DOI: 10.5061/dryad.2jm63xt36
title: New hypoglycemic effects of indorenate mediated by the 5-HT1a and 5-HT2a receptors: In vivo and in silico studies

description: The treatment of metabolic syndrome (MS), characterized by type 2 diabetes
 (T2D), obesity, dyslipidemias, and cardiovascular problems, requires an
 integral treatment. In addition to its central activity, serotonin also
 has peripheral effects, implying regulation of blood glucose and insulin
 levels. Indorenate is a serotonin analog with antihypertensive properties
 and possible activity on the metabolism of carbohydrates. However, its
 effect on glucose levels has not been explored, which is relevant in
 searching for the indorenate's potential as an alternative to the
 treatment of MS. This investigation aimed to study the effects of
 indorenate on glycemia through in vivo and in silico assays. In normal
 rats, indorenate was co-administered with two serotonergic antagonists:
 pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist).
 Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and
 WAY-100635 inhibited this effect. In diabetic rats, indorenate increased
 insulin levels. In addition, indorenate decreased glycemia in an
 euglycemic clamp test, while pelanserin inhibited this effect. In silico,
 indorenate exhibited a higher affinity and interactions than serotonin for
 5-HT2a and 5-HT1a receptors. The data suggest that the hypoglycemic effect
 of indorenate requires the participation of the 5-HT2a receptor and
 partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal
 effects for blood pressure and glycemic control, such as indorenate, might
 be relevant for treating MS and its associated pathologies.
description: # New hypoglycemic effects of indorenate mediated by the 5-HT1a and 5-HT2a
 receptors: In vivo and in silico studies Dataset DOI:
 [10.5061/dryad.2jm63xt36](https://doi.org/10.5061/dryad.2jm63xt36) ##
 Description of the data and file structure These data were used to perform
 the statistical analysis: Figure 2A (OGTT in normal male Wistar rats)
 2-way ANOVA analysis of repeated measures complemented with Sidak test,
 for figure 2B (AUC of Figure 2A) data for a one-way ANOVA analysis posthoc
 Tukey-Kramer test, Figure 3A (Insulin secretion with glucose in normal
 Wistar rats) data 2-way ANOVA analysis of repeated measures complemented
 with Sidak test, 3B (Insulin secretion without glucose in normal Wistar
 rats) data 2-way ANOVA analysis of repeated measures complemented with
 Sidak test, Figure 3C (AUC insulin secretion with or without glucose in
 normal Wistar male rats) one-way ANOVA analysis posthoc Tukey-Kramer test,
 Figure 4 (Capilar glucose by the euglycemic clamp in an OGTT  in normal
 Wistar male rats) data 2-way ANOVA analysis of repeated measures
 complemented with Sidak test and Figure 5 (OGTT in diabetic model Wistar
 male rats) data 2-way ANOVA analysis of repeated measures complemented
 with Sidak test. Instructions and conditions of molecular docking are
 added in a PDF. ### Files and variables #### File: Figure_2A_OGTT.csv
 **Description:** Oral glucose tolerance test in normal male Wistar rats
 (mg/dL) ##### Variables * Time (min): minutes * CT1: Vehicle * CT2:Vehicle
 * CT3:Vehicle * Indorenate [10 mg/Kg] 1: Treatment rat 1 * Indorenate [10
 mg/Kg] 2: Treatment rat 2 * Indorenate [10 mg/Kg]3: Treatment rat 1 *
 Pelanserine [2.5 mg/Kg] 1: Treatment rat 1 * Pelanserine [2.5 mg/Kg]
 2: Treatment rat 2 * Pelanserine [2.5 mg/Kg] 3: Treatment rat 3 *
 Indorenato-pelanserine 1: Treatment rat 1 * Indorenato-pelanserine
 2: Treatment rat 2 * Indorenato-pelanserine 3: Treatment rat 3 *
 Indo-pel-WAY 1: Treatment rat 1 * Indo-pel-WAY 2: Treatment rat 2 *
 Indo-pel-WAY 3: Treatment rat 3 #### File: Figure_2B_AUC_of_Figure_2A.csv
 **Description:** Area Under the Curve of Figure 2A (Arbitrary units) #####
 Variables * CT: Vehicle * Indorenate: Treatment with indorenate *
 Pelanserine: Treatment with pelanserine * Indorenate+pelanserin : reatment
 with indorenate + pelanserine * Indo+Pel+Way: reatment with indorenate +
 pelanserine + Way #### File:
 Figure_3A_Insulin_secretion_without_glucose.csv **Description:**  Insulin
 secretion without glucose (ng/mL) ##### Variables * Time (min): minutes *
 CT 1: Vehicle 1 * CT 2: Vehicle 2 * CT 3: Vehicle 3 * CT 4: Vehicle  4 *
 CT 5: Vehicle 5 * Indorenate [10 mg/Kg] 1: Rat 1 treated with indorenate *
 Indorenate [10 mg/Kg] 2: Rat 2 treated with indorenate * Indorenate [10
 mg/Kg] 3: Rat 3 treated with indorenate * Indorenate [10 mg/Kg] 4: Rat 4
 treated with indorenate * Indorenate [10 mg/Kg] 5: Rat 5 treated with
 indorenate * Pelanserine [2.5 mg/Kg] 1: Rat 1 treated with pelanserine *
 Pelanserine [2.5 mg/Kg] 2: Rat 2 treated with pelanserine * Pelanserine
 [2.5 mg/Kg] 3: Rat 3 treated with pelanserine * Pelanserine [2.5 mg/Kg]
 4: Rat 4 treated with pelanserine * Pelanserine [2.5 mg/Kg] 5: Rat 5
 treated with pelanserine * Indorenate+pelanserin 1: Rat 1 treated with
 indorenate + pelanserine * Indorenate+pelanserin 2: Rat 2 treated with
 indorenate + pelanserine * Indorenate+pelanserin 3: Rat 3 treated with
 indorenate + pelanserine * Indorenate+pelanserin 4: Rat 4 treated with
 indorenate + pelanserine * Indorenate+pelanserin 5: Rat 5 treated with
 indorenate + pelanserine #### File:
 Figure_3B_INsulin_secretion_with_glucose.csv **Description:**  Insulin
 secretion with glucose (ng/mL) ##### Variables * Time (min): minutes *
 CT+glucose 1: Rat 1 treated with vehicle + glucose * CT+glucose 2: Rat 2
 treated with vehicle + glucose * CT+glucose 3: Rat 3 treated with vehicle
 + glucose * CT+glucose 4: Rat 4 treated with vehicle + glucose *
 CT+glucose 5: Rat 5 treated with vehicle + glucose * Indorenate+glucose
 1: Rat 1 treated indorenate + glucose * Indorenate+glucose 2: Rat 2
 treated indorenate + glucose * Indorenate+glucose3: Rat 3 treated
 indorenate + glucose * Indorenate+glucose 4: Rat 4 treated indorenate +
 glucose * Indorenate+glucose 5: Rat 5 treated indorenate + glucose *
 Pelanserin+glucose 1: Rat 1 treated pelanserine + glucose *
 Pelanserin+glucose 2: Rat 2 treated pelanserine + glucose *
 Pelanserin+glucose 3: Rat 3 treated pelanserine + glucose *
 Pelanserin+glucose 4: Rat 4 treated pelanserine + glucose *
 Pelanserin+glucose 5: Rat 5 treated pelanserine + glucose *
 Indo+Pel+glucose 1: Rat 1 treated indorenate + pelanserine + glucose *
 Indo+Pel+glucose 2: Rat 2 treated indorenate + pelanserine + glucose *
 Indo+Pel+glucose 3: Rat 3 treated indorenate + pelanserine + glucose *
 Indo+Pel+glucose 4: Rat 4 treated indorenate + pelanserine + glucose *
 Indo+Pel+glucose 5: Rat 5 treated indorenate + pelanserine + glucose ####
 File: Figure_3C_AUC_secretion_with_or_whitout_glucose.csv
 **Description:**  Area under the curve with or without glucose  (Figures
 3A and 3B) in normal male Wistar rats (arbitrary units) ##### Variables *
 CT:  Treatments with vehicle * Indorenate: Treatments with indorenate *
 Pelanserin: Treatments with pelanserin * Indorenate+pelanserin: Treatments
 with indorenate + pelanserine * CT+Glucose: Treatments with glucose *
 Indorenate+glucose: Treatments with indorenate + glucose *
 Pelanserin+glucose: Treatments with pelanserine + glucose *
 Indo+Pel+glu: Treatments with indorenate + pelanserine + glucose ####
 File: Figure_4_Capilar_glucose.csv **Description:** Capillary glucose by
 the euglycemic clamp in an OGTT Wistar male rats (mg/mL) ##### Variables *
 Time (min): minutes * CT 1: Vehicle 1  * CT 2: Vehicle 2  * CT 3: Vehicle
 3  * CT 4: Vehicle 4 * CT 5: Vehicle 5 * Indorenate 1: Treatment with
 indorenate rat 1 * Indorenate 2: Treatment with indorenate rat 2 *
 Indorenate 3: Treatment with indorenate rat 3 * Indorenate 4: Treatment
 with indorenate rat 4 * Indorenate 5: Treatment with indorenate rat 5 *
 Pelanserin 1: Treatment with pelanserine rat 1 * Pelanserin 2: Treatment
 with pelanserine rat 2 * Pelanserin 3: Treatment with pelanserine rat 3 *
 Pelanserin 4: Treatment with pelanserine rat 4 * Pelanserin 5: Treatment
 with pelanserine rat 5 * WAY-100635 1: Treatment with WAY-100635 rat 1 *
 WAY-100635 2: Treatment with WAY-100635 rat 2 * WAY-100635 3: Treatment
 with WAY-100635 rat 3 * WAY-100635 4: Treatment with WAY-100635 rat 4 *
 WAY-100635 5: Treatment with WAY-100635 rat 5 * Indorenate+Pelanserin
 1: Treatment with indorenate + pelanserine rat 1 * Indorenate+Pelanserin
 2: Treatment with indorenate + pelanserine rat 2 * Indorenate+Pelanserin
 3: Treatment with indorenate + pelanserine rat 3 * Indorenate+Pelanserin
 4: Treatment with indorenate + pelanserine rat 4 * Indorenate+Pelanserin
 5: Treatment with indorenate + pelanserine rat 5 * Indorenate+WAY-100635
 1: Treatment with indorenate + WAY-100635 rat 1 * Indorenate+WAY-100635
 2: Treatment with indorenate + WAY-100635 rat 2 * Indorenate+WAY-100635
 3: Treatment with indorenate + WAY-100635 rat 3 * Indorenate+WAY-100635
 4: Treatment with indorenate + WAY-100635 rat 4 * Indorenate+WAY-100635
 5: Treatment with indorenate + WAY-100635 rat 5 #### File:
 Figure_5_OGTT_in_diabetic_model.csv **Description:**  Oral GLucose
 Tolerance Test in an experimental diabetic model, Wistar male rats (mg/dL)
 ##### Variables * Time (min): minutes * CT 1: Vehicle 1 * CT 2: Vehicle 2
 * CT 3: Vehicle 3 * Indorenate 1: Treatment with indorenate rat 1 *
 Indorenate 2: Treatment with indorenate rat 2 * Indorenate 3: Treatment
 with indorenate rat 3 * Metformin 1: Treatment with metformin rat 1 *
 Metformin 2: Treatment with metformin rat 2 * Metformin 3: Treatment with
 metformin rat 3 #### File:
 Statical_analysis_and_docking_structions_CJPP_Giacoman-Martínez_et_al.pdf
 **Description:** Parameters of statistical analysis and molecular docking
 instructions in PDF format ## Code/software The data were processed using
 GraphPad Prism version 8.0 software. For molecular docking analysis,
 Autodock version 2.4.6, UCSF Chimera version 1.0, PyMOL Molecular Graphics
 System Version 3.0, Schrödinger, and Discovery Studio version 21.1.0 are
 required.