dextromethorphan and Diabetes-Mellitus--Type-1

Diabetes mellitus is the most common metabolic disorder in children and adolescents. Optimal control of blood glucose concentration is essential to prevent acute and diabetic long-term complications. The options to treat diabetes have clearly improved over the last decades, however, to date neither type 1 diabetes nor type 2 diabetes mellitus can be cured. Therefore, diabetes research aims at developing β-cell protective agents that prevent or even reverse diabetes onset. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are widely expressed in the central nervous system (CNS) where they hold central roles in CNS function. NMDAR dysfunction is associated with several neurological and psychiatric disorders and therefore NMDAR modulators have several potential therapeutic indications. Only little is known about the role of pancreatic NMDA receptors. Our data provide evidence that inhibition of pancreatic NMDARs, either genetically or pharmacologically with the over-the-counter drug dextromethorphan, increases glucose-stimulated insulin secretion from mouse and human pancreatic islets, improves glucose tolerance in mice and individuals with diabetes and promotes islet cell survival under diabetogenic conditions. Thus, our data indicate for the first time that NMDAR antagonists could serve as adjunct treatment for diabetes mellitus. The development of a safe, blood glucose lowering and particularly β-cell protective medication would significantly enhance current diabetes treatment.

Topics: Adolescent; Animals; Blood Glucose; Cell Survival; Child; Dextromethorphan; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Receptors, N-Methyl-D-Aspartate

Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes' activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study.. Male Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity.. The average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively.. In type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group. Graphical abstract .

Topics: Animals; Cytochrome P450 Family 2; Dextromethorphan; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hepatobiliary Elimination; Hypoglycemic Agents; Insulin; Male; Metformin; Niacinamide; Rats; Rats, Wistar; Streptozocin

Topics: Adolescent; Antitussive Agents; Child; Dextromethorphan; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Male; Meningitis, Bacterial