Recent Updates on Phytoconstituent Alpha-Glucosidase Inhibitors: An Approach towards the Treatment of Type Two Diabetes

Abstract

Diabetes is a common metabolic disorder marked by unusually high plasma glucose levels, which can lead to serious consequences such as retinopathy, diabetic neuropathy and cardiovascular disease. One of the most efficient ways to reduce postprandial hyperglycemia (PPHG) in diabetes mellitus, especially insulin-independent diabetes mellitus, is to lower the amount of glucose that is absorbed by inhibiting carbohydrate hydrolyzing enzymes in the digestive system, such as α-glucosidase and α-amylase. α-Glucosidase is a crucial enzyme that catalyzes the final stage of carbohydrate digestion. As a result, α-glucosidase inhibitors can slow D-glucose release from complex carbohydrates and delay glucose absorption, resulting in lower postprandial plasma glucose levels and control of PPHG. Many attempts have been made in recent years to uncover efficient α-glucosidase inhibitors from natural sources to build a physiologic functional diet or lead compound for diabetes treatment. Many phytoconstituent α-glucosidase inhibitors have been identified from plants, including alkaloids, flavonoids, anthocyanins, terpenoids, phenolic compounds, glycosides and others. The current review focuses on the most recent updates on different traditional/medicinal plant extracts and isolated compounds' biological activity that can help in the development of potent therapeutic medications with greater efficacy and safety for the treatment of type 2 diabetes or to avoid PPHG. For this purpose, we provide a summary of the latest scientific literature findings on plant extracts as well as plant-derived bioactive compounds as potential α-glucosidase inhibitors with hypoglycemic effects. Moreover, the review elucidates structural insights of the key drug target, α-glucosidase enzymes, and its interaction with different inhibitors.

Keywords: natural compounds; postprandial hyperglycemia; type 2 diabetes; α-glucosidase.

Figure 3

(a) Ribbon diagram of the structure of human ctMGAM/acarbose complex. (b) Human ctMGAM important active site residues (catalysis/substrate binding). The acarbose is colored cyan and is shown as sticks. (a,b) were adopted from the structure, with PDB entry code: 3TOP [44], and were generated using PyMol [40].

Scheme 1

Flow chart for the pathophysiology of type 2 diabetes.

Figure 1

(a) Ribbon diagram of the structure of Human Nt MGAM/acarbose complex as a representative for GH31 α-glucosidase. Different domains are colored as follows: N-terminal domain, blue; catalytic domain, green; subdomain b1, pale green; subdomain b2, lemon; C-terminal domain 1, red; and C-terminal domain 2, orange. (b) Human Nt MGAM/acarbose complex active site; sticks represent residues situated within a 4-A° radius of a valienamine unit. The acarbose is colored cyan and is shown as sticks and wire for a and b, respectively. (a,b) were adopted from the structure, with PDB entry code: 2QMJ [39], and were generated using PyMol [40].

Figure 2

(a) Ribbon diagram of Human Nt SI crystal structure in complex with kotalanol. (b) Human Nt SI important active site residues (catalysis/substrate binding). The kotalanol is colored cyan and is shown as sticks. (a,b) were adopted from the structure, with PDB entry code: 3LPP [43], and were generated using PyMol [40].

Figure 4

Chemical structure of some of the reported flavonoids as α-glucosidase inhibitors; (a) Calodenin A, (b) (-) Epigallocatechin-gallate, and (c) Myricetin-3-O-(2″-O-galloyl)-α-L-rhamnoside.

Figure 5

Chemical structure of some of the reported terpenoids as α-glucosidase inhibitors; (a) Gauleucin E, (b) Taxumariene F, (c) Betulin, and (d) Betulinic acid.

Figure 6

Chemical structure of some of the reported phenolic acids as α-glucosidase inhibitors; (a) Caffeic acid, (b) Vanilic acid, and (c) Ellagic acid.

Figure 7

Chemical structure of some of the reported tannins as α-glucosidase inhibitors; (a) procyanidin A2, and (b) 1,2,3-tri-O-galloyl-β-D-glucopyranose.

Figure 8

Chemical structure of some bioactive compounds reported as potential α-glucosidase inhibitors; (a) Cyanidin, (b) Chysalodin, (c) Parmosidone I, (d) 3β,8β,14β,20-tetrahydroxy-(20S)-pregn-5-ene-3-O-β-D-glucopyranosyl-(1→4)-O-β-D-digitaloside-20-O-3-isoval-β-D-glucopyranoside, (e) Fucoxanthin, (f) 2-(3′,4′-dihydroxyphenyl)-2,3-dihydro-4,6-dihydroxy-2-(methoxy)-3-benzofuranone, and (g) Mangoxanthone A.