Insulin resistance

9 December 2001. Related: Conference reports, Lipodystrophy Workshop (IWADRLH) 3rd Athens 2001.

The role of insulin resistance dominated the first of the basic science sessions looking to identify the underlying mechanisms for lipodystrophy and metabolic changes. Protease inhibitors have previously been shown to cause insulin resistance and at last year’s meeting a study in HIV-negative individuals receiving indinavir showed a decrease of insulin-stimulated glucose disposal.

Murata and colleagues from Washington University in St Louis hypothesised that direct inhibition of the transport activity of the glucose responsive transporter GLUT-4 contributes to the insulin resistance seen in HIV-positive people on PI therapy. [1] They found that indinavir inhibited insulin-stimulated glucose uptake in 3T3-L1 adipocytes and that this was acute and reversible. Further research from this group was presented by Paul Hruz showing acute and reversible changes in whole body homeostasis in rats that again supported the contribution of GLUT-4 inhibition to the development of insulin resistance.

Noor and colleagues from UCSF showed evidence of the acute effect of indinavir on glucose disposal in vivo. [2] The proposed mechanism for this was again that PIs acutely block the GLUT-4 transporter. This study therefore looked at whether a single therapeutic dose of indinavir would decrease insulin-stimulated glucose disposal without affecting other aspects of insulin action.

Six individuals were studied twice within a 7-10 day period, once with 1200mg indinavir and once with placebo during a 180-minute euglycemic hyperinsulinemic clamp. Comparable insulin and glucose concentrations were reached during the clamp period. However, the rate of glucose infusion required to maintain euglycemia was significantly lower on indinavir (P<0.05) compared to placebo. The glucose disposal rate per unit of insulin (m/l) also decreased significantly on indinavir (14.1 ±1.2 to 9.2±0. mg/kg/min, P<0.001).

Although these studies specifically focused on indinavir, researchers see this as a class rather than drug specific effect – the greater solubility of indinavir making it an easier compound to investigate.

Behrens and colleagues from Hanover Medical School used positronemission tomography (PET) to identify defects of muscle uptake in 6 HIV-positive patients on HAART to 6 patients who were treatment naïve, finding whole body glucose was significantly reduced in patients on HAART (1.4±0.38mg/kg/min) compared to untreated patients (4.07 ±0.90 mg/kg/min; p=0.025). [3]

Medical interventions

Caron and colleagues from Paris looked for a preventative impact of the insulin sensitising drug rosiglitazone that augments the activity of PPARgamma. [4] This group looked at the action and impact of protease inhibitors on adipogenesis and the response to insulin and apoptosis in 3T3F442A adipocytes and found adipocyte differentiation to be decreasing in rank order for indinavir, nelfinavir and amprenavir respectively. Rosizlitazone was found to prevent this PI effect on cell differentiation and was suggested as a therapeutic possibility.

Elevated levels of free fatty acid (FFA) associated with lipodystrophy were hypothesised by Grinspoon and colleagues as being responsible for insulin resistance. This group reported improved insulin sensitivity following administration of 1000mg acipimox, a powerful lipolysis inhibitor, in two divided doses. This was a randomised controlled placebo study in seven HIV-positive men with lipodystrophy and hyperinsulineamia. Frequently sampled intravenous glucose tolerance tests were performed twice for each patient (separated by 37 days) and acipimox or placebo was given in a doubleblinded randomised order.

Baseline characteristics:

Results

Acipimox produced a clear and statistically significant reduction in free fatty acid AUC and increase in insulin sensitivity. The study concluded that strategies to reduce FFA concentrations might be appropriate as a treatment for people with metabolic disturbances and lipodystrophy.

References:

1. Murata et al – Inhibition of cellular glucose uptake by indinavir. Abstract 1. Antiviral Therapy 2001; 6 (Supplement 4):3.
2. Noor et al – HIV protease inhibitor indinavir inhibits insulin stimulated glucose disposal: a randomised placebo controlled study. Abstract 3. Antiviral Therapy 2001; 6 (Supplement 4):4.
3. Behrens et al – Impaired glucose transport and glucose phosphorylation in skeletal muscle assessed by flourodesoxyglucose positron emission tomography in HIVpatients on HAART. Abstract 4. Antiviral Therapy 2001; 6 (Supplement 4):4.
4. Caron et al – Differential in vitro effects of indinavir, nelfinavir and amprenavir on cell differentiation, insulin sensitivity and apoptosis in an adapted adipose cell model: preventive impact of rosiglitazone. Abstract 24. Antiviral Therapy 2001; 6 (Supplement 4):17.
5. Grinspoon et al – Acute inhibition of lipolysis improves insulin sensitivity in patients with HIV lipodystrophy and insulin resistance.