Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy

Abstract

Insulin resistance is a frequently observed side effect of highly active antiretroviral therapy (HAART). Currently, very little is known about the mechanisms or specific tissues involved. We aimed to identify possible defects in skeletal muscle glucose uptake and metabolism in HIV patients receiving HAART. Whole-body glucose disposal and oxidation were determined by combination of the euglycemic-hyperinsulinemic clamp technique and indirect calorimetry. Muscle glucose uptake of the thighs was measured simultaneously by dynamic 2[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. Patients receiving HAART had signs of lipodystrophy as confirmed by dual energy x-ray absorptiometry. Whole-body glucose disposal was significantly reduced in these patients compared with untreated patients. Analysis of kinetic constants using a three-compartment model indicated reduced skeletal glucose uptake caused by significantly impaired glucose transport and phosphorylation. Skeletal muscle glucose uptake was reduced by 66% in treated patients and explained 46% and 43% of whole-body glucose disposal in patients on HAART and therapy-naive patients, respectively. Insulin-stimulated whole-body oxidative and nonoxidative glucose disposal was significantly lower in the treated group, as was suppressive insulin action on lipolysis. To our knowledge, this is the first report providing in vivo evidence that, in lipodystrophic HIV patients, impaired glucose transport and phosphorylation cause reduced insulin-mediated glucose uptake.

Figure 1

Three-compartment model for the F-18-FDG kinetics of the PET data. Dynamically acquired PET data and arterial plasma time course of F-18-FDG activity were used as input functions in the compartmental modeling. The rate constants represent inward transport (k₁), outward transport (k₂), and phosphorylation (k₃) of F-18-FDG.

Figure 2

Whole-body glucose utilization during euglycemic-hyperinsulinemic clamp. The left panel represents the insulin-stimulated systemic glucose uptake (M) per kg FFM during clamp in both patient groups. The middle and right panels depict the correlation between whole-body glucose utilization and the rate constants k₃ (middle) and K (right) for F-18-FDG uptake from three-compartment modeling. K is a PET parameter of F-18-FDG clearance from blood to muscle.

Figure 3

Influence of insulin infusion on glucose metabolization assessed by indirect calorimetry. (a) Glucose oxidation, basal (white bars) and during clamp conditions (black bars), in untreated HIV patients and patients on HAART. (b) Nonoxidative glucose metabolism during clamp in both study groups.

Figure 4

Rate constants from three-compartment modeling of dynamic PET for F-18-FDG metabolism. Comparison of therapy-naive patients (white regions) and patients on HAART (gray regions). k₁ (ml/min/ml) and k₂ (min^–1) represent the inward and outward transport, respectively, from the extracellular into the intracellular compartment. k₃ (min^–1) is the rate constant for the phosphorylation of F-18-FDG. Data are median and interquartile range; the bars represent the complete range. P values represent results of Mann-Whitney statistics between groups.

Figure 5

Differences in the distribution volume (DV_CE) and the PF of F-18-FDG metabolism. DV_CE (left panel) reflects glucose transport, and PF (right panel) quantitatively describes the relative influence of glucose phosphorylation on the overall rate of glucose utilization. Both parameters were significantly higher in therapy-naive patients (white regions) than in patients with lipodystrophy on HAART (gray regions).