How does insulin affect lipodystrophy?

The first day of the Third International Worskhop on Adverse Drug Reactions and Lipodystrophy in Athens was largely devoted to research into insulin resistance – the loss of sensitivity to the effects of insulin, the hormone which governs the uptake of glucose into skeletal muscle – and its relationship with the lipid disturbances and body fat redistribution seen in the HIV-associated lipodystrophy syndrome.

Insulin resistance has been proposed by some as the motor which is driving the development of lipid abnormalities and fat redistribution in the lipodystrophy syndrome, but a study in healthy adults has previously shown that insulin resistance can be induced by administering free fatty acids. A study presented at this workshop by Dr Steven Grinspoon of Massachusetts General Hospital in Boston showed that inhibiting lipolysis, and thus reducing free fatty acid levels in the blood, has a direct effect on insulin resistance in patients with lipodystrophy. (Protease inhibitors have previously been shown to increase free fatty acid production.)

He administered acipomox, a compound which inhibits free fatty acid (FFA) oxidation to patients with severe hyperinsulinemia in a randomised study. Using a frequent sampled intravenous glucose tolerance test at days 3 and 7, he showed that patients who received acipomox experienced significant reductions in FFAs and a significant improvement in insulin sensitivity. While FFAs were restored to normal levels when compared with healthy control values, insulin sensitivity did not return to the normal range.

Dr Grinspoon noted that other factors may be encouraging and sustaining insulin resistance in patients on HAART. Insulin resistance itself will upregulate production of free fatty acids, and other factors shown at this workshop to affect insulin sensitivity include:

• An impaired ability in all HIV-positive individuals to extract insulin from the bloodstream when it passes through the liver, allowing more insulin into the circulation
• Indinavir (and by implication other protease inhibitors) affects glucose uptake in skeletal muscle by inhibiting GLUT 4, a glucose transporter, possibly by binding directly to the protein. The inhibition was shown to occur within minutes of feeding indinavir to rats, and to decline quickly once indinavir infusion was stopped (Hruz; Noor).
• Existing fat distribution, genetics and insulin sensitivity at the time of beginning therapy will also affect insulin metabolism

However, a study in healthy volunteers showed that whilst indinavir had an immediate effect on glucose disposal, this change was not accompanied by any increase in free fatty acid levels when a single dose of indinavir was administered (Noor). Effects of long-term indinavir treatment on insulin sensitivity and free fatty acid production need to be evaluated further to shed more light on which factor comes first, and which of these factors is reinforcing the primary driver of the mechanism once it gets underway.

Measuring insulin resistance may be critical to understanding how the syndrome begins to take shape. Several speakers recommended that insulin resistance needs to be measured at the time of peak drug concentration in order to capture a drug’s effect on insulin sensitivity, since all the studies presented today showed that peak drug concentrations correlated with the greatest reduction in glucose uptake. However, it is worth noting that this recommendation is based on the assumption that one agent alone in any combination would be responsible for inducing insulin resistance; in practice, it may be more difficult to determine which drug is associated reduced insulin sensitivity, and time measurements accordingly. Steven Grinspoon showed that d4T was the only drug significantly associated with insulin resistance – and an increased rate of free fatty acid flux. However, this study did not look at the effect of d4T with or without protease inhibitor treatment because the study group wasn’t large enough to draw statistically meaningful conclusions.

Regardless of the potential effects of multiple agents in a regimen, these findings do raise the possibility that the incidence of insulin resistance is currently being underestimated in clinical trials, and in cross-sectional studies which have helped to establish the prevalence in the population. The definitions of lipodystrophy used in studies may themselves have an effect on the insulin resistance detected in a population, leading to further confusion about the significance of insulin resistance in this syndrome.

Stephen O’Rahilly of Cambridge University pointed out that genetically engineered mice which lack the GLUT 4 transporter protein do not become centrally obese immediately after developing hyperinsulinemia; it is a slow process, and similarly, some people treated with HAART may compensate for reduced glucose uptake in a variety of ways which are not immediately evident, or may develop relatively moderate insulin resistance.

What is the relationship between insulin resistance and fat redistribution?

In HIV-negative adults, insulin resistance and reduced glucose tolerance are associated with central obesity. Insulin sensitising treatment with drugs of the glitazone class may work by increasing levels of subcutaneous fat at the expense of intrabdominal fat. A group from Baylor College in Houston, Texas, reported on 9 patients with insulin resistance and lipodystrophy but normal glucose tolerance, who were treated with rosiglitazone for a median of 24 weeks. Four patients experienced improvements in lipoatrophy and reductions in waist to hip ratio, as might be predicted, but no changes in lipid levels were observed. In one case, the results are muddied by a concomitant switch to a PI and d4T-sparing regimen (Visnegarwala).

In individuals who do not experience substantial increases in LDL cholesterol (the form associated with an increased risk of heart disease), the effect of impaired glucose tolerance and insulin resistance short of diabetes on cardiovascular disease is still controversial.