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.
Highlights
The use of Second-Generation Antipsychotics (SGAs) such as olanzapine has increased dramatically in recent years[1]
Olanzapine treatment resulted in a significant (p = 0.007) increase in the blood glucose area under the curve (AUC) and this was completely prevented by a prior bout of exhaustive exercise (p < 0.001 sedentary compared to exercised mice treated with olanzapine) (Fig. 1a,b)
While these studies suggest that exercise can be used to offset the chronic metabolic side effects of SGAs, it is difficult to determine if exercise has direct effects on protecting against SGA-induced perturbations in glucose homeostasis, or if it is secondary to a prevention of weight gain/the induction of weight loss
Summary
The use of Second-Generation Antipsychotics (SGAs) such as olanzapine has increased dramatically in recent years[1]. Metformin only partially reverses olanzapine-induced hyperglycemia[23] and has been reported to worsen psychoses[24] Though thiazolidinediones such as rosiglitazone dampen olanzapine-induced perturbations in glucose metabolism[22] they are associated with weight gain, a worsening of coronary heart disease and increased risk of heart attack[25]. Given the pleiotropic effects of exercise on glucose metabolism, it is surprising that the effects of exercise on acute SGA-induced hyperglycemia have never been explored Within this context, the purpose of the present investigation was to determine if a prior bout of exercise would protect against olanzapine-induced increases in blood glucose. We hypothesized that exercise would blunt SGA-induced hyperglycemia through a mechanism involving IL-6
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