Skeletal muscle, but not subcutaneous fat, exhibits dose-dependent resistance to insulin’s antilipolytic activity in postmenopausal women with prediabetes and obesity

Insulin resistance is a hallmark of metabolic disorders, and its effects can vary across tissues. Understanding how major metabolic tissues respond to insulin in populations at risk for diabetes is crucial for elucidating the mechanisms underlying metabolic dysregulation. Objective: The purpose of our study was to examine tissue-specific impairments, or lack thereof, in the antilipolytic effects of insulin in sedentary postmenopausal women with prediabetes and obesity. Methods: Lipolysis was assessed in skeletal muscle (SkM) and subcutaneous adipose tissue (SCAT) during a hyperinsulinemic-euglycemic clamp involving low- and moderate-dose insulin infusions. Using microdialysis, local glycerol was sampled from SkM as well as abdominal and gluteal SCAT in sedentary postmenopausal women (age: 58.89 ± 1.33 yr; n = 9) with obesity (BMI: 33.83 ± 1.0 kg/m 2 ) and prediabetes (HbA1c 5.7–6.4% or fasting blood glucose 100-125 mg/dL, or 2-hour OGTT blood glucose 140-199 mg/dL). Results: Our results reveal distinct tissue-specific differences in the antilipolytic response to insulin, as assessed by dialysate glycerol concentrations. Baseline dialysate glycerol concentrations were lower in SkM compared to gluteal SCAT (SkM: 25.9 ± 5.9 µmol/L vs. Gluteal; 57.0 ± 6.1 µmol/L P < 0.01) and similar to those of abdominal SCAT (37.2 ± 3.2 µmol/L). During the low-dose insulin infusion, lipolysis was not suppressed in SkM (0.40 ± 3.0% reduction of basal levels, P = N.S.), which was in contrast to both depots of SCAT, in which there were significant reductions (abdominal: - 14.5 ± 6.0%, P < 0.01; gluteal: - 21.1 ± 5.0%, P < 0.001) in dialysate glycerol concentrations. However, lipolysis was reduced in SkM (- 20.4 ± 5.6%; P < 0.01) during the moderate-dose insulin infusion, though the reduction remained less pronounced (P < 0.05) than in the SCAT tissues (abdominal: - 40.1 ± 6.3%, P < 0.001; gluteal: - 37.8 ± 5.9%, P < 0.001). Interestingly, we observed a strong correlation (r = 0.85; R 2 = 0.72, P < 0.01) between HbA1c levels and basal SkM lipolytic activity, a relationship that was absent in both abdominal and gluteal SCAT. Conclusions: Our findings demonstrate that SkM in these postmenopausal women with prediabetes and obesity exhibits early signs of impairment in the suppression of lipolysis, particularly in response to low doses of insulin. In contrast, SCAT remained sensitive to both low- and moderate-doses of insulin, suggesting preserved antilipolytic responsiveness in these depots. These results highlight the tissue-specific nature of insulin resistance and emphasize the need for targeted strategies to address skeletal muscle dysfunction in at-risk populations. NIH R01 DK125728, Robert C. Hickner This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.