has improved muscle function after receiving treatment for insulin resistance.

Dr. Hanaoka, an associate professor clinical at the College of Medicine, says they’ve recruited half of their target enrollment of 110 patients, and early results are promising.

“So far we’ve seen that the patients with RA are significantly insulin-resistant compared to the non-RA controls,” she explains. “We’re also seeing that inflammation is associated with higher energy expenditure, which is typical in RA patients who have muscle wasting, and that higher protein consumption may diminish that.”

Following completion of the study, which just entered its fourth year, Dr. Hanaoka says they may be one step closer to finding an important new application for an existing drug.

“If our results show that insulin resistance is an underlying but treatable cause of skeletal muscle dysfunction, it could be a game-changer,” she says. “Ultimately, we may be able to provide novel targets to prevent or manage a devastating complication of RA.”

 

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