AMPK β1 activation suppresses antipsychotic‐induced hyperglycemia in mice

Abstract

Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK b1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK b1 suppresses these effects. Female AMPK b1 2/2 or wild-type (WT) control mice were treated with OLZ, and changes in blood glucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK b1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK b1 2/2 mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK b1 2/2 mice, consistent with A769662's specificity for the AMPK b1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK b1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.

A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models

“…The current doses of drugs were chosen to be consistent with prior studies that have observed metabolic effects of risperidone in both our laboratory and by other groups [36,37,57], and at preclinical doses comparable to those observed with other antipsychotic drugs which exert effects of a similar magnitude to those noted in humans [45]. The present experimental procedures provide complementary techniques to assess the overall metabolic side-effects of antipsychotic drugs, as we and multiple other groups have demonstrated previously [39][40][41][42][43][44]68,69]. Fasting glucose levels are the simplest and most common way used to detect hyperglycemia in humans (and animals), but can be prone to error in a significant proportion of individuals [70].…”

“…To this end, animal models of antipsychotic-induced metabolic side-effects have been helpful and informative in characterizing the acute metabolic effects of antipsychotics [32]. These studies have confirmed that treatment with most second generation antipsychotics can cause glucose intolerance and insulin resistance, often within minutes [33][34][35][36][37][38][39][40][41][42][43][44]-effects that have been confirmed in non-psychiatric human subjects [45][46][47] including in a recent metaanalysis [48]. In current clinical practice, both paliperidone and the parent drug risperidone are often prescribed interchangeably [49], as they have a similar therapeutic profile and both exist in depot formulations [50][51][52].…”

Differential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines

“…The use of preclinical paradigms offers the additional benefit of helping to disentangle the multifactorial causes of metabolic dysregulation in psychiatric illness, where variables such as diet, exercise, and drug use can all contribute to cardiometabolic dysregulation (25)(26)(27). Fortunately, the past 10-15 years has seen significant advances in animal models of the metabolic side-effects of antipsychotic drugs (28), which have demonstrated that many of these compounds cause acute glucose dysregulation and insulin resistance independent of weight gain (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

AMPK mediates energetic stress‐induced liver GDF15

“…A colony of AMPKβ1 knockout mice (AMPKβ1 −/− ) was generated and maintained as previously described. 27,28 Genotypes were determined for all mice from ear notches and subsequently confirmed by immunoblot. Experiments were performed on male mice between 10 and 18 weeks of age with the approval of the University of Guelph Animal Care Committee in compliance with the guide for the care and use of laboratory animals and the Canadian Council on Animal Care.…”

“…For some experiments, mice were fed a high‐fat diet for 24 weeks (60% kcal from fat, #D12492; Research Diets, New Brunswick, NJ USA). A colony of AMPKβ1 knockout mice (AMPKβ1 −/− ) was generated and maintained as previously described 27,28 . Genotypes were determined for all mice from ear notches and subsequently confirmed by immunoblot.…”