Endocrine Abstracts

JOINT2488

Introduction: Impaired metabolic flexibility (MetFlex) is a key pathophysiological mechanism underlying metabolic dysregulation in obesity. It is characterised by a reduced ability to adapt metabolism in response to substrate availability. This study examined the relationship between insulin sensitivity and MetFlex in normal-weight and women with obesity and explored their association with mitochondrial respiratory function in skeletal muscle.

Methods: A pilot study included 21 normal-weight women (age 32 ± 5, BMI 21.4 ± 1.5) and 15 women with obesity (age 36 ± 7, BMI 34.3 ± 3.6). Anthropometric and biochemical parameters as well as insulin sensitivity (hyperinsulinemic-euglycemic clamp, HEC), glucose tolerance (oral glucose tolerance test, OGTT), metabolic flexibility (indirect calorimetry during HEC, OGTT) and cardiorespiratory fitness (exercise test) were assessed. Skeletal muscle biopsies were obtained for mitochondrial respiration analysis (O2K, Oroboros).

Results: All women were eumenorrheic and none had thyroid dysfunction. Women with obesity exhibited higher triglyceride levels (1.2 ± 0.5 vs. 0.7 ± 0.4 mmol/l, P = 0.0142), lower cardiorespiratory fitness (23 ± 4.5 vs 40.8 ± 5.4 ml^-1kg^-1min^-1, p=<0.0001), and reduced insulin sensitivity (5, 5 ± 2, 0 vs 11, 0 ± 2, 1 mg. kg^-1min^-1, P = 0, 001) compared to normal-weight women. Contrary to our hypothesis, MetFlex, assessed as change in respiratory quotient (ΔRQ) during HEC or glucose tolerance tests, did not differ between groups. In women with obesity, mitochondrial respiratory capacity, ATP production and fatty acid oxidation were reduced, with impaired mitochondrial membrane integrity. In all participants, respiratory capacity, ATP production and fatty acid oxidation correlated with insulin sensitivity and cardiorespiratory fitness, but not with MetFlex.

Conclusion: Our findings suggest that impaired insulin sensitivity in obese women may precede detectable changes in MetFlex. Insulin sensitivity is strongly associated with mitochondrial integrity and muscle respiratory capacity, independent of adiposity and metabolic flexibility.