UC San Diego

A key metabolic action of insulin is to stimulate skeletal muscle to take up glucose from the systemic circulation. This “insulin-stimulated” glucose uptake is critical during the post-prandial period (i.e. after meal ingestion) as it reduces large excursions in blood glucose concentration; in fact, skeletal muscle accounts for as much as 85% of peripheral glucose uptake after a meal, thereby making it a fundamental organ to not just glycemic control, but also to overall health. Nevertheless, despite its obvious importance, there is still much unknown about the regulation of insulin-stimulated glucose uptake by skeletal muscle. To study this regulation, the field commonly uses mouse models, as insulin signaling and action in mouse skeletal muscle closely replicates that seen in human skeletal muscle. Remarkably, however, the physiological action of insulin on the dynamics of glucose uptake in mouse skeletal muscle, especially as it relates to the contributions of sex, fiber type, and insulin concentration have not been systematically analyzed. Thus, the objective of this Thesis was to investigate the interactive effect of time, sex, fiber type, and insulin concentration on basal and insulin-stimulated glucose uptake in mouse skeletal muscle. Specifically, we used an ex vivo radioactive 2-deoxyglucose uptake (2DOGU) approach and measured basal and insulin-stimulated (insulin concentration: 0.36 nM and 6 nM) glucose uptake for 5, 10, 15, 20, or 30 minutes in paired extensor digitorum longus (EDL) and soleus muscles from 12-15 week old female and male (6nM insulin only) mice. In both the soleus and EDL of female mice, 2DOGU in response to physiological insulin (0.36nM; i.e the circulating insulin concentration typically seen after a meal) was statistically greater than basal at 15 and beyond, but not at 5 or 10 min. In contrast, a supraphysiological insulin concentration (6nM) 2DOGU more rapidly increased 2DOGU above basal, such that it was greater than basal at by 5 minutes in soleus and 10 minutes in EDL, regardless of sex. As it relates to fiber type, the soleus (i.e. primarily slow twitch) had greater insulin-stimulated glucose uptake than the EDL (i.e. primarily fast-twitch), regardless of sex or insulin concentration. Finally, as it relates to sex differences, female mice had greater insulin-stimulated 2DOGU as compared to male, regardless of fiber type or time point. Taken together, this work demonstrates that in response to physiological insulin there is a delay of ~15 minutes from insulin exposure to when there is a robust increase in insulin-stimulated glucose uptake, and that increasing insulin concentration shortens this biological delay. Overall, this work demonstrates the importance sex, fiber type, insulin concentration and time to the regulation of insulin-stimulated glucose uptake by mouse skeletal muscle.