Sugar Highs

An Ongoing Study Looks at Insulin Resistance as a Possible Cause of
Abdominal Fat Accumulation
by Chael Needle

[Treatment Horizons]

Lipodystrophy—abnormal fat changes—in HIV-positive individuals remains a persistent problem: We don't know exactly why our body’s fat is redistributed and we don't know how to treat it. A currently enrolling trial, ACTG 5082, is a treatment study looking at the relationship, if any,
between hyperinsulinemia (high insulin levels) and an elevated waist/hip ratio in HIV-positive individuals, currently using anti-HIV meds, in an effort to better understand lipodystrophy and map out possible treatment directions.

Insulin, a hormone produced by the pancreas, regulates blood sugar levels: After a meal, sugar is absorbed into the bloodstream from the intestines; in response to this increase in blood sugar level, insulin is produced in order to absorb sugar from the bloodstream. Insulin resistance, which typifies type II diabetes, means that the body’s cells are responding sluggishly to insulin and not absorbing the sugar efficiently. Increased blood sugar levels can lead to diabetes, which can be life-threatening.

Dr. Kathleen Mulligan, who, along with Dr. Steven Grinspoon, is co-chairing the study, specified, however, that the ACTG study was not looking at “lipodystrophy”—a term whose definition has not yet been agreed upon and unusable if one wants to focus on a particular site on the body, where fat has accumulated or wasted away, with the intent to treat. “In fact,” she says, “a treatment that might help one person may also be harmful to someone else, depending on what their specific symptoms are. For example, a drug that works for fat accumulation in the belly may make peripheral fat wasting worse.” The study, then, is looking to see if increased waist/hip ratio is caused by hyperinsulinemia, a condition often found in HIV-positive patients with lipodystrophy, by using two drugs that have been FDA-approved for the treatment of type II diabetes, rosiglitazone and metformin. “[T]hey work in different ways,” says Dr. Mulligan, an Associate Professor of Medicine at the University of California, San Francisco. “Rosiglitazone mainly improves the way that muscle responds to insulin, while metformin works more by decreasing the amount of sugar the liver puts out. By studying each drug alone and the two drugs in combination, we can learn if it is better to attack one or the other target or if the best approach is to attack both.” The study, she says, also has to take into account that not everyone with lipodystrophy has insulin resistance.

Both metformin and rosiglitazone work toward the same result: overcoming insulin resistance by controlling blood sugar. This regulation can lessen the accumulation of fat. Hyperinsulinemia and abdominal obesity have been associated with increasing the risk of coronary artery disease.

Says Dr. Mulligan: “We don't know if insulin resistance is a cause or a consequence of altered fat distribution. We do know that each of these drugs has been shown to have some—although not consistent—efficacy in patients with HIV infection and fat distribution abnormalities, either by improving insulin sensitivity or through some other mechanism.” Dr. Judith Currier, who heads the UCLA trial site, explains how these drugs are being used as a “probe”: “If we give medicine that improves insulin sensitivity, and [this form of] lipodystrophy gets better, that tells us maybe that it is a key factor in the development of lipodystrophy. Then we would determine how we can prevent people from getting insulin resistance, which drugs [if any] are associated with it, and how we can reduce it.”

She continues: “The premise is that there's evidence to suggest that some HIV medications may predispose people to developing insulin resistance and a fair number of people with body shape changes, particularly increases in abdominal fat and possibly lipoatrophy, have some degree of insulin resistance. So to try to understand the link between insulin resistance and lipodystrophy, researchers have designed studies to test that by giving medications that will improve insulin sensitivity and then looking to see if improving insulin sensitivity improves body shape changes.” Whether metformin or rosiglitazone would become drugs that are routinely used to treat lipodystrophy is not the issue, she says. “It would be as if we are using a drug to treat the side effect of another drug, and we’re really using them to understand the cause and it may be beneficial for some people but we also have to ideally remove whatever’s causing the insulin resistance in the first place.”

Chael Needle wrote about the Patient History Card in the July issue.

August 2003