Abstract

Olanzapine (OLZ) is an antipsychotic drug used in the treatment of schizophrenia. Although effective in reducing psychoses, OLZ causes acute increases in blood glucose. The acute effects of OLZ on hyperglycemia are likely caused by reductions in insulin secretion, insulin resistance, and increased hepatic glucose production. 5AMP-activated protein kinase (AMPK) is an energy sensor activated during exercise that can increase insulin sensitivity and insulin-independent glucose uptake in muscle. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is a pharmacologic agent that, among other effects, can activate AMPK in vivo. Conversely, hypothalamic activation of AMPK has been suggested to mediate the hyperglycemic effects of OLZ. The purpose of this investigation was to determine whether cotreatment with AICAR could prevent acute OLZ-induced hyperglycemia in lean and obese C57BL6/J mice. OLZ (5 mg/kg, i.p.) caused rapid increases in blood glucose, a blunted insulin response, and pyruvate intolerance, all of which were prevented with AICAR cotreatment in both lean and obese mice. AICAR did not affect OLZ-induced changes in whole-body substrate oxidation or energy expenditure. Peripheral injection of AICAR, but not OLZ, activated AMPK signaling in the hypothalamus. The results of the current study provide evidence that AICAR prevents OLZ-induced hyperglycemia, despite increasing hypothalamic AMPK signaling. These protective effects were associated with the preservation of whole-body insulin action and reductions in markers of liver glucose production.