Reply to CJ Kelly

Department of Internal Medicine and Public Health
University of L'Aquila
Piazzale S Tommasi n.1
67100 Coppito
L'Aquila
Italy E-mail: claudio.ferri{at}cc.univaq.it

Dear Sir:

In our recent paper (1), we observed a significant decrease in blood pressure and a significant amelioration of insulin sensitivity and insulin resistance indexes in healthy volunteers who consumed dark chocolate bars (100 g) over a period of 15 d. Throughout the study, total daily energy intake remained unchanged through appropriate diet changes. Therefore, no weight gain occurred in our study population. Because white chocolate bars did not modify blood pressure or insulin sensitivity, we suggested that the flavanols contained in the dark chocolate bars were responsible for the observed changes.

The above hypothesis is supported by in vitro data indicating that flavanols contained in cocoa can increase nitric oxide production (2) and decrease superoxide anion generation (2) and thereby have all the biological potential to positively influence blood pressure regulation and insulin-mediated glucose uptake (3). In vivo data also indicate that intake of dark chocolate reduces blood pressure and improves endothelium-dependent vasorelaxation in healthy humans (4) and elderly subjects with isolated systolic hypertension (5). In keeping with this, obesity, diabetes, and hypertension are relatively rare among Kuna Indians, a population of Amerinds living in the San Blas Island chain off the cost of Panama, who are known to ingest large amounts of cocoa (6).

Although convincing evidence supports our flavanol hypothesis, we think the additional explanation suggested by Kelly is of extreme interest. Kelly correctly emphasized that cocoa also contains methylxanthines, particularly theobromine and, to a lesser extent, caffeine (7). As is known, methylxanthines inhibit phosphodieterase and thereby increase the intracellular concentration of cyclic AMP (cAMP) in pancreatic ß cells, antagonizing P₁ purinoreceptors (8). In contrast, methylxanthines are negatively coupled to adenylate cyclase in hepatocytes and induce a decrement in cAMP concentration in these cells (8). Because both insulin secretion from pancreatic ß cells and liver glucose output are directly dependent on the intracellular concentration of cAMP, we agree with Kelly's hypothesis that it is reasonable to speculate that methylxanthines may positively influence glucose metabolism in humans. Kelly indicated that no data from the literature are available on his own intriguing hypothesis. However, we found that Cerasi and Luft (9) observed an amelioration of glucose-mediated insulin secretion after aminophylline administration. Similarly, Arias et al (10) reported a mild but significant decrease in serum glucose concentrations by stimulation of insulin secretion in patients with type 2 diabetes mellitus who received an intravenous infusion of the same drug. Furthermore, caffeine ingestion was recently reported to significantly reduce glucose disposal without variations in insulin concentrations during an euglycemic hyperinsulinemic clamp (11). Therefore, the hypothesis that theobromine contained in dark but not white chocolate bars may have influenced blood pressure and insulin sensitivity in our study population is not only intriguing but also supported by some data from the literature. Therefore, we agree with the extremely interesting suggestion from Kelly, ie, that future studies should focus not only on flavanols but also on theobromine to fully understand the potential benefits of cocoa.

It is intriguing to speculate that cocoa could help to counteract the pandemic explosion of cardiovascular disease risk factors and their sequelae. Nevertheless, the high energy density of cocoa must be taken into account. Because most vegetables are relatively low in calories, whereas each of the dark chocolate bars (100 g) that we used in our study (1) contained 500 kcal, we must ensure that each person consuming small amounts of chocolate per day simultaneously reduces his or her daily energy intake (particularly of calories derived from unhealthy foods). If not, the potential benefit of flavanols contained in cocoa would be contrasted, or even reversed, by increases in body weight.

ACKNOWLEDGMENTS

The authors had no undisclosed financial or personal interest in any company or organization connected in any way with the research represented in the article.

REFERENCES

1. Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr 2005;81:611–4.
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