(T1030-04-24) Oren-gedoku-to, a Traditional Chinese Medicine, Prevents the Hyperglycemia Caused by Chronic Olanzapine Administration via Hypothalamic AMP-Activated Protein Kinase Activity

Purpose: Olanzapine (OLZ) is an atypical antipsychotic widely used to treat schizophrenia and bipolar disorder. Serious cases of diabetic ketoacidosis and coma caused by elevated blood glucose levels during OLZ administration have been reported. We previously demonstrated that adrenaline is involved in blood glucose elevation following the administration of a single dose of OLZ.¹⁾ Furthermore, activation of hypothalamic AMP-activated protein kinase (AMPK) by the administration of a single dose of paliperidone (a drug of the same family) was involved in adrenaline secretion and blood glucose elevation.²⁾ However, the mechanism underlying hyperglycemia development during long-term treatment remains unclear. In this study, we investigated the hypothalamic AMPK activity, blood adrenaline concentration, and blood glucose levels after long-term OLZ administration to elucidate the mechanism underlying hyperglycemia. Additionally, we examined the possibility of using Oren-gedoku-to (OGT, a traditional Chinese medicine containing berberine that suppresses hypothalamic AMPK activation) as a prophylactic agent against atypical antipsychotic-induced hyperglycemia by examining its effect on blood glucose levels in combination with OLZ.

Methods: Female Wistar rats were divided into three treatment groups—saline/water (control), OLZ (20 mg/kg/day)/water, and OLZ (20 mg/kg/day)/OGT (500 mg/kg/day). Each treatment was orally administered twice daily for 2 weeks. On the last day of the administration period, the rats were fasted overnight, and the hypothalamus and blood samples were collected to determine the serum concentrations of glucose and adrenaline and hypothalamic AMPK activity

Results: Serum glucose and adrenaline levels were elevated in rats receiving OLZ but not in rats concomitantly receiving OGT (Fig. 1 and 2). Additionally, the increase in hypothalamic AMPK activity observed in rats receiving OLZ was not observed in those concomitantly treated with OGT (Fig. 3). This suggested that OGT administration suppressed the hyperglycemia induced by chronic administration of OLZ and that the suppression of increased AMPK activity and adrenaline secretion were involved in the inhibition of hyperglycemia.

Conclusion: AMPK activation in the hypothalamus due to long-term administration of OLZ and the accompanying adrenaline secretion are involved in the elevation of blood glucose levels. Combination therapy with OGT may prevent OLZ-induced elevation of blood glucose levels.

References: 1) Biol Pharm Bull. 2016; 39(5):754-761
2) Biol Pharm Bull. 2022; 45(11):1669-1677

Acknowledgements: Fundings: This work was supported by JSPS KAKENHI (grant no. JP22K06720).
Other disclosure: The Institutional Animal Care and Use Committee of Tokyo Medical and Dental University approved all the animal experiments (approval no. A2023-126A).


Fig. 1 Effect of OLZ and OGT administration on serum glucose concentrations.
*: p < 0.05 vs the control (Tukey-Kramer test)


Fig. 2 Effect of OLZ and OGT administration on serum adrenaline concentrations.
*: p < 0.05 vs the control (Tukey-Kramer test)


Fig. 3 Effect of OLZ and OGT administration on hypothalamic AMPK activity.
*: p < 0.05 vs the control (Tukey-Kramer test)