Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test

 Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low‑ (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS‑P and IS‑L, respectively) were steeply decreased by aging and a HFD. This preceded the age‑dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS‑P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS‑L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.