XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro and in-vivo animal models are viewed, including recent human intervention studies. Finally, possible mechanisms of action involving antioxidant and pro-oxidant activity as well as interference with cellular functions are discussed.

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Plant phenolics: extraction, analysis and their antioxidant and anticancer properties.

There has been increasing interest in the research on flavonoids from plant sources because of their versatile health benefits reported in various epidemiological studies. Since flavonoids are directly associated with human dietary ingredients and health, there is need to evaluate structure and function relationship. The bioavailability, metabolism, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about their nuclear structure. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. Most recent researches have focused on the health aspects of flavonoids for humans. Many flavonoids are shown to have antioxidative activity, free radical scavenging capacity, coronary heart disease prevention, hepatoprotective, anti-inflammatory, and anticancer activities, while some flavonoids exhibit potential antiviral activities. In plant systems, flavonoids help in combating oxidative stress and act as growth regulators. For pharmaceutical purposes cost-effective bulk production of different types of flavonoids has been made possible with the help of microbial biotechnology. This review highlights the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production.

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Chemistry and Biological Activities of Flavonoids: An Overview

The biochemistry and medical significance of the flavonoids.

Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review

Citrus flavonoids encompass a diverse set of structures, including numerous flavanone and flavone O- and C-glycosides and methoxylated flavones. Each of these groups of compounds exhibits a number of in vitro and in vivo anti-inflammatory and anticancer actions. These biological properties are consistent with their effects on the microvascular endothelial tissue. Evidence suggests that the biological actions of the citrus flavonoids are possibly linked to their interactions with key regulatory enzymes involved in cell activation and receptor binding. The citrus flavonoids show little effect on normal, healthy cells, and thus typically exhibit remarkably low toxicity in animals. The citrus flavonoids extend their influence in vivo through their induction of hepatic phase I and II enzymes, and through the biological actions of their metabolites. Evidence clearly indicates to the potential health promoting properties of these dietary compounds.

Biological properties of citrus flavonoids pertaining to cancer and inflammation.

Fourteen tropical fruits from south Florida (red guava, white guava, carambola, red pitaya (red dragon), white pitaya (white dragon), mamey sapote, sapodilla, lychee, longan, green mango, ripe mango, green papaya, and ripe papaya) were evaluated for antioxidant activity, total soluble phenolics (TSP), total ascorbic acid (TAA), total dietary fiber (TDF), and pectin. ORAC (oxygen radical absorbance capacity) and DPPH (1,1-diphenyl-2-picrylhydrazyl, radical scavenging activity) assays were used to determine antioxidant activity. The TSP, ORAC, and DPPH ranged from 205.4 to 2316.7 g gallic acid equiv/g puree, <0.1 to 16.7 Imol Trolox equiv/g puree, and 2.1 to 620.2 Ig gallic acid equiv/g puree, respectively. The TAA, TDF, and pectin ranged from 7.5 to 188.8 mg/100 g, 0.9 to 7.2 g/100 g, and 0.20 to 1.04 g/100 g, respectively. The antioxidant activities, TSP, TAA, TDF, and pectin were influenced by cultivar (papaya, guava, and dragon fruit) and ripening stage (papaya and/or mango). Antioxidant activity showed high correlations with levels of TSP compounds (r ) 0.96) but low correlations with levels of ascorbic acid (r ) 0.35 and 0.23 for ORAC and DPPH data, respectively). The antioxidant activities evaluated by both ORAC and DPPH showed similar trends where red guava and carambola exhibited the highest and sapodilla and green papaya exhibited the lowest levels. Guava and mamey sapote exhibited the highest TDF and pectin levels. Many of the tropical fruits were shown to contain an abundance of hydrolyzable tannins, ellagic acid conjugates, and flavone glycosides. Preliminary descriptions are given of the phenols in red/white pitaya (dragonfruit), lychee, and mamey sapote, these fruit being thus far uncharacterized in the literature.

Total Antioxidant Activity and Fiber Content of Select Florida-Grown Tropical Fruits

Citrus fruits contain high concentrations of several classes of phenols, including numerous hydroxycinnamates, flavonoid glycosides, and polymethoxylated flavones. The latter group of compounds occurs without glycosidic linkages and has been shown to inhibit the proliferation of a number of cancer cell lines. This antiproliferative property was further demonstrated against additional human cancer cell lines, and the antiproliferative actions of a series of synthetic methoxylated flavones were also studied. Similar to the naturally occurring compounds, the synthetic compounds exhibited strong antiproliferative activities. In many cases the IC(50) values occurred below 10 microm. Other hydroxylated flavone and flavanone aglycons also exhibited antiproliferative activities against the cancer cell lines, with the flavones showing greater activities than the flavanones. Glycosylation of these compounds removed their activity. The strong antiproliferative activities of the polymethoxylated flavones suggest that they may have use as anticancer agents in humans.

Antiproliferative activities of citrus flavonoids against six human cancer cell lines.

In addition to the main flavanone glycosides (i.e., hesperidin and naringin) in citrus peel, polymethoxylated flavones and numerous hydroxycinnamates also occur and are major phenolic constituents of the molasses byproduct generated from fruit processing. Although a small number of the hydroxycinnamates in citrus occur as amides, most occur as esters and are susceptible to alkaline hydrolysis. This susceptibility to alkaline hydrolysis was used in measuring the concentrations of hydroxycinnamates in citrus peel molasses. The highest concentrations of hydroxycinnamates occurred in molasses of orange [C. sinensis (L.) Osbeck] and tangerine (C. reticulata Blanco.) compared to grapefruit (C. paradisi Macf.) and lemon [C. limon (L.) Burm.]. Concentrations of two phenolic glucosides, phlorin (phloroglucinol-beta-O-glucoside) and coniferin (coniferyl alcohol-4-beta-O-glucoside), were also measured. Measurements of the polymethoxylated flavones in molasses from several tangerine and orange varieties showed that these compounds occurred in the highest amounts in Dancy tangerine, whereas samples from two other tangerine molasses contained significantly lower levels, similar to those in the molasses samples from late- and early/mid-season oranges.

Phenols in citrus peel byproducts. Concentrations of hydroxycinnamates and polymethoxylated flavones in citrus peel molasses.

Formulations containing citrus polymethoxylated flavones (PMFs), mainly tangeretin, or citrus flavanone glucosides, hesperidin and naringin, were evaluated for cholesterol-lowering potential in hamsters with diet-induced hypercholesterolemia PMF metabolites were also investigated Diets containing 1% PMFs significantly reduced serum total and very low-density lipoprotein (VLDL) + LDL cholesterol (by 19−27 and 32−40%, respectively) and either reduced or tended to reduce serum triacylglycerols Comparable reductions were achieved by feeding a 3% mixture of hesperidin and naringin (1:1, w/w), implying lower hypolipidemic potency of the hesperidin/naringin vs PMFs HPLC-MS analysis identified high serum, liver, and urine concentrations of tangeretin metabolites including dihydroxytrimethoxyflavone and monohydroxytetramethoxyflavone glucuronides and aglycones Total liver concentrations of tangeretin derivatives corresponded to hypolipidemic concentrations of intact tangeretin in earlier experiments in vitro

John A. Manthey

Papers

Biological properties of citrus flavonoids pertaining to cancer and inflammation.

Total Antioxidant Activity and Fiber Content of Select Florida-Grown Tropical Fruits

Antiproliferative activities of citrus flavonoids against six human cancer cell lines.

Phenols in citrus peel byproducts. Concentrations of hydroxycinnamates and polymethoxylated flavones in citrus peel molasses.

Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia.