La flessibilità metabolica nelle donne affette da sindrome dell'ovaio policistico

Context: Metabolic inflexibility is the impaired ability of the body to adjust fuel oxidation to fuel availability. It allows the body to switch from predominant lipid oxidation during fasting conditions to predominant glucose oxidation during insulin-stimulated conditions. This alteration in metabolic plasticity is associated with insulin resistance. Metabolic inflexibility can potentially lead to organ dysfunction and is considered a key issue among the abnormalities of the metabolic syndrome. It is still unknown whether this phenomenon occurs in women with polycystic ovary syndrome (PCOS), a condition which is frequently characterized by insulin resistance. Women with PCOS may also have reduced cardiorespiratory fitness, which is linked to insulin resistance. The metabolic flexibility in response to graded exercise intensity has not been explored in PCOS women. Objective: Our objective was to examine whether metabolic inflexibility is a feature of PCOS women, and which features may possibly contribute to this phenomenon. In this regard, we used two different models: - Study A: hyperinsulinemic euglycemic clamp - Study B: cycle ergometer exercise test Patients and Design - Study A: Eighty-nine Caucasian women with PCOS were submitted to hyperinsulinemic euglycemic clamp (insulin infusion rate 80 mU/m2 min). Respiratory exchange ratios were evaluated at baseline and during hyperinsulinemia by indirect calorimetry, to quantify substrate oxidative metabolism. Metabolic flexibility was assessed by the change in respiratory quotient upon insulin stimulation. - Study B: Fourteen sedentary lean women with PCOS and 14 sedentary age- and BMI-matched healthy controls were submitted to a maximal incremental cardiopulmonary exercise test, with breath-by-breath analysis of oxygen consumption and carbon dioxide production. After a warm-up period, 15-W increments were applied each minute up to voluntary exhaustion. In both studies total testosterone was measured by liquid chromatography mass spectrometry, and free testosterone by equilibrium dialysis. Setting: Outpatients in a tertiary care academic center. Results - Study A: Sixty-eight of the 89 PCOS women (76%) were insulin resistant, and 62 (70%) showed an impaired metabolic flexibility during the clamp. Comparison of hyperandrogenemic and normoandrogenemic women showed that the two subgroups differed in terms of several anthropometric and metabolic features. In particular, hyperandrogenemic women had greater body mass index (32.9±1.0 vs 24.7±0.9 kg/m2, P<0.001) and lower glucose utilization during the clamp (9.2±0.4 vs 10.9±0.7 mg/kg fat-free mass • min, P<0.023) and metabolic flexibility (0.09±0.06 vs 0.12±0.01, P<0.014). In multivariate analysis, metabolic flexibility was directly associated with baseline respiratory quotient and insulin sensitivity and inversely with free testosterone and free fatty acid concentrations under insulin suppression (R2=0.634, P<0.001). - Study B: Insulin sensitivity was similar in PCOS subjects and controls. VO2peak and maximal workload were significantly reduced in PCOS women. In multivariate models, VO2peak was independently predicted by serum free testosterone levels. The difference between groups in the increase in respiratory quotient during the incremental exercise test was of borderline significance (p=0.060). Conclusions: Metabolic inflexibility in response to hyperinsulinemia is a feature of PCOS women. Both insulin resistance and androgen excess might contribute to this abnormality. Further research is required to establish whether these women also show metabolic inflexibility during exercise.