Dynamic Change in Insulin Resistance Induced by Free Fatty Acids Is Unchanged Though Insulin Sensitivity Improves Following Endurance Exercise in PCOS

Abstract

Background: Insulin resistance (IR) is the hallmark of PCOS and it is known that exercise may decrease it. What is unknown is whether exercise may mechanistically alter the underlying IR, attenuating the dynamic lipid induced IR in insulin resistant subjects.Methods: 12 women with polycystic ovary syndrome (PCOS) and 10 age and body mass index matched controls completed an 8 week supervised exercise program at 60% maximal oxygen consumption. Before and after the exercise program, all participants underwent hyperinsulinaemic euglycaemic clamps with either saline or intralipid infusions. Skewed data were log transformed and expressed as mean ± SEM.Results: Before exercise, women with PCOS had a higher HOMA-IR and lower VO2 max than controls. Compared to saline, lipid infusion lowered the rate of insulin stimulated glucose disposal (M value; mg/kg/min) by 67 ± 5% (from 0.5 ± 0.03 to −0.25 ± 0.2, p = 0.01) in PCOS, and by 49 ± 7% (from 0.65 ± 0.06 to 0.3 ± 0.1, p = 0.01) in controls. The M value was significantly less in PCOS compared to controls for both saline (p < 0.01) and lipid (p < 0.05). Endurance exercise in PCOS improved VO2 max and HOMA-IR, but not weight, to those of pre-exercise control subjects. The glucose disposal rate during the lipid infusion was reduced following exercise in PCOS, indicating decreased IR (67 ± 5 vs. 50 ± 7%, p = 0.02), but IR was not altered in controls (49 ± 7 vs. 45 ± 6%, p = 0.58). The incrementally increased IR induced by the lipid infusion did not differ between controls and PCOS.Conclusion: Insulin sensitivity improved with exercise in the PCOS group alone showing that IR can be modified, though likely transiently. However, the maximal IR response to the lipid infusion did not differ within and between control and PCOS subjects, indicating that the fundamental mechanism underlying insulin resistance was unchanged with exercise.Precis: Maximal insulin resistance induced by lipid infusion determined at baseline and 8 weeks after exercise in control and PCOS women did not differ, though insulin sensitivity increased in PCOS after exercise.

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women

“…As reported previously, intralipid infusion induced insulin resistance both in control and PCOS subjects as shown by the lowering of insulin stimulated glucose disposal rates during the intralipid clamp (16). Compared to controls, the insulin stimulated glucose disposal rate showed greater suppression in PCOS (16). In our study, fetuin-A was found to be significantly higher in PCOS compared to controls, but there were no significant differences observed for FGF19, FGF21, and FGF23 between the groups.…”

“…We further studied the role of short-term hyperlipidemia mediated insulin resistance induced by intravenous administration of intralipid via lipid clamp and insulin administration via HIEC on plasma levels of endocrine FGFs and fetuin-A. As reported previously, intralipid infusion induced insulin resistance both in control and PCOS subjects as shown by the lowering of insulin stimulated glucose disposal rates during the intralipid clamp (16). Compared to controls, the insulin stimulated glucose disposal rate showed greater suppression in PCOS (16).…”

“…Exercise sessions achieved heart rate equivalent to 60% of baseline VO 2 max. The heart rate and inspired/expired gas fractions were monitored continuously using the same instrument used in the training program for each patient (16,23). After the exercise intervention, anthropometric measurements, blood biochemistry, saline, lipid infusions, and HIEC were repeated in these subjects as reported previously (22).…”

“…Acute intralipid administration elevates circulating free fatty acid (FFA) and triglycerides, decreases peripheral glucose Abbreviations: PCOS, Polycystic ovary syndrome; T2D, Type 2 diabetes; IR, insulin resistance; IS, Insulin sensitivity; Endocrine FGF, FGF19, FGF21, and FGF23; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TCH, total cholesterol; HDL, high density lipoprotein; LDL, low density lipoprotein; TG, triglycerides; HbA1c, glycated hemoglobin; ALT, alanine aminotransferase; HIEC, hyperinsulinemic-euglycemic clamp; FGF, fibroblast growth factor; NAFLD, non-alcoholic fatty liver disease; HOMA-IR, homeostatic model assessment of insulin resistance; NEFA, non-esterified fatty acids; FSH, follicle-stimulating hormone; SHGB, sex hormone binding globulin; FAI, free androgen index. uptake resulting in increased insulin resistance (16)(17)(18). Regular exercise improves insulin signaling in skeletal muscle, promotes insulin sensitivity, improves cardio-metabolic fitness, and overall health (19).…”

Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

“…31 Increased physical activity and weight loss improve the biochemical and phenotypic features of PCOS, thus reducing metabolic complications and thereby improving quality of life. [32][33][34] Endurance exercise intervention did not reduce weight or alter plasma MOTS-c significantly in either group; however, enhanced glucose utilization, through an improvement in IS, 35 and a reduction in IR with lower plasma glucose levels were seen following the hyperinsulinemic-euglycaemic clamp in PCOS subjects ( Table 2 and Table 4). Increasing physical activity is a therapeutic option for reducing abnormalities associated with metabolic syndrome.…”