Anthocyanins as Antidiabetic Agents-In Vitro and In Silico Approaches of Preventive and Therapeutic Effects

Abstract

Many efforts have been made in the past two decades into the search for novel natural and less-toxic anti-diabetic agents. Some clinical trials have assigned this ability to anthocyanins, although different factors like the food source, the amount ingested, the matrix effect and the time of consumption (before or after a meal) seem to result in contradictory conclusions. The possible mechanisms involved in these preventive or therapeutic effects will be discussed-giving emphasis to the latest in vitro and in silico approaches. Therapeutic strategies to counteract metabolic alterations related to hyperglycemia and Type 2 Diabetes Mellitus (T2DM) may include: (a) Inhibition of carbohydrate-metabolizing enzymes; (b) reduction of glucose transporters expression or activity; (c) inhibition of glycogenolysis and (d) modulation of gut microbiota by anthocyanin breakdown products. These strategies may be achieved through administration of individual anthocyanins or by functional foods containing complexes of anthocyanin:carbohydrate:protein.

Keywords: anthocyanins; anti-diabetic; carbohydrate; enzyme; microbiota; preventive; therapeutic.

Figure 1

Structure of different anthocyanins (flavylium cation form) commonly found in typical diets. Cyanidin-3-O-glucoside can be found in different berries, while cyanidin-3,5-O-diglucoside may be found in pomegranates. Malvidin-3-O-glucoside is the main anthocyanin in Vitis vinifera grapes and red wine, while sophoroside anthocyanins are abundant in purple sweet potato and purple cabbage.

Figure 2

Cellular signaling pathways by which anthocyanin can modulate glucose homeostasis.

Figure 3

Impact of anthocyanin consumption within food matrix and as a supplement (individual compounds).

Figure 4

Main gut anthocyanin metabolites. Metabolites can be formed by enzymatic/microbiota action, and result from the breakdown of the C6-C3-C6 structure. Thus, metabolites can be either derived from ring A or B of the parent anthocyanin structure.

Figure 5

Target proteins and genes of anthocyanins and their metabolites with antidiabetic activity. After reaching the gastrointestinal tract, anthocyanins may be directly absorbed or metabolized. Once in the blood stream, they may be absorbed by target tissues of further transformed in kidney or liver. Nevertheless, upon reaching their targets, these compounds can act as antidiabetic agents at different levels, such as glucose transport, the hepatic machinery or modulation of β-cells, and on different metabolic pathways, like Mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) or nuclear factor kappa B (NF-κB), or even act on the lipid metabolism level by modulating peroxisome proliferator-activated receptors (PPARs). SLC2: Facilitative GLUT transporter family; Pi3K: Phosphoinositide 3-kinases; IRs-1: Insulin receptor substrate 1; G6P: Glucose 6-phosphatase; PEPCK: Phosphoenolpyruvate carboxykinase; F-1,6-BP: Fructose 1,6-bisphosphatase; GK: Glucokinase; JNK: c-Jun N-terminal kinase; Bcl2: B-cell lymphoma 2 proteins; LKB-1: liver kinase B1; CAMKKB: calcium/calmodulin-dependent protein kinase 2; TAK-1: Transforming growth factor beta-activated kinase 1.