New hypoglycemic effects of indorenate mediated by the 5-HT1a and 5-HT2a receptors: In vivo and in silico studies

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.