October 24, 2001
Data from two linked presentations by Dr. Steven Grinspoon indicated that certain fats in circulation, known as free fatty acids, may contribute to worsening insulin resistance. Free fatty acids are derived from lipolysis, the breakdown of fat stored in fat cells. The presentations first looked at a cross-section of individuals and subsequently an intervention to reduce lipolysis.
In the first study, 19 HIV-positive individuals (58% of whom were on protease inhibitors (PIs), 74% on nucleoside analogs and 58% considered to have lipodystrophy) were compared with eight HIV-negative age and body mass index (BMI -- a combined measure of height and weight) matched controls.
Dr. Grinspoon and colleagues demonstrated that the treated HIV-positive patients had elevated fasting lipolysis and that lipolysis increased after a glucose challenge. This is in contrast to the control patients who saw a fall in lipolysis after a glucose challenge. This indicates that there is a reduced responsiveness or sensitivity to insulin. He also found that the amount of visceral adipose tissue -- the fat inside the abdomen -- was correlated with the levels of free fatty acids released by this increased lipolysis. The more free fatty acids, the more visceral fat. Additionally, lower levels of subcutaneous fat were correlated to higher levels of free fatty acids. Furthermore, the rate of lipolysis correlated with the severity of insulin resistance in these individuals. Insulin resistance may be a marker of risk of development of type II diabetes and may be an independent risk factor for future heart disease.
Why this is happening is unclear. Several hypotheses are possible and, in particular, it is uncertain what came first here: does increased insulin resistance contribute to increased lipolysis or does increased lipolysis contribute to increased insulin resistance? Additionally, it is unclear where and how, if at all, antiretrovirals, or indeed immune cytokines, are contributing to these findings.
In the second study, Dr. Grinspoon and colleagues evaluated the potential to intervene to reduce lipolysis and thereby reduce insulin resistance. This study evaluated just seven HIV-positive patients with lipodystrophy, high waist-hip ratio, stable on protease inhibitor therapy (on average for >3 years) and with normal fasting glucose, but with insulin levels elevated above 15 U/ml. The study evaluated the acute effects of reducing lipolysis using a drug called acipimox (1 gram given over two divided doses). Each patient repeated the study given placebo doses so that each patient could act as their own control in the analysis.
As in the previous study, when given a placebo, patients had high fasting free fatty acid levels that rose with a glucose challenge. When individuals received acipimox, the free fatty acid levels fell from their high baseline levels and fell further, as in healthy individuals, after the glucose challenge. Insulin sensitivity improved, albeit not to normal, coincident with fall in free fatty acids after acipimox. These data, therefore, indicate that the high levels of free fatty acid in persons with metabolic disturbances are contributory to insulin resistance in these patients. However, since insulin resistance did not normalize, it suggests that high free fatty acid levels are not the only answer.
What does this mean regarding potential interventions? Acipimox is not a treatment option. However, two groups of antidiabetic agents -- metformin and the thiazolinadiones, such as pioglitazone and rosiglitazone -- do lead to reductions in free fatty acids and independently act as insulin sensitizers.
Therefore these drugs may be useful in several ways in metabolic and morphological changes. This is now being investigated in a randomized ACTG organized study. As limited safety data with these drugs are available in persons with HIV, they should not be considered for use in clinical practice until data enabling evaluation of the risks and benefits of these agents are established.