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Gender Factors Affect Fatty Acids-Induced Insulin Resistance in Nonobese Humans: Effects of Oral Steroidal Contraception¹

Divisions of Internal Medicine I (G.P., A.B., S.B., L.L.), Nuclear Medicine (P.S.), Diagnostic Radiology (P.S., A.D.M.), and Laboratory Medicine-Centro San Luigi (L. S.), Unit of Clinical Spectroscopy (G.P., P.S., A.D.M., L.L.), Università Vita e Salute San Raffaele, Istituto Scientifico H San Raffaele, 20132 Milan; and International Center for the Assessment of Nutritional Status, Università degli Studi di Milano (E.P., G.T., L.L.), 20100 Milan, Italy

Address all correspondence and requests for reprints to: Gianluca Perseghin, M.D., Division of Internal Medicine I, Laboratory of Amino Acids and Stable Isotopes/Unit of Clinical Spectroscopy, Via Olgettina 60, 20132 Milan, Italy. E-mail: perseghin.gianluca{at}hsr.it

Abstract

Plasma free fatty acids and intramyocellular triglycerides (IMCL) content modulate whole body insulin sensitivity in humans. To test whether the interactions between fatty acid metabolism and insulin action in nonobese humans are related to gender factors, we studied 15 young, normal weight, healthy men and 15 women matched for life habits and whole body insulin sensitivity, determined with the euglycemic-hyperinsulinemic clamp, by means of indirect calorimetry to assess substrate oxidation, localized ¹H nuclear magnetic resonance spectroscopy of calf muscles to assess IMCL content, and dual energy x-ray absorption to assess body composition. In addition, to test whether perturbation of the feminine hormonal milieu modifies these interactions, we studied 15 matched females using oral steroidal contraception (OSC). Insulin sensitivity in women, notwithstanding increased body fatness, plasma free fatty acids, IMCL content, and circulating ß-hydroxybutyrate levels and reduced lipid oxidation, was similar to that in men. Women using OSC showed a 40% reduction of insulin sensitivity associated with increased plasma free fatty acids, ß-hydroxybutyrate, cholesterol, and triglycerides levels and a slight increment in IMCL content compared with women with intact hormonal cycles. In all groups the IMCL content was inversely related to insulin sensitivity. In conclusion, nonobese, healthy, young women are as insulin sensitive as men, notwithstanding the higher levels of postabsorptive circulating and tissue-stored fatty acids; OSC-induced insulin resistance is associated with abnormal fatty acid metabolism and loss of this gender-related feature.

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