Effects of Polyphenols on Glucose-Induced Metabolic Changes in Healthy Human Subjects and on Glucose Transporters

Abstract

Dietary polyphenols interact with glucose transporters in the small intestine and modulate glucose uptake after food or beverage consumption. This review assesses the transporter interaction in vitro and how this translates to an effect in healthy volunteers consuming glucose. As examples, the apple polyphenol phlorizin inhibits sodium-glucose linked transporter-1; in the intestinal lumen, it is converted to phloretin, a strong inhibitor of glucose transporter-2 (GLUT2), by the brush border digestive enzyme lactase. Consequently, an apple extract rich in phlorizin attenuates blood glucose and insulin in healthy volunteers after a glucose challenge. On the other hand, the olive phenolic, oleuropein, inhibits GLUT2, but the strength of the inhibition is not enough to modulate blood glucose after a glucose challenge in healthy volunteers. Multiple metabolic effects and oxidative stresses after glucose consumption include insulin, incretin hormones, fatty acids, amino acids, and protein markers. However, apart from acute postprandial effects on glucose, insulin, and some incretin hormones, very little is known about the acute effects of polyphenols on these glucose-induced secondary effects. In summary, attenuation of the effect of a glucose challenge in vivo is only observed when polyphenols are strong inhibitors of glucose transporters.

Keywords: OGTT; dihydrochalcone; flavonoid; insulin; post prandial; sugar.

Figure 1

Changes in metabolic parameters after an OGTT (75 g glucose) in healthy volunteers. Panel A). Mean of glucose changes from refs. [7, 14, 49, 50, 51]. Panel B). Glucose (●); ornithine (○); β‐hydroxybutyrate (♦); citrulline (▲); pyruvate (■); malate (□); (◊); lactate (∆); citrate (●); acetate (■); acetoacetate (▲). Data replotted from refs. [51, 52]. Panel C): Total lysoPC (●); total free fatty acids (○); large VLDL (very low‐density lipoprotein) (♦); glycerol (▲); very large HDL (■); VLDL TG (very low‐density lipoprotein triglycerides) (□); C10:0 + C12:0 + C14:1 carnitine (◊); HDL TG (high‐density lipoprotein triglycerides) (●, dotted line); the two lines for triglycerides (TG) are derived from two separate publications (^[7] (∆);^{[ 52 ]} (●)). Data replotted from refs. [7, 14, 51, 52]. Panel D). Glycine (●); alanine (○); tyrosine (♦); isoleucine (▲); glutamine (■); phenylalanine (□); leucine (◊); valine (●); histidine, (∆). Data replotted from ref. [52].

Figure 2

Changes in markers and hormones after an OGTT (75 g glucose) in healthy volunteers. Panel A). Total bile acids (●); glucagon, no significant changes (○); total GIP (♦); insulin (▲); C‐peptide (■); amylin (□); GLP‐1 (∆); active GIP (●). Data replotted from refs. [49, 50, 53, 54, 55]. Panel B). A significant change is seen in at least one time point for TNFSF14 (“LIGHT,” tumor necrosis factor superfamily member 14) (●); osteopontin (○); MDC (CCL‐22, chemokine (C‐C motif) ligand 22) (♦); VEGF (vascular endothelial growth factor) (■); ANG (angiotensin) (∆); MCP3 (CCL‐7, chemokine (C‐C motif) ligand 7) (●). No significant changes are seen in MCP1 (CCL‐2, chemokine (C‐C motif) ligand 2) (□) and MCSF (macrophage colony stimulating factor) (◊); data replotted from ref. [52]. Panel C). A significant change is seen in at least one time point for hypoxanthine (●); IL‐6 (▲); peroxides (∆). No significant changes are seen in H₂O₂ (□); MDA (■); α‐TNF (○); data replotted from refs. [7, 16]. Panel D). A significant change is seen in at least one time point for CRP (□); IL‐8 (◊); thioredoxin (○); RBP4 (retinol binding protein 4) (■); leptin (●). No significant changes are seen in IL‐6 (♦); resistin (∆); adiponectin (●). Data replotted from ref. [17].

Figure 3

Diagrammatic representation of the pathways involved in glucose absorption and distribution, and some examples of inhibitors. Example inhibitors of α‐amylase and of α‐glucosidase are from refs. [56, 57]. Example inhibitors of GLUT2 and of SGLT1 are from Table 1. Proposed steps where polyphenols may affect glucose distribution are shown with red arrows, and response hormones are shown in blue. Effect of some metabolites of polyphenols on glucose transport into human muscle cells^{[ 58 ]} is shown (IVAS, isovanillic acid sulfate, a microbial metabolite of anthocyanins; R3S, resveratrol‐3‐sulfate and R4G, resveratrol‐4‐glucuronides, conjugates of resveratrol found in the blood after resveratrol consumption; FA4S, ferulic acid‐4‐sulfate, conjugate of ferulic acid found in blood after, e.g., coffee consumption). Quercetin and EC are shown as two examples of polyphenols that affect pancreatic β‐cells.^{[ 59} , ^{60 ]}. The polyphenols and metabolites shown are examples, and the lists are not exhaustive.

Figure 4

Chemical structure of SGLT1 and GLUT2 inhibitors. Sotagliflozin and phlorizin are molecules with similar shapes and key substitutions, allowing binding to key amino acids at the active site of SGLT1. Phloretin is the aglycone form of phlorizin, and is a relatively strong inhibitor of GLUT2. One of the strongest inhibitors of GLUT2 ((4‐(5‐(4‐fluorophenyl)‐1‐{[(2‐methyl‐1H‐indol‐3‐yl)sulfanyl]acetyl}‐4,5‐dihydro‐1H‐pyrazole‐3‐yl) phenylmethylester) is not related structurally to phloretin or other polyphenols.