Acute Exercise Improves Insulin Clearance and Increases the Expression of Insulin-Degrading Enzyme in the Liver and Skeletal Muscle of Swiss Mice

<div><p>The effects of exercise on insulin clearance and IDE expression are not yet fully elucidated. Here, we have explored the effect of acute exercise on insulin clearance and IDE expression in lean mice. Male Swiss mice were subjected to a single bout of exercise on a speed/angle controlled treadmill for 3-h at approximately 60–70% of maximum oxygen consumption. As expected, acute exercise reduced glycemia and insulinemia, and increased insulin tolerance. The activity of AMPK-ACC, but not of IR-Akt, pathway was increased in the liver and skeletal muscle of trained mice. In an apparent contrast to the reduced insulinemia, glucose-stimulated insulin secretion was increased in isolated islets of these mice. However, insulin clearance was increased after acute exercise and was accompanied by increased expression of the insulin-degrading enzyme (IDE), in the liver and skeletal muscle. Finally, C2C12, but not HEPG2 cells, incubated at different concentrations of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) for 3-h, showed increased expression of IDE. In conclusion, acute exercise increases insulin clearance, probably due to an augmentation of IDE expression in the liver and skeletal muscle. The elevated IDE expression, in the skeletal muscle, seems to be mediated by activation of AMPK-ACC pathway, in response to exercise. We believe that the increase in the IDE expression, comprise a safety measure to maintain glycemia at or close to physiological levels, turning physical exercise more effective and safe.</p></div

Acute exercise decreased plasma insulin and glucose.

<p>Blood glucose (A) and plasma insulin (B) were reduced in mice after a single bout of 3-h exercise on the treadmill. The data are presented as the mean ± S.E.M., n = 4–5. *p≤0.05 <i>vs</i> control.</p

Acute exercise increased AMPK-ACC but not IR-AKT pathway activity.

<p>The p-IR (A) and p-AKT (B) protein levels were unaltered, whereas p-AMPK (C) and p-ACC (D) were increased in the liver, gastrocnemius (GCK) and soleus after a single bout of 3-h exercise on the treadmill. The data are presented as the mean ± S.E.M., n = 4–5. *p≤0.05 <i>vs</i> control.</p

Acute exercise increased VO₂ without affecting body composition.

<p>Total body weight (A), relative liver weight (B), relative perigonadal fat weight (C) and relative gastrocnemius muscle weight (D) were unaltered in mice after a single bout of 3-h exercise on the treadmill under an increased VO₂ (E). The data are presented as the mean ± S.E.M., n = 3–5. *p≤0.05 <i>vs</i> control.</p

Acute exercise improved insulin tolerance.

<p>The ipITT (A), constant rate for the glucose decay (B) and AUC of glucose (C) of mice after a single bout of 3-h exercise on the treadmill. The data are presented as the mean ± S.E.M., n = 5. *p≤0.05 <i>vs</i> control.</p

Acute exercise increased insulin clearance and decay.

<p>A single bout of 3-h exercise on the treadmill reduced insulin clearance (A), insulin decay rate (B) and AUC of insulin (C) during ipITT. The data are presented as the mean ± S.E.M., n = 3–4. *p≤0.05 <i>vs</i> control.</p

Acute exercise impaired insulin secretion and pancreatic islet function.

<p>A single bout of 3-h exercise on the treadmill reduced insulin secretion from isolated pancreatic islets under basal and stimulatory glucose conditions (A) and impaired pancreatic islets function as evaluated by GSIS (B) without affecting islets total insulin content (C). The data are presented as the mean ± S.E.M., n = 4. *p≤0.05 <i>vs</i> respective control and #p≤0.05 <i>vs</i> control 3 mmol.l^-1 glucose.</p

Acute exercise increased IDE expression.

<p>A single bout of 3-h exercise on the treadmill increased IDE protein levels in the liver (approximately 2×), gastrocnemius (approximately 2×) and soleus (approximately 8×) of mice. The data are presented as the mean ± S.E.M., n = 4–5. *p≤0.05 <i>vs</i> control.</p

AICAR increases the IDE expression in C2C12 cells, but not in HEPG2 cells.

<p>The IDE protein levels did not change in HEPG2 cells after 3-h treatment at 250, 500 and 750 μmol l-1 AICAR (A), but it increased in C2C12 cells after 3-h treatment at 250 and 500 μmol l-1 AICAR (B). The data are presented as the mean ± S.E.M., n = 3–4. *p≤0.05 <i>vs</i> control.</p