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Cited by 311Phytochemicals and Antioxidant ActivitiesDementia and Cognitive Impairment ResearchMedicinal Plants and Neuroprotection

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment: The Cocoa, Cognition, and Aging (CoCoA) Study

Desideri, Giovambattista, Kwik-Uribe, Catherine, Grassi, Davide, Necozione, Stefano, Ghiadoni, Lorenzo, Mastroiacovo, Daniela, Raffaele, Angelo, Ferri, Livia +4 more·2012·Hypertension
DOI 10.1161/hypertensionaha.112.193060
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Abstract

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups ( P =0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly ( P <0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly ( P <0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r 2 =0.4013; P <0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

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Crossref · 10.1161/hypertensionaha.112.193060

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Claims the paper makes

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  • Findingown data

    TMT A time decreased significantly in the HF group (mean change -14.3±4.2 s; P<0.0001).

    “The time required to complete TMT A significantly changed throughout the study period (PϽ0.0001), with significant reductions observed in subjects assigned to HF (Ϫ14.3Ϯ4.2 seconds; PϽ0.0001) and IF (Ϫ8.8Ϯ3.4 seconds; PϽ0.0001) interventions but not in those assigned to the LF intervention (ϩ1.1Ϯ13.0seconds; Pϭ0.65; Table 1).”
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  • Findingown data

    TMT A completion time significantly changed over the study period (P<0.0001).

    “The time required to complete TMT A significantly changed throughout the study period (PϽ0.0001), with significant reductions observed in subjects assigned to HF (Ϫ14.3Ϯ4.2 seconds; PϽ0.0001) and IF (Ϫ8.8Ϯ3.4 seconds; PϽ0.0001) interventions but not in those assigned to the LF intervention (ϩ1.1Ϯ13.0seconds; Pϭ0.65; Table 1).”
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  • Findingown data

    TMT A time decreased significantly in the IF group (mean change -8.8±3.4 s; P<0.0001).

    “The time required to complete TMT A significantly changed throughout the study period (PϽ0.0001), with significant reductions observed in subjects assigned to HF (Ϫ14.3Ϯ4.2 seconds; PϽ0.0001) and IF (Ϫ8.8Ϯ3.4 seconds; PϽ0.0001) interventions but not in those assigned to the LF intervention (ϩ1.1Ϯ13.0seconds; Pϭ0.65; Table 1).”
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    • cites Table 1

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  • Findingown data

    MMSE score did not significantly change with treatment over the study period (P=0.13).

    “Mini Mental State Examination score did not significantly change in relation to the 3 different treatments during the study period (Pϭ0.13;Table 1).”
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  • Findingown data

    Plasma glucose decreased significantly in HF group (-0.6±0.3 mmol/L; P<0.0001).

    “Plasma glucose levels significantly changed during the study period (PϽ0.0001), with significant reductions observed in subjects assigned to HF (Ϫ0.6Ϯ0.3 mmol/L; PϽ0.0001) and IF (Ϫ0.5Ϯ0.1 mmol/L; PϽ0.0001) but not in those assigned to LF (Ϫ0.1Ϯ0.5 mmol/L; Pϭ0.19; Table 2).”
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  • The quote only partly states this claim. 2
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 20

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    Findingown data

    Cocoa flavanol consumption significantly improved insulin resistance.

    “In this regard, we found a significant improvement of insulin resistance after cocoa flavanol consumption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant differences in total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides were found among the three groups at end of follow-up.

    “With regard to total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides concentrations, no significant differences were found among the 3 treatment groups at the end of follow-up (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Findingown data

    Among older adults with mild cognitive impairment, regular intake of cocoa flavanols for eight weeks produced significant gains on a neuropsychological test battery, primarily in executive function, and also in working memory, short-term memory, long-term episodic memory, processing speed, and global cognition.

    “We found significant improvements in performance on a battery of neuropsychological tests mainly exploring executive function but also aspects of working memory, short-term memory, long-term episodic memory, processing speed, and global cognition, after 8 weeks of regular cocoa flavanol consumption.”
    • Also stated in: § Additional information · boosted
      “For the first time, regular cocoa flavanol consumption has been shown to positively affect cognitive function in older adults with early memory decline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The cognitive benefits were especially clear for processing speed, executive function, and working memory, as shown by improvements in TMT A and TMT B scores.

    “In particular, the benefits were remarkably evident for processing speed, executive function, and working memory, as indicated by the improvement in TMT A and TMT B scores.”
    Quote in the paperSubstantial claim

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    Findingnone given

    Subjects enrolled in the study were generally in good health and without known cardiovascular disease.

    “Finally, subjects enrolled in our study were generally in good health and without known cardiovascular disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Regular cocoa flavanol consumption significantly reduced both systolic and diastolic blood pressure.

    “The current demonstration of significant reductions in both systolic and diastolic blood pressure levels after regular cocoa flavanol consumption is consistent with previous findings obtained both in normotensives and in hypertensive subjects, as well as medicated individuals.17,18,29,30”
    Quote in the paperSubstantial claim

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    Study design and conductown data

    Baseline cognitive test performance was similar across the three treatment groups, indicating adequate randomization.

    “Baseline performance on the cognitive function tests was similar for the 3 treatment groups, indicating an adequate randomization procedure (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The CoCoA study was an 8-week double-blind randomized parallel-arm trial in 90 elderly people with mild cognitive impairment.

    “We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing Ϸ990 mg (high flavanols), Ϸ520 mg ( intermediate flavanols), or Ϸ45 mg (low flavanols) of cocoa flavanols per day.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Overall compliance was 99.6% at week 4 and 99.4% at week 8, with no difference among the LF, IF, and HF interventions.

    “The overall compliance was 99.6% at week 4 and 99.4% at week 8, without difference among the LF, IF, and HF interventions.”
    Quote in the paperNot a substantial claim

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    Study design and conductown data

    The planned sample of 90 subjects, 1:1:1 across groups, was calculated to give 90% power to detect a moderate effect size (Cohen d=0.40) on the global cognitive z score between HF and LF at alpha 0.05.

    “Thus, the study was based on an estimated sample size of 90 subjects, with a ratio of 1:1:1 for the 3 treatment groups, which has been calculated to be adequate to achieve 90% power to detect a moderate effect size (Cohen dϭ0.40) with 2 degrees of freedom and an ␣ of 0.05 on the global cognitive z score between HF and LF.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Dietary total flavanol intake was similar across groups at enrollment and decreased similarly during the run-in period.

    “Dietary total flavanol intake was also similar in the 3 study groups at enrollment and slightly decreased during the run-in period to a similar degree in all of the groups, a consequence of the dietary prescriptions (Table S3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Study design and conductown data

    The three cocoa drinks were designed to be indistinguishable in taste and appearance, calorically balanced, and similar in macronutrient, mineral, theobromine, and caffeine content, differing significantly only in cocoa flavanols.

    “The dairy-based cocoa drinks used in this study were specially designed so that they were indistinguishable in taste and appearance, calorically balanced, and contained similar macronutrient, mineral, theobromine, and caffeine content, varying significantly only in the content of cocoa flavanols (Table S1, available in the online-only Data Supplement).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Study design and conductnone given

    The statistical analysis followed the intention-to-treat principle.

    “The statistical analysis was conducted according to the intention-totreat principle.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A composite cognitive z score was predefined and built by converting log-transformed raw test scores to standardized scores based on baseline means and pooled SDs of the whole population.

    “As a predefined procedure, an integrated measure of overall cognitive function, composite cognitive z score, was also constructed for each participant by converting the logtransformed raw scores from the individual tests to standardized scores (z score) that were based on the means and pooled SDs of the whole population at baseline.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    No significant differences in body weight or BMI were observed among the three groups at the end of follow-up.

    “Furthermore, caloric intake was controlled throughout the study, because no significant differences in body weight (HF, 70.67Ϯ8.39kg; IF, 68.59Ϯ8.19kg; LF, 71.17Ϯ8.65 kg; Pϭ0.486) or body mass index (HF, 27.20Ϯ2.7 kg/m 2 ; IF, 26.27Ϯ2.50kg/m 2 ; LF, 26.90Ϯ2.75kg/m 2 ; Pϭ0.427) among the 3 study groups were observed at the end of follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The three groups were comparable in sex, age, anthropometric characteristics, cardiovascular risk factor prevalence, and pharmacological treatments.

    “The 3 study groups were comparable with regard to sex, age, anthropometric characteristics, cardiovascular risk factor prevalence, and pharmacological treatments (Table S2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table S2

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomly assigned to daily dairy-based cocoa drinks containing high, intermediate, or low cocoa flavanols for 8 weeks.

    “After a 1-week run-in period, participants were randomly assigned to consume once daily a dairy-based cocoa drink containing cocoa flavanols either at a high (HF; Ϸ990 mg of flavanols per serving), intermediate (IF; Ϸ520 mg of flavanols per serving), or low level (LF; Ϸ45 mg of flavanols per serving) for 8 weeks.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cognitive function was assessed with four well-validated standardized tests: MMSE, TMT A, TMT B, and verbal fluency.

    “Cognitive testing was performed at baseline and after 8 weeks (Ϯ2 days) using a combination of 4 well-validated standardized tests: the Mini Mental State Examination, Trail Making Test (TMT) A, TMT B, and a verbal fluency test.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary flavanol consumption induces vasodilation of the peripheral and cerebral vascular system and increases brain blood flow and perfusion.

    “In this regard, dietary flavanol consumption has been shown to reduce blood pressure and improve insulin sensitivity, 17,18 as well as to induce vasodilation of the peripheral 17,18 and cerebral vascular system, 19 increasing brain blood flow and perfusion.19,20”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    Cognitive performance improved with regular cocoa flavanol consumption without evidence of relevant adverse effects.

    “We found that cognitive performance was improved with regular cocoa flavanol consumption without evidence of any relevant adverse effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Improvement in cognitive performance was associated with a reduction in insulin resistance, suggesting a possible influential role of glucose metabolism in modulating cognitive function in these subjects.

    “Interestingly, the improvement of cognitive performance was associated with a reduction in insulin resistance, suggesting a possible influential role of glucose metabolism in modulating cognitive function in these subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary flavanol consumption has been shown to reduce blood pressure and improve insulin sensitivity.

    “In this regard, dietary flavanol consumption has been shown to reduce blood pressure and improve insulin sensitivity, 17,18 as well as to induce vasodilation of the peripheral 17,18 and cerebral vascular system, 19 increasing brain blood flow and perfusion.19,20”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    High blood pressure has been linked with the pathophysiology of MCI and with Alzheimer disease and vascular dementia.

    “In particular, high blood pressure has been linked with the pathophysiology of MCI other than with Alzheimer disease and vascular dementia.10,11”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Flavonoids have been reported to provide additional benefits to established hypoglycemic therapy in postmenopausal women with type 2 diabetes.

    “Interestingly, flavonoids have been reported recently to exert additional benefits to established hypoglycemic therapy in postmenopausal type 2 diabetic patients.26”
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    Premisecitation

    Alterations in the insulin signaling pathway have been suggested as potential contributors to cognitive dysfunction.

    “Alterations in the insulin signaling pathway have also been suggested as potential contributors to cognitive dysfunction because of the pivotal role of this hormone in modulating brain structure and function.[12][13][14]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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  • May combine two claims.

    Interpretationown data

    Regular dietary inclusion of cocoa flavanols was associated with significant reductions in blood pressure and improvements in some metabolic markers.

    “In addition to these cognitive improvements, the regular dietary inclusion of cocoa flavanols was associated with significant reductions in blood pressure, as well as in improvements in some metabolic markers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The insulin sensitizer rosiglitazone could protect against cognitive decline in diabetic subjects with MCI.

    “Supportive of this concept, it has been demonstrated recently that the insulin sensitizer rosiglitazone could protect against cognitive decline in diabetic subjects with MCI.27”
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    Premisecitation

    The blood pressure reductions are consistent with previous findings in normotensive, hypertensive, and medicated individuals.

    “The current demonstration of significant reductions in both systolic and diastolic blood pressure levels after regular cocoa flavanol consumption is consistent with previous findings obtained both in normotensives and in hypertensive subjects, as well as medicated individuals.17,18,29,30”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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  • May combine two claims.

    Interpretationown data

    The findings suggest that regular dietary inclusion of flavanols could be one element of a dietary approach to maintaining and improving cardiovascular health and specifically brain health.

    “Although additional confirmatory studies are warranted, the findings reported herein suggest that the regular dietary inclusion of flavanols could be one element of a dietary approach to the maintaining and improving not only cardiovascular health but also specifically brain health.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It is unclear whether the observed neurocognitive benefits are a direct consequence of cocoa flavanols or a secondary effect related to general improvements in cardiovascular function or health.

    “Third, from pathophysiological perspective, it is yet unclear whether the observed benefits in neurocognition are a direct consequence of cocoa flavanol themselves or a secondary effect related to general improvements in cardiovascular function or health.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Cognitive testing used a battery of well-validated, standardized, and widely used neuropsychological tests, but these explored only some aspects of the complex cognitive dysfunction in MCI.

    “First, because standard MCI criteria do not define optimal tests to establish cognitive performance in subjects with MCI, 22 cognitive testing was performed using a battery of well-validated, standardized, and widely used neuropsychological tests exploring only some aspects of the complex cognitive dysfunction in subjects with MCI.1,2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Interpretationreasoning

    General improvements in cardiovascular function and specific metabolic parameters could have, alone or in combination, played a role in improving cognitive performance in this study population.

    “Other than the possible direct effects of flavanols on cognitive function, general improvements in cardiovascular function and specific metabolic parameters could have, alone or in combination, played a role in improving cognitive performance in this study population.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    F2-isoprostanes are generated from arachidonic acid through nonenzymatic free radical-catalyzed lipid peroxidation and are an established marker of oxidative stress.

    “F2-isoprostanes are generated from arachidonic acid through a process of nonenzymatic free radical-catalyzed lipid peroxidation, thus representing an established marker of oxidative stress.33”
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    Premisecitation

    A direct antioxidant effect of polyphenols in vivo has been questioned because blood concentrations are low compared with other antioxidants and extensive metabolism after ingestion lowers their antioxidant activity.

    “Indeed, a direct antioxidant effect of polyphenols in vivo has been questioned recently, because concentrations in blood are low compared with other antioxidants, and extensive metabolism after ingestion lowers their antioxidant activity.34”
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    Interpretationcitation

    It cannot be excluded that blood pressure reductions may contribute to supporting cognitive improvements and preventing blood pressure-related cognitive decline over a longer time course.

    “However, we cannot exclude that these reductions in blood pressure, in addition to improving cardiovascular health, may contribute to supporting improvements in cognitive performance and even help in the prevention of blood pressure-related cognitive declines across a longer time course.31”
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    Premisecitation

    Flavonoids improve nitric oxide bioavailability in the vasculature, which in turn plays a pivotal role in modulating cerebrovascular tone.

    “In this regard, although we did not specifically evaluate the effect of cocoa flavanols on endothelial function, a number of studies, some also from our group, clearly demonstrated the ability of flavonoids to improve NO bioavailability in vasculature, 17,18,25 which, in turn, plays a pivotal role in modulating cerebrovascular tone.28”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    Interpretationcitation

    Exclusion of habitual consumers of dietary supplements with antioxidant properties likely did not affect the representativeness of the study population because consumption of these supplements among the elderly population is quite low, generally less than 10%, similar to other cohorts from the country.

    “On the other hand, the exclusion of habitual consumers of dietary supplements with antioxidant properties likely did not affect the representativeness of our study population, because the consumption of these supplements among our elderly population is quite low, generally Ͻ10%, similar to that observed in other cohorts from our country.35”
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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The extent of the cognitive benefits, their duration, and their impact on the clinical course of MCI remain to be established because the intervention lasted two months.

    “Second, because our study consisted of a 2-month intervention, the extent of the cognitive benefits and their duration, as well as their impact on a clinical course of MCI, remain to be established.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study did not specifically evaluate the effect of cocoa flavanols on endothelial function.

    “In this regard, although we did not specifically evaluate the effect of cocoa flavanols on endothelial function, a number of studies, some also from our group, clearly demonstrated the ability of flavonoids to improve NO bioavailability in vasculature, 17,18,25 which, in turn, plays a pivotal role in modulating cerebrovascular tone.28”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Standard MCI criteria do not define optimal tests to establish cognitive performance in subjects with MCI.

    “First, because standard MCI criteria do not define optimal tests to establish cognitive performance in subjects with MCI, 22 cognitive testing was performed using a battery of well-validated, standardized, and widely used neuropsychological tests exploring only some aspects of the complex cognitive dysfunction in subjects with MCI.1,2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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40 of 40

  • The paper relies on this without support.

    No dietary intervention study had yet specifically investigated neurocognitive performance in response to dietary flavanols in subjects with MCI.

    “To the best of our knowledge, no dietary intervention study has yet specifically investigated the topic of neurocognitive performance in response to dietary flavanols in subjects with MCI.”
1 of 1

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  • Dietary polyphenols from sources including cocoa and dealcoholized red wine are linked to improved vascular function.

    “Dietary interventions have indicated improved vascular function linked to the consumption of polyphenols from different sources, including cocoa and dealcoholized red wine (60, 168, 225, 417, 834).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [225]

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Authors
Desideri, G., Kwik-Uribe, C., Grassi, D., Necozione, S., Ghiadoni, L., Mastroiacovo, D., Raffaele, A., Ferri, L., Bocale, R., Lechiara, M. C., Marini, C., & Ferri, C.
Affiliations
University of Pisa (IT)
ORCID
Venue
Hypertension
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-09
Volume
60
Issue
3
Pages
794-801
ISSN
  • 0194-911X (ISSN-L)
  • 1524-4563
DOI
10.1161/hypertensionaha.112.193060
OpenAlex
W2157857601
Semantic Scholar
b5ec6c4ca070b47009785a99a925182aa2a856b6
Cited by
311
References
41
Citations by year
2026: 17 · 2025: 14 · 2024: 21 · 2023: 25 · 2022: 30 · 2021: 18 · 2020: 23 · 2019: 24 · 2018: 30 · 2017: 21 · 2016: 23 · 2015: 25 · 2014: 14 · 2013: 22 · 2012: 4
FWCI
14.54
Type
journal article
Language
en
Open access
closed
Locations
  • Hypertension (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion)
Topics
  • Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
Keywords
cocoa flavanols, mild cognitive impairment, cognitive function, older adults, insulin resistance, blood pressure, lipid peroxidation, dietary intervention, Trail Making Test, verbal fluency, Mini-Mental State Examination
MeSH terms
Aged, Aged, 80 and over, Aging, Blood Pressure, Cacao, Cognition, Cognition Disorders, Dose-Response Relationship, Drug, Double-Blind Method, Eating, Female, Follow-Up Studies, Humans, Insulin Resistance, Intelligence Tests, Male, Middle Aged, Lipid Peroxidation, Treatment Outcome, Flavanones

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