Estrogen replacement reverses olanzapine-induced weight gain and hepatic insulin resistance in ovariectomized diabetic rats.
OBJECTIVE
We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham).


METHODS
OVX diabetic rats were subcutaneously injected with estrogen replacement (17beta-estradiol, 30 microg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets.


RESULTS
OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine-monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats.


CONCLUSIONS
OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period.
Park
Sunmin
S
Department of Food and Nutrition, Diabetes/Obesity Center, College of Natural Science, Hoseo University, Asan, South Korea. smpark @ hoseo.edu
Hong
Sang Mee
SM
Ahn
I L Sung
IL
Kim
Da Sol
DS
Kim
Sung Hoon
SH
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004435:Eating / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D010052:Ovariectomy; D010180:Pancreatectomy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000009:adverse effects / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects*
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D004958:Estradiol; D005947:Glucose; D018967:Risperidone; D000077152:Olanzapine