Am J Physiol Endocrinol Metab. 2013 Sep 15;305(6):E679-86

Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications.

Munir KM, Chandrasekaran S, Gao F, Quon MJ.

Division of Endocrinology, Diabetes, and Nutrition, University of MarylandSchool of Medicine, Baltimore, MD21201USA.



The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives.  This is fueled by overwhelming increases in the incidence and prevalence of obesity.  Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality.  Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications.  Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes.  Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits.  Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand.  Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols.  However, precise molecular mechanisms of action for food polyphenols are largely unknown.  Moreover, translation of these insights into effective clinical therapies has not been fully realized.  Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications.  In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperidin) that are related to improving metabolic and cardiovascular pathophysiology.  We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe medications derived from functional foods that will complement existing conventional drugs.



Diabetes, one of the most important human metabolic diseases, has reached pandemic proportions worldwide. Public sentiment has recently been supporting the use ‘natural’ remedies to treat chronic health-related conditions, including diabetes that conventional treatments do not fully address. Many epidemiologic studies have shown benefits of various foods and food-derived compounds on health promotion and disease treatment and prevention. Functional foods, or foods with health benefits beyond their nutritive value alone, have long been considered as alternatives to conventional therapies. Unfortunately, the efficacy of many, if not most food-based remedies are supported mainly by anecdotal evidence, folklore, or small, poorly designed clinical studies. Most functional foods have never undergone rigorous scientific evaluation to determine putative mechanisms of action and to establish reasonable safety standards. Ethical drugs require extensive evaluation on molecular, cellular, animal, and human levels to establish dose ranges, safety profiles and measures of efficacy. Human clinical trials of conventional drugs are undertaken in multiple phases to determine overall safety, efficacy, and effectiveness of drugs. Initially small studies are done to evaluate safety and further investigation with studies including larger numbers of patients validate safety and provide more robust data on efficacy. These trial programs often run for years and cost hundreds of millions of dollars to complete. Even after approval of conventional therapeutics, post-marketing programs are put in place to continuously monitor for safety signals which may not be detected until tens or hundreds of thousands of patients are exposed to a specific drug.

Polyphenols, a class of functional foods found in foods including citrus, chocolate, and green tea represent an intriguing class with putative benefits in treating metabolic diseases including obesity, metabolic syndrome, diabetes and their associated cardiovascular complications (Fig. 1). In our manuscript, we outline a robust, systematic paradigm for studying food polyphenols (Fig. 2). After identifying promising foods from large epidemiologic studies, a single putative bioactive ingredient is chosen for rigorous evaluation. Cellular and molecular mechanisms of action need are elucidated prior to initiation of animal studies of safety and efficacy. Dose-ranging studies performed in cell-based assays are useful for designing appropriate dosages to evaluate for in vivo studies in animals and humans.  Doses required in cell-based studies tend to overestimate requirements in vivo due to differences in sensitivity of physiological systems in whole organisms. Therefore, it is important to evaluate bioavailability, tissue distribution, pharmacokinetics, and pharmacodynamics to further inform dosing schemes. These characterizations are often neglected in evaluation and development of complementary and alternative therapies.

Kashif M. Munir fig1

Human trials should include multistep studies to establish safety and efficacy of the food compound. Smaller studies should be followed by subsequent larger trials to assure favorable benefit to risk ratios. These series of trials should culminate in placebo-controlled randomized, double-blind clinical studies with a single quantifiable prospectively identified primary outcome that has the potential for clinical relevance and significance in terms of progression of the natural history of the disease.  Again, as with animal studies, it is essential to establish pharmacokinetic and pharmacodynamics parameters.  Relevant biomarkers determined from animal studies are useful when assessing efficacy in humans and to confirm mechanistic insights.

Kashif M. Munir fig2Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction and are associated with higher rates of cardiovascular morbidity and mortality.  Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Our research describes a comprehensive, robust, and paradigmatic approach to studying food polyphenols found in green tea (EGCG),  citrus fruits (hesperidin), and cocoa (ECG), to treat insulin resistance, endothelial dysfunction and their related cardiovascular complications. Recent progress in elucidation of the molecular, cellular, and physiological actions of polyphenols makes their use in cardiovascular and metabolic disease treatment and prevention an attractive possibility in the near future. These food polyphenols mimic or augment insulin signaling through the PI 3-kinase (PI3K) pathway which predominates in normal physiology.  This leads to increased insulin-dependent glucose uptake in muscle and fat with simultaneous improvements in vascular endothelial function. Signaling through PI3K-dependent insulin signaling pathways are in balance with and oppose MAPK-dependent insulin signaling pathways that mediate pathophysiological conditions of insulin resistance leading to enhanced mitogenic activity and diminished NO-mediated vasodilation that contribute to endothelial dysfunction and metabolic insulin resistance.  The food polyphenols discussed above are often touted for their potent antioxidant activity.  However, mechanisms of action for food polyphenols to promote metabolic and cardiovascular health are unrelated to oxidant scavenging and are most likely mediated by low-level pro-oxidant-induced signal transduction pathways that are beneficial for maintaining metabolic and cardiovascular homeostasis by favoring PI3K-dependent insulin signaling pathways and opposing MAPK-dependent insulin signaling.

Rigorous scientific investigation of functional foods and nutritional supplements for potential therapeutic health benefits represents an exciting new approach for discovering and developing effective safe treatments for diabetes and its cardiovascular complications that complement existing conventional therapies.  Since the use of dietary supplements is a popular practice many people use to improve their health, it is essential use rigorous scientific methods such as the research paradigm outlined above to understand and validate the benefits of functional foods and their derivatives.  Without such research, there will be no solid foundation for recommending functional foods to promote health or prevent and treat disease.  Polyphenols derived from functional foods offer a novel and important approach for adjunctive treatment of the pathophysiology of metabolic disorders associated with insulin resistance and their cardiovascular complications.



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