2447-P: Mitragynine Regulates Glucose and Inflammatory Pathways Independent of Insulin Signaling in Diabetic Male Mice

Introduction and Objective: Kratom (Mitragyna speciosa), from Southeast Asia, is used for pain relief and effects on glucose metabolism. Its active alkaloid, mitragynine (MTG), acts on opioid and adrenergic receptors. This study investigates the effects of mitragynine and morphine on glucose regulation and insulin signaling, the metabolic impact of chronic mitragynine in diabetic mice, and its interaction with insulin. Methods: Male C57BL/6J mice were fed regular chow (RC) or a high-fat diet (HFD; 60% fat) for 6 weeks, then received a single IP injection of morphine (10 mg/kg), mitragynine (MTG; 10 mg/kg), or vehicle. Blood glucose was measured every 15 minutes, and tissues were collected 60 minutes post-injection. After 12 weeks on RC or HFD, mice received streptozotocin (150 mg/kg, IP). Hyperglycemia developed by day 3, and mice were treated daily with MTG (1-10 mg/kg) for 7 days. Plasma, liver, and pancreas were collected to assess glucose and insulin signaling.To test acute interactions, mice received insulin (5 U/kg), MTG (10 mg/kg), insulin + MTG, or vehicle (IP). Blood glucose was monitored every 15 minutes, and tissues were collected at 60 minutes. Results: In acute experiments, mitragynine (10 mg/kg) raised blood glucose, while morphine (10 mg/kg) lowered it; both reduced corticosterone. In chronic experiments, low-dose MTG (1 mg/kg) improved glucose levels in the RC group; high doses improved glucose levels in the HFD group. Liver function improved, as shown by lower ALT levels, and IL-6 levels dropped, indicating anti-inflammatory effects. Combining insulin with high-dose mitragynine caused severe hypoglycemia after 60 minutes. Conclusion: Mitragynine shows dose and diet-dependent effects, acutely increasing glucose independently of insulin or corticosterone, while chronic treatment improves glycemia and liver function. Reduced IL-6 levels suggest anti-inflammatory effects, suggesting that mitragynine may improve metabolic outcomes. Disclosure L. Alsarkhi: None. N.T. Bello: None. Funding USDA-NIFA (NJ06220)