Response to Comment on: Høeg et al. Lipid-Induced Insulin Resistance Affects Women Less Than Men and Is Not Accompanied by Inflammation or Impaired Proximal Insulin Signaling. Diabetes 2011;60:64–73

Thank you for commenting (1) on our article (2) in the January issue of Diabetes. The main issue raised by Dr. Cusi is that no sex difference was noted in his intralipid infusion study by Belfort et al. (3), whereas we report that women are less susceptible than men to lipid-induced insulin resistance. A difference between the study by Belfort et al. (3) and ours (2) is that we measure leg glucose uptake in addition to wholebody glucose infusion rate. Leg glucose uptake is probably a better measure of muscle glucose uptake than whole-body glucose infusion rate, and we repeatedly find higher insulinstimulated leg glucose uptake in young, healthy, lean, and moderately physically active women than in men matched according to fitness level, age, and BMI (2,4). This finding might be explained by a higher percentage of the more oxidative type 1 fibers (2,4), higher capillary density (4), and higher hexokinase II expression (2) in women than in men. Along with a higher expression of lipid handling proteins in muscle from women (5), these findings may be responsible for the ability in women to better handle acute lipid-induced insulin resistance at the muscle level. A difference in muscle glucose uptake is likely more difficult to demonstrate when only measuring whole-body insulin sensitivity. Furthermore, a sex difference is hard to demonstrate when only 5–6 men are compared with 2–3 women in each group as was the case in the study by Belfort et al. (3). This was the reason for not citing this study in the introduction. It should be noted that decreased susceptibility to lipid-induced insulin resistance in women has been reported by others (6). Another issue raised by Dr. Cusi (1) is that we do not observe impaired insulin signaling in muscle as a consequence of intralipid infusion despite the unquestionable induction of insulin resistance. We are reassured about our signaling data because they were measured both before and after 30-min and 120-min clamps, and particularly that glycogen synthase (GS) activation was not impaired by intralipid. This strongly indicates that the proximal insulin signaling cascade, which via inhibition of GSK3 leads to activation of GS, indeed was not inhibited by intralipid. Also, as discussed in our article (2), several other publications have reported that acute lipid-induced insulin resistance occurs in the absence of reduced proximal insulin signaling. Nevertheless, we agree with Dr. Cusi that current dogmas need to be challenged in order to advance science, and we hope that our article stimulates further research into lipid-induced insulin resistance.