Enhancement of Metformin's Efficacy by Betel Nut Polyphenols in Type 2 Diabetic Rats Exposed to High Altitude

High-altitude environment inhibited the metabolism and increased the absorption of metformin in type 2 Diabetes Mellitus (T2DM), but the therapeutic effect of metformin was impaired. This study aimed to investigate the effect of betel nut polyphenols (BP) on the therapeutic efficacy of metformin at high altitude.

Firstly, we prepared the T2DM rat model by combining a high-sugar/high-fat diet with streptozotocin. For the pharmacokinetic (PK) study, 12 diabetic rats were randomly divided into the model + metformin (DMM) group and the DMM + BP (DMMB) group. Thirty-two diabetic rats were randomly divided into four groups for the pharmacodynamic (PD) study: model (DM) group, DM + metformin (DMM) group, DMM + high altitude (DMMH) group, and DMMH + BP (DMMHB) group, with the normal diet (DN) group as the control. Subsequently, fasting glucose, insulin resistance index (HOMA-IR), lactic acid (LA), pyruvate (PA), lactate dehydrogenase (LDH), oxidative stress, and inflammatory factors were measured in all groups.

The PK results showed that BP did not affect the PK behaviour of metformin in vivo in T2DM rats. The PD results showed that, compared with the DMM group, fasting glucose and HOMA- IR were significantly higher in the DMMH group. Meanwhile, PA, LA, and LDH levels were significantly increased, the metformin content in liver tissue was significantly decreased, and oxidative stress and inflammatory damage were aggravated at high altitude. After treatment with BP, the beneficial effects of metformin were enhanced, the content of metformin in liver tissue was significantly increased, and oxidative stress and inflammatory damage were ameliorated in the DMMHB group.

The therapeutic effect of metformin was impaired in a high-altitude environment. This study confirmed that the beneficial effects of metformin were enhanced when it was co-administered with the anti-hypoxic drug BP in a high-altitude environment, providing a new therapeutic approach for treating diabetic patients in such environments.

BP obviously enhanced the therapeutic effect of metformin by improving the antioxidant capacity of T2DM Rats in a high-altitude environment. Therefore, BP can serve as a potential adjuvant to enhance the beneficial effects of metformin in a high-altitude environment.