Structure-Activity Relationship Study of Acyclic Terpenes in Blood Glucose Levels: Potential α-Glucosidase and Sodium Glucose Cotransporter (SGLT-1) Inhibitors.

Miguel Valdes,Fernando Calzada,Jessica Mendieta-Wejebe

doi:10.3390/molecules24224020

Abstract

Twelve terpenoids were evaluated in the treatment of type 2 diabetes mellitus: seven monoterpenes (geranyl acetate (1), geranic acid (2), citral (3), geraniol (4), methyl geranate (5), nerol (6), and citronellic acid (7)), three sesquiterpenes (farnesal (8), farnesol (9), and farnesyl acetate (10)), one diterpene (geranylgeraniol (11)), and one triterpene (squalene (12)) were selected to carry out a study on normoglycemic and streptozotocin-induced diabetic mice. Among these, 2, 3, 7, 8, 9, and 10 showed antihyperglycemic activity in streptozotocin-induced diabetic mice. They were then selected for evaluation in oral sucrose and lactose tolerance tests (OSTT and OLTT) as well as in an oral glucose tolerance test (OGTT). In the OSTT and OLTT, compounds 3, 7, 8, 9, and 10 showed a reduction in postprandial glucose peaks 2 h after a sucrose or lactose load (comparable to acarbose). In the case of the OGTT, 2, 7, 8, 9, and 10 showed a reduction in postprandial glucose peaks 2 h after a glucose load (comparable to canagliflozin). Our results suggest that the control of postprandial hyperglycemia may be mediated by the inhibition of disaccharide digestion, such as sucrose and lactose, and the regulation of the absorption of glucose. The first case could be associated with an -glucosidase inhibitory effect and the second with an inhibition of the sodium–glucose type 1 (SGLT-1) cotransporter. Finally, five acyclic terpenes may be candidates for the development and search for new α-glucosidase and SGLT-1 cotransporter inhibitors.

Highlights

Diabetes mellitus (DM) is considered to be a group of metabolic diseases characterized by high glucose levels resulting from alterations in the metabolism of carbohydrates, lipids, and proteins
In an acute test using normoglycemic mice (NM), compound 4, glibenclamide, and pioglitazone showed a decrease in glycemia values at 2 and 4 h; in the case of 5, 6, and 11, there was activity at 4 h
We observed that in terpenes with a higher quantity of carbon as well as squalene (12), the activity in terms of glycemic values was lost. This effect was observed in geranyl acetate (1), where we observed that monoterpenes with a presence of acetate groups in C1 completely lost their activity in terms of the blood glucose values

Summary

Introduction

Diabetes mellitus (DM) is considered to be a group of metabolic diseases characterized by high glucose levels resulting from alterations in the metabolism of carbohydrates, lipids, and proteins. These alterations are generated by defects in insulin secretion, action, or both [1]. If patients do not control their glycemic levels, this can cause long-term damage or dysfunction in several organs, including the retinas, kidneys, nervous system, heart, and blood vessels, which in time becomes a deadly situation for the patient [2,3]. There are several treatments for this disease, including sulfonylureas, meglitinides, biguanides, Molecules 2019, 24, 4020; doi:10.3390/molecules24224020 www.mdpi.com/journal/molecules. Molecules 2019, 24, 4020 thiazolidinediones, glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium–glucose cotransporter (SGLT) inhibitors [6,7,8,9].

Methods

Results

Discussion

Conclusion