Table 3.

Flavanols: hypolipidemic and hypoglycemic effects.

Type OF Study	Product/Compound	Dose/Duration	Intervention	Target	Outcome (s)	Reference
Comparative, double-blind study in normo and mild hyper cholesterolemic japanese subjects (n = 160)	Low PFT cocoa powder (64.5 mg epicatechin and 36.3 mg pB2/g)  middle PFT cocoa powder (96.7 mg epicatechin and 54.4 mg pB2/g)  high PFT cocoa powder (129 mg epicatechin and 72.5 mg pB2/g)	Consumption of 13 g low PFT cocoa; or 19.5 g middle PFT cocoa; or 26 g high PFT cocoa, during 4 weeks	Intake of low PFT cocoa powder vs. middle PFT cocoa vs. high PFT cocoa in normo and mild hyper cholesterolemic subjects	Serum LDL, HDL and oxLDL	Consumption of 3 cocoa doses in subjects with LDL ≥3.23 mmol/L, resulted in significantly ↓ serum [LDL], after 4 wk  Consumption of 3 cocoa doses (normo and mild hypercholesterolemic subjects) resulted in ↑ serum [HDL], compared with baseline after 4 wk  Plasma oxLDL levels were significantly ↓ after 4 wk consumption of 3 cocoa doses (normo and mild hyper cholesterole-mic subjects)	[72]
Randomized, placebo-controlled, double blind, crossover study in   DM 2 subjects (n = 12)	High (16.6 mg epicatechin) and low (<2 mg epicatechin) polyphenol content chocolate	45 g high or low polyphenol chocolate, during 8 week	High polyphenol chococolate (HPC) intake vs. low polyphenol chococolate (LPC) intake	Serum c-HDL, c-LDL, TG, HbA1c, fasting glucose and insulin and C- reactive protein	Consumption of HPC and LPC improved lipid profile through ↑ HDL/↓ LDL   No changes were observed in fasting glucose or HbA1c levels in none of the 2 treat-ment groups  Insulin levels showed an ↑ after LPC intake   No changes were observed in C-reactive protein levels in none of the 2 treatment groups	[75]
Cross-sectional study in 4098 patients from NHLBI	Chocolate	-	Association between self-reported chococlate consumption and prevalence of metabolic syndrome (MS) in adult population	ATP-III criteria for clinical diagnosis of metabolic syndrome	Higher intake of chocolate was associated with ↓ prevalence of coronary heart disease and ↓ glycemia  From the lowest to the highest levels of choco-late consumption, the prevalence of MS odd ratios were:  + women: 1.0 (0/wk); 1.26 (<1/wk); 1.15 (1–4/wk) and 0.9 (+5/wk)  + men: 1.0 (0/wk); 1.13 (<1/wk); 1.02 (1-4/wk) and 1.21 (+5/wk)  the highest odd ratios of obesity prevalence were observed with higher chocolate consumption	[71]
9-week-old male Sprague–Dawley rats (n = 40)            12-week-old female Sprague–Dawley rats (n = 56)	Cacao procya-nidins (CP) extracted from cacao liquor (CLPr: 79.3% total polyphenols; 5.9% epicatechin; and 4% PB2)            Cocoa powder	High-cholesterol diet (HCD: 1% cholesterol and 15% fat) supplemented with 0.5 or 1.0% of CLPr        C1: methionine-choline deficient diet (MCD) + 28 d of 12.5% cocoa supplementation  C2: MCD diet + 56 d of cocoa supplementation  C3: 80 d of MCD + cocoa supp.  C4: 108 d of MCD + cocoa supplementation	HCD with 0.5% CP vs. HCD with 1.0% CP            C1 and C2 were selected to test NASH treatmet effects of cocoa supplementation   C3 and C4 were used to test if cocoa supple- mentation could prevent NASH development	Plasma and liver cholesterol  liver and feces TG            mRNA and protein expression of LFABP  serum TG, glucose and superoxide levels	Both CP groups (0.5 and 1%) inhibited drastic elevation of plasma TC levels  Liver cholesterol and TG levels were significantly ↓ in HCD groups supplemented with both CP doses (more marked effects in 1% CP)          All cocoa supplemented groups showed ↓ serum TG and glucose levels   C3 group had the ↓ superoxide levels, compared to C1, janeC2 and C4 groups  C1 had the ↑ mRNA and protein expression levels of LFABP	[76]             [77]
3-week-old female diabetic obese mice  (n = 44)            Streptozotocin-diabetic male Wistar rats  (n = 80: 200–300 g)	Cacao liquor procyanidins (72.32% total polyphenols; 5.89% epi-catechin and 3.93% PB2)            Cocoa beans extract (CE)	Supplementation with 0.5 or 1 % CLPr, during 3 weeks            Supplementation with 1, 2 or 3% CE (1 g CE/100 g diet)	Dietary  supplementation with 0% CLPr vs. supplementation with 0.5 or 1.0% CLPr          Streptozotocin-diabetic rats + normal diet vs. diabetic induced rats + 1, 2 or 3% CE	Plasma glucose (hyperglycemia) and renal function            Serum CT, HDL, LDL, TG and glucose	Levels of blood glucose were significantly ↓ in mice fed 1% CLPr  At the end of the study, group supplemented with 1% CLPr had ↓ levels of BUN and creatinine and suppressed membrane lipoxidation in kidney (↓ 4-hidroxy-2-nonenal antibody levels)      All 3 diabetic groups treated with CE showed significant ↓ in body weight gain and serum TG levels  Diabetic groups treated with 1 and 3% CE exhibited significant ↓ in plasma glucose levels  Diabetic group treated with 1% CE had the ↓ serum levels of CT and LDL	[78]             [79]
Male Sprague–Dawley rats (n= 90)	Polyphenol-rich cocoa extract (CE)	Intragastric administration of 1, 2 or 3% CE (1 mL/100 g bw) during 4 weeks	Assessment of CE effectiveness in reducing hyperglyce-mia in diabetic-induced rats	Plasma glucose levels and body weight gain	A significant body weight reduction was observed (p < 0.05) in diabetic-induced rats treated with 1 and 2% CE  Diabetic-induced rats treated with 3% CE showed the most significant ↓ in glucose levels	[80]
Glucose-responsive pancreatic cell lines (BRIN-BD11)                      Randomized, crossover trial in patients with hypertension (HTA-I) and impaired glucose tolerance (IGT) (n = 19)	Polyphenol-rich cocoa extract (CE)            Flavanol-rich dark chocolate bar (FRDC: 110.9 mg epicatechin/bar)	Incubation with CE at 2, 1, 0.5, 0.1 and 0.05 mg/mL            100 g of dark chocolate bar, during 15 days	Evaluation of different concentrations of CE on insulin secretion             Flavanol rich dark chocolate bar vs. flavanol free chocolate bar	Insulin-release from rat pancreatic β-cells            Fasting glucose and insulin sensitivity  Serum C-reactive protein (CRP)  Serum lipid profile (HDL, CT, LDL and TG)	Pancreatic cell lines treated with 0.1 mg/mL of CE showed the ↑ insulin secretion            FRDC intake enhanced insulin sensitivity and β-cell function in HTA-I patients with IGT (measured by ↑ QUICKI; ↓ HOMA-IR; ↑ ISI0 and ICI20)  FRDC ingestion significantly ↑ FMD  FRDC intake ↓ serum CT and LDL, but did not affect TG and HDL  neither FRDC nor FFWC ingestion affected serum CRP	[81]
Male C57BL/6 4-week-old mice (n = 36)	cacao liquor procyanidin extract  (CLPr: 6.12% epicatechin and 3.60% PB2)	Supplementation with 0.5 or 2% CLPr, during 13 weeks	High fat diet (HFD) vs. HFD + 0.5% (HF-0.5) or 2% (HF-2) CLPr	Glucose parameters  mRNA and protein expression of UCP-1, UCP-2, GLUT-4 and AMPKα	At week 7, fasting glucose levels in HF-2 group were significantly lower  At week 11, OGTTe showed ↓ glucose levels in HF-2 group (0 and 15 minutes after glucose load)  At the end of the study, HF-0.5 and HF-2 completely suppressed HF diet-induced hyper-glycemia, hyper-insulinemia (↓ HOMA-IR) and hypercholestero-lemia, compared to control group  CLPr supplementation promoted AMPKα phosphorilation (BAT, WAT, liver and skeletal muscle), which enhanced GLUT-4 translocation to plasma membrane in BAT and skeletal muscle in a dose-dependent manner  CLPr ↑ UCP-1 and UCP-2 gene and protein expression in BAT and WAT, respectively	[82]

PFT: total polyphenols; OGTT: oral glucose tolerance test; oxLDL: oxidized LDL; HbA1c: glycated hemoglobin; NHLBI: National Heart, Lung, and Blood Institute; NASH: non-alcoholic steatohepatitis; LFAP: liver fatty acid binding protein; bw: body weight.↑ increased; ↓decreased.