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Abstract
Flavanols from chocolate appear to increase nitric oxide bioavailability, protect vascular endothelium, and decrease
cardiovascular disease (CVD) risk factors. We sought to test the effect of flavanol-rich dark chocolate (FRDC) on
endothelial function, insulin sensitivity, b-cell function, and blood pressure (BP) in hypertensive patients with impaired
glucose tolerance (IGT). After a run-in phase, 19 hypertensives with IGT (11 males, 8 females; 44.8 6 8.0 y) were
randomized to receive isocalorically either FRDC or flavanol-free white chocolate (FFWC) at 100 g/d for 15 d. After a washout period, patients were switched to the other treatment. Clinical and 24-h ambulatory BP was determined by
sphygmometry and oscillometry, respectively, flow-mediated dilation (FMD), oral glucose tolerance test, serum
cholesterol and C-reactive protein, and plasma homocysteine were evaluated after each treatment phase. FRDC but not
FFWC ingestion decreased insulin resistance (homeostasis model assessment of insulin resistance; P , 0.0001) and
increased insulin sensitivity (quantitative insulin sensitivity check index, insulin sensitivity index (ISI), ISI0; P , 0.05) and
b-cell function (corrected insulin response CIR120; P 0.035). Systolic (S) and diastolic (D) BP decreased (P , 0.0001) after
FRDC (SBP, 23.82 6 2.40 mm Hg; DBP, 23.92 6 1.98 mm Hg; 24-h SBP, 24.52 6 3.94 mm Hg; 24-h DBP, 24.17 6 3.29
mm Hg) but not after FFWC. Further, FRDC increased FMD (P , 0.0001) and decreased total cholesterol (26.5%; P ,
0.0001), and LDL cholesterol (27.5%; P , 0.0001). Changes in insulin sensitivity (D ISI 2 D FMD: r 0.510, P 0.001;
D QUICKI 2 D FMD: r 0.502, P 0.001) and b-cell function (D CIR120 2 D FMD: r 0.400, P 0.012) were directly
correlated with increases in FMD and inversely correlated with decreases in BP (D ISI 2 D 24-h SBP: r 20.368, P
0.022; D ISI 2 D 24-h DBP r 20.384, P 0.017). Thus, FRDC ameliorated insulin sensitivity and b-cell function,
decreased BP, and increased FMD in IGT hypertensive patients. These findings suggest flavanol-rich, low-energy cocoa
food products may have a positive impact on CVD risk factors. J. Nutr. 138: 16711676, 2008.
Introduction
Several studies indicate fruits and vegetables as well as red wine,
tea, and cocoa rich in polyphenols may reduce the risk of
cardiovascular disease (CVD)6 (1). Cocoa beans contain 68%
polyphenols by dry weight and are particularly rich in mono1
Supported by the Italian Ministero della Universitae della Ricerca Scientifica.
Support for J. B. Blumberg was provided by the USDA Agricultural Research
Service under Cooperative Agreement no. 58-1950-4-401. The contents of this
publication do not necessarily reflect the views or policies of the USDA nor does
mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
2
Author disclosures: D. Grassi, G. Desideri, S. Necozione, C. Lippi, R. Casale,
G. Properzi, J. B. Blumberg, and C. Ferri, no conflicts of interest.
3
Supplemental Tables 15 are available with the online posting of this paper at
jn.nutrition.org.
* To whom correspondence should be addressed. E-mail: davide.grassi@cc.
univaq.it.
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Grassi et al.
Results
Baseline characteristics. Baseline characteristics and laboratory results of the IGT EH patients showed a marked degree of
insulin resistance, with high HOMA-IR and low QUICKI and
ISI values (15,18,19). Per study inclusion criteria, none of the
patients had Type 2 diabetes (Supplemental Table 2).
Insulin resistance and b-cell function. Consuming FRDC for
15 d decreased HOMA-IR (Fig. 1A) and increased QUICKI (Fig.
1B) compared with baseline and FFWC values. No change was
observed in HOMA-IR (Fig. 1A) or QUICKI (Fig. 1B) after
consumption of FFWC. ISI increased compared with baseline
FIGURE 1 Effect of consuming FRDC and FFWC for 15 d on HOMA-IR (A), QUICKI (B), ISI0 (C), and CIR120 (D) in IGT EH patients. Data are
means 6 SD, n 19. *Different from baseline and FFWC, P , 0.05. Baseline data are pooled (mean) from 2 separate baselines.
Chocolate in glucose-intolerant hypertensives
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Discussion
Insulin resistance and IGT are associated with increased risk of
type 2 diabetes and CVD. Hypertension, a well-established risk
factor for CVD, has also been associated with IGT (1416). This
randomized, cross-over trial shows for the first time, to our
knowledge, that FRDC is able to enhance insulin sensitivity and
b-cell function, decrease BP, and increase FMD in EH patients
with IGT but absent other risk factors for CVD and type 2
diabetes such as dyslipidemia, obesity, and smoking. These data
also reveal that the changes in insulin sensitivity, b-cell function,
and BP following FRDC are directly correlated with the amelioration of endothelial dysfunction.
Impairment of insulin sensitivity and vascular reactivity
appear linked to CVD risk via a mutual dependence on the
endothelial bioavailability of NO (28). For example, reactive
oxygen species inactivate endothelium-derived NO in diabetic
animals and humans and reduce vasodilatory responses (28).
Insulin infusion under euglycemic glucose-clamp increases
NO-dependent skeletal muscle blood flow and stimulates
peripheral glucose transport, uptake, and disposal (29). Normal
glucose tolerance is modulated via a balance between insulin
TABLE 1
BP, mm Hg
FRDC
Baseline
86.8 6 3.7
134.6 6 4.4
90.9 6 4.0
78.7 6 4.4
139.5 6 4.4
124.9 6 5.5
After
82.6 6 5.4*y
130.1 6 5.0*y
86.5 6 5.7*y
74.5 6 6.0*y
134.9 6 5.3*y
120.1 6 5.4*y
FFWC
Baseline
87.0 6 3.5
133.8 6 3.9
91 6 3.5
78.9 6 4
138.5 6 4.0
124.2 6 5.0
After
87.0 6 3.1
133.9 6 3.6
90.8 6 3.0
79.2 6 3.3
138.8 6 4.1
124.0 6 3.3
Data are means 6 SD, n 19. *Different from respective baseline, P , 0.05;
Different from FFWC at that time, P , 0.05.
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Grassi et al.
Literature Cited
Acknowledgment
We thank Napoleone Neri, Chairman, Sugar Company S.p.A.
for the donation of the dark chocolate bars.
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