Global Journal of Endocrinology and Diabetes

Global Journal of Endocrinology and Diabetes Vol. 9 (3), pp. 001-008, March, 2024. © International Scholars Journals

Full Length Research Paper

Persistent brain serotonergic imbalance in diabetes despite insulin therapy

Gabriel Manjarrez-Gutiérrez^1,2*, Teresa Neri-Gómez¹, Rocío Herrera-Márquez¹, José Antonio Mondragón-Herrera¹, Alfonso Boyzo-Montes de Oca³ and Jorge Hernandez-Rodríguez³

¹Laboratory of Molecular Pathology, Cardiology Hospital, National Medical Center (CMN-SXXI), Mexican Institute of Social Security (IMSS), Mexico City, Mexico

²Medical Research Unit in Neurological Diseases, Specialties Hospital, CMN-SXXI, IMSS, México, DF, México

³Laboratory of Neurontogeny, Department of Physiology, Biophysics and Neurosciences, Center of Research and Advanced Studies (CINVESTAV) IPN, Mexico City, Mexico.

Accepted 05 OCTOber 2023

Abstract

The aim of this study was to determine whether changes in the kinetics and the capacity of phosphorylation of the tryptophan-5-hydroxylase (TPH) in diabetic rats are normalized with insulin, or if there are changes in expressions of TPH1 or TPH2 as mechanisms that explain the chronic inhibition of the biosynthesis of brain 5-hydroxytryptamine (5-HT). A diabetic mellitus (DM) model was produced through the administration of streptozotocin and controls (STZ). After 7 days,the diabetic rats were divided into two subgroups. One group was treated with insulin and the other did not receive treatment. After 7, 14 and 21 days, the brainstem was removed to determine: L-tryptophan (L-Trp), 5-HT, TPH activity, by observing the kinetics and activation through phosphorylating conditions. Besides, the expressions of TPH1, TPH2 and TPH-phosphorylated–S19 (TPH2-^PS-19) were assessed by Western blot. The diabetic rats had a decrease of L-Trp, 5-HT and TPH activity; a decrease of the V_max and an increase in K_m. They also showed less activation of the TPH by phosphorylation and a reduced expression of TPH1, TPH2 and TPH2-^PS-19. Interestingly enough, all these changes are not normalized in the diabetic rats subgroup treated with insulin. A decrease in the synthesis of brain serotonin during the diabetic state was confirmed, due to changes in the kinetics and phosphorylation capacity of TPH and a decreased expression of TPH1, TPH2 and TPH2-^PS-19, which did not return to normal levels with insulin. These findings support the fact that chronic inhibition of 5-HT biosynthesis resistant to insulin is due to the decrease of TPH’s expression and activity as a consequence of metabolic changes during the diabetic state.

Keywords: Brain, Diabetes mellitus, Insulin, Serotonin, Tryptophan-5-hydroxylase