Exercise Protects Against Olanzapine-Induced Hyperglycemia in Male C57BL/6J Mice

Abstract

Olanzapine is a widely prescribed antipsychotic drug. While effective in reducing psychoses, treatment with olanzapine causes rapid increases in blood glucose. We wanted to determine if a single bout of exercise, immediately prior to treatment, would attenuate the olanzapine-induced rise in blood glucose and if this occurred in an IL-6 dependent manner. We found that exhaustive, but not moderate exercise, immediately prior to treatment, prevented olanzapine-induced hyperglycemia and this occurred in parallel with increases in serum IL-6. To determine if IL-6 was involved in the mechanisms through which exhaustive exercise protected against olanzapine-induced hyperglycemia several additional experiments were completed. Treatment with IL-6 (3 ng/g bw, IP) alone did not protect against olanzapine-induced increases in blood glucose. The protective effects of exhaustive exercise against olanzapine-induced increases in blood glucose were intact in whole body IL-6 knockout mice. Similarly, treating mice with an IL-6 neutralizing antibody prior to exhaustive exercise did not negate the protective effect of exercise against olanzapine-induced hyperglycemia. Our findings provide evidence that a single bout of exhaustive exercise protects against acute olanzapine-induced hyperglycemia and that IL-6 is neither sufficient, nor required for exercise to protect against increases in blood glucose with olanzapine treatment.

Housing temperature affects the acute and chronic metabolic adaptations to exercise in mice

“…The EX protocol consisted of a single bout of treadmill running at an incline of 15% and an initial speed of 12 m min −1 . In line with previous work from our laboratory (Castellani et al 2018), the speed was increased by 1 m min −1 at 2, 5 and 10 min, and every 10 min thereafter until mice fatigued as evidenced by the inability to remain halfway up the treadmill belt despite gentle prodding. The SED groups remained in their cages during this time without access to food.…”

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism

“…A single treatment of olanzapine has been shown to rapidly and significantly increase blood glucose in male mice [61,82–84,89,91] and rats [48,81,85,87,88,92], with peak blood glucose occurring approximately 1–2 h post treatment (Table 4B). Indeed, both a single dose of olanzapine (administered via subcutaneous injection [85], intravenous infusion [79,94], intragastric infusion [87], oral gavage [85]) as well as a twice daily dose via oral gavage (one dose in the evening, one dose one hour preceding measures) [48,81] increased blood glucose in male rats.…”

“…Indeed, both a single dose of olanzapine (administered via subcutaneous injection [85], intravenous infusion [79,94], intragastric infusion [87], oral gavage [85]) as well as a twice daily dose via oral gavage (one dose in the evening, one dose one hour preceding measures) [48,81] increased blood glucose in male rats. Similarly, a single injection of olanzapine (intraperitoneal injection [82–84,89] or intracerebral ventricular infusion [79,89,91]) in male mice significantly increased blood glucose levels compared to vehicle treated mice. Interestingly, olanzapine-induced hyperglycemia is more pronounced in the fed compared to the fasted state.…”

Cardiac CapZ regulation during acute exercise

“…Exhaustion was taken as the point when mice stopped swimming and sank to the bottom for ~5 s. For the running test mice were acclimated with two 10 min exercise sessions (separate 2 days) on the treadmill at a 5% grade incline, paced at 15 m/min. Fatigue testing began with a treadmill speed of 12 m/min on an incline of 40% and pacing was increased by 1 m/min at 2, 5, 10 and every subsequent 10 min (15). Exhaustion was defined as an inability/refusal of the mouse to continue running when gently encouraged with a bottle brush.…”