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dilatation of the brachial artery.9 Relative to placebo, DHA but not EPA significantly reduced

collagen aggregation and thromboxane release, whereas platelet aggregation, fibrinolysis, or vascular function did not change. It appeared that highly purified DHA might be a more effective

antithrombotic agent than EPA. A report from Nomura and colleagues10 indicated that EPA supplementation reduced monocyte activation markers, platelet activation markers, soluble adhesion

molecule E-selectin and the autoantibodies directed against oxidized LDL. These findings suggest

that fish oils reduce CAD risk through multiple mechanisms, above and beyond their beneficial

effects on the plasma lipids. Unfortunately, it is not yet known whether these beneficial outcomes

also occur in diabetic patients.

Another use for fish oils may be in the prevention of diabetes.11 Suresh and Das12 tested the

effects of individual fatty acids on the development of alloxan induced diabetes in rats. Eicosapentanoic acid and DHA, administered either for 5 d prior to alloxan or along with alloxan, protected

against diabetes. In vitro studies in a rat insulinoma cell line suggested that EPA and DHA rendered

this protective effect by preventing alloxan-induced cytotoxicity. In humans, use of cod liver oil,

but not other vitamin D supplements, during the first year of life was associated with a significantly

lower risk of type-1 diabetes, suggesting possible protective effects of fish oils.13

Thus, patients who have diabetes or who are insulin resistant may be asked to supplement their

diet with either fish or fish oils for several reasons. Because earlier studies indicated that fish oils

may have adverse effects on glycemic control,6,14 it is important to review the current information

about the effects of fish oils on various aspects of diabetes.



II. MAINTENANCE OF GLUCOSE HOMEOSTASIS

Normal glucose homeostasis is achieved by a delicate balance among pancreatic insulin secretion,

hepatic glucose production, and peripheral glucose utilization. A change in any one of these can

be compensated for by an alteration in another. For example, impaired insulin action in the peripheral

tissues or increased hepatic glucose output can be compensated for by increased pancreatic insulin

secretion and hyperinsulinemia. In contrast, improvement in peripheral insulin action may result

in decreased pancreatic insulin secretion.

Effects of fish oils on glucose homeostasis have been studied at various levels. Their overall

effect on glycemic control is assessed by measuring blood glucose, glycosylated hemoglobin (Hgb

A1C), and urine glucose excretion. Secretion of insulin from the pancreas is determined by

measuring insulin and C-peptide responses to administration of oral or intravenous glucose, by

mixed meal, and by hyperglycemic insulin clamp technique. Hepatic glucose production and

peripheral insulin action are assessed by the euglycemic clamp technique and by simultaneous use

of radioisotopes. All these assays and techniques have been adapted to animal models. Furthermore,

in vitro studies were carried out to identify the cellular and molecular mechanisms of the effects

of fish oils. In this chapter, the recent research about the effects of fish oils has been reviewed. The

studies included in the earlier publication of this chapter15 have been mentioned briefly.



III. EFFECTS OF N-3 FISH OILS ON GLYCEMIC CONTROL

Earlier clinical studies showed that fish oil supplementation caused either no change16–19 or deterioration of glycemic control.6,14 Two recent meta analyses20,21 concluded that although fish oil

supplementation increased fasting glucose by 5 to 7 mg/dl and HgBA1 by 0.15 to 0.2%, these

changes were not statistically significant. An evidence-based review of the health effects of the fish

oils also found similar elevations in blood glucose and HgBA1 levels, and agreed with the conclusion

of the meta analyses that these changes were not significant (Figure 8.1 and Figure 8.2).22 The

studies included in these analyses showed a wide range of changes in fasting blood glucose levels,

indicating that individual response to fish oil supplementation can be quite variable. All of the

effects of fish oils were reversible after the discontinuation of the therapy.



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–114



157



0 5.87



Favors

treatment



Favors control



61



Mean difference



FIGURE 8.1 An evidence based review of the effects of fish oils on fasting blood glucose. (From Effects of

omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on

inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evid Rep Technol Assess (Summ): 1–4, 2004. With permission.)



–8.5



Favors

treatment



0 .21



Favors control



8.5



Mean difference



FIGURE 8.2 An evidence based review of the effects of fish oils on HgBA1 levels. (From Effects of omega3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory

bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evid Rep

Technol Assess (Summ): 1–4, 2004. With permission.)



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IV. EFFECTS OF N-3 FISH OILS ON PANCREATIC

INSULIN SECRETION

Secretagogues such as glucose and arginine stimulate insulin secretion by acting at the β-cell surface

receptors and modulating the concentrations of several second messengers, such as cyclic AMP,

calcium, and diacylglycerol, which act through protein kinase (PK) A, calcium-calmodulin-dependent

PK and PKC, respectively.23,24 Specific secretagogues may use specific second messengers. Thus,

insulin response to a glucose load may be different from the response to a mixed meal. Metabolic

products of arachidonic acid and various prostaglandins modulate insulin secretion,25–31 and fish oils

may alter insulin secretion from the pancreas by interfering with the metabolism of arachidonic acid.

Consistent with this concept, several recent experimental studies show that fish oils alter insulin

secretion. Studies in rats provided variable results, depending on the strain and gender of the animals

and the duration of the supplementation. Holness and colleagues32 investigated the acute effects of

fish oils in female albino Wistar rats. After receiving a saturated fat enriched diet for four weeks,

a subgroup of animals was fed a fish oil diet for 24 h. As expected, saturated fat diet caused insulin

resistance and hyperinsulinemia. Although this short-term fish oil supplementation reversed the

hyperinsulinemia, it failed to correct insulin resistance. Consequently, plasma glucose levels

increased. Insulin secretion from the pancreatic islet cells mimicked the in vivo findings. When the

fish oils were fed throughout the 4-week study, the long-term fish oil supplementation corrected

the hyperinsulinemia and increased peripheral glucose disposal.33 Fish oil feeding also completely

reversed hyperinsulinemia in a rat model of sucrose-induced metabolic syndrome.34 In other rat

models of type-2 diabetes,35 hypertension,36 and a mouse model of obesity,37 fish oil feeding

improved glucose disposal and decreased plasma glucose but had variable effects on insulin levels.

Several earlier studies described previously in detail15 had reported variable effects of fish oils on

insulin secretion.38–40 In summary, studies in animal models suggest that fish oils acutely decrease

insulin secretion from the pancreas and therefore increase plasma glucose. However, long-term

administration of fish oils increases peripheral utilization of glucose and reverses the hyperglycemia.

In humans, earlier studies had reported that fish oil either decreased insulin secretion in response

to a mixed meal or glucagon41 oral glucose42,43 and fructose,44 or did not affect the insulin secretion.19,45,46 Recent studies did not investigate the changes in insulin secretion specifically. To my

knowledge, there is no evidence in humans to demonstrate that fish oils increase insulin secretion.



V. EFFECTS OF N-3 FISH OILS ON HEPATIC

GLUCOSE PRODUCTION

In experimental animals, fish oils interfered with the suppression of hepatic glucose output by

insulin.33 In humans, earlier studies in patients with impaired glucose tolerance and type-2 diabetes

reported that fish oil treatment either increased41,47 or did not change46,48 hepatic glucose output. A

recent study investigating the effects of fish oil, both at rest and during exercise,49 reported that at

rest, fish oils did not affect hepatic glucose production; during exercise, fish oils blunted the increase

in hepatic glucose production.



VI. EFFECTS OF N-3 FISH OILS ON PERIPHERAL INSULIN ACTION

As reviewed by Saltiel and Pesin,50 glucose transport to the cell is accomplished through a series

of events that are set into motion by binding of insulin to its receptor. The insulin receptor is a

tyrosine kinase that undergoes autophosphorylation upon binding insulin. This increases kinase

activity of the receptor for the intracellular insulin receptor substrate proteins (IRS). Once phosphorylated, the IRS proteins interact with phosphatidylinositol 3-kinase (PI3-K) and lead to the

production of polyphosphoinositide phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which in turn

interacts with and localizes protein kinases such as phosphoinositide-dependent kinase 1 (PDK1).



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These kinases then initiate a cascade of phosphorylation events, resulting in the activation of Akt

and atypical protein kinase C (PKC), and stimulate the trafficking of Glut 4 vesicles to the plasma

membrane, and consequently, transportation of glucose. In the sucrose-fed rat model of insulin

resistance, fish oils restore Glut-4 protein quantity in adipocytes but not in muscle.51 To my

knowledge, there is no information about the effects of fish oils on the other steps of this cascade.

In humans, earlier studies showed that fish oils either did not affect41,45,48 or increased peripheral

glucose uptake.46 A recent study demonstrated that fish oils failed to improve the insulin resistance

caused by fructose-feeding in humans.52 It was previously reported that diabetes decreases the

polyunsaturated fatty acid content of adipocyte plasma membrane phospholipids, particularly

arachidonic acid.53 The decrease in the polyunsaturated and saturated fatty acid ratio results in

decreased fluidity of the cell membrane and interferes with insulin-binding to the receptor. This

can be reversed by increasing the polyunsaturated fat content of the membrane, which is accomplished by using either n-3 or n-6 polyunsaturated fatty acids, and the effect is not limited to n-3

fish oils.54

Recent research has demonstrated that in rats, fish oil treatment increased whole body glucose

utilization and insulin-stimulated glucose disposal by increasing glucose storage in the skeletal

muscle but not the oxidative pathway.55 In the sucrose-fed insulin resistance model, fish oil reversed

the decrease in whole body glucose utilization,56,57 restored insulin induced glycogen and lipid

accumulation in the muscle, and increased the active form of pyruvate dehydrogenase complex and

the PDH kinase activities.56 Similarly, in the high-fat fed rat model, fish oil treatment reversed the

insulin resistance.58 These results are in agreement with the findings of several earlier

reports59–61described in detail in the previous version of this chapter.15

Interestingly, a synthetic metabolite of DHA has been found to have potent insulin sensitizer

activity — similar to the thiazolidinedione drugs used for the treatment of diabetes.62 However, so

far, there is no evidence to suggest that fish oil supplementation can lead to the synthesis of such

metabolites in vivo.



VII. EFFECTS OF N-3 FISH OILS ON ADIPOKINES

It was previously proposed that the effects of fish oils on glucose homeostasis may be related to

their effects on the adipose tissue because fish oils caused less weight gain.63 In recent years, it

became clear that the adipose tissue produces and secretes several cytokines (adipokines) that have

profound effects on glucose homeostasis. These are adiponectin, TNFα, leptin, and resistin.64,65

Experimental data suggest that TNFα and resistin promote insulin resistance whereas adiponectin

increases insulin sensitivity. There are conflicting data about the effects of leptin.66 These adipokines

may provide a link between obesity and insulin resistance. Obesity is associated with increased

serum levels of leptin and TNFα, and reduced levels of adiponectin.67 As fish oils have antiinflammatory actions, it is conceivable they also affect the adipokines and therefore alter insulin

action. Although there is a large body of literature related to fish oils and cytokines in the fields of

infection and inflammation, there is not much information relating these changes to insulin action.

In the sucrose-fed rat model of obesity and insulin resistance, both leptin and adiponectin levels

are decreased. Here, fish oils decreased insulin resistance and increased plasma levels of adiponectin

and leptin.66,68 In a similar model, fish oils did not affect TNFα levels.34 On the other hand, in a

mouse model of insulin resistance, fish oils reduced TNFα levels but did not correct insulin

resistance.69 To my knowledge, there is no information about the effects of fish oils on resistin.



VIII. CONCLUSION

The primary use of fish oils in diabetic patients is aimed to reduce CAD risk, especially in women.

The available evidence does not support a beneficial effect of fish oils on the glycemic control in

diabetic patients. Although fish oils decrease insulin resistance and therefore may prevent progres-



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sion of metabolic syndrome to type-2 diabetes, there is no evidence-based support for this hypothesis. The cytokines secreted by the adipose tissue have profound effects on the peripheral insulin

resistance. Effects of fish oils and their metabolites on the adipokines are being studied.



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stimulating protein, and adiponectin. Curr Opin Lipidol 13: 51–59, 2002.

66. Rossi, A.S., Lombardo, Y.B., Lacorte, J.M., Chicco, A.G., Rouault, C., Slama, G., and Rizkalla, S.W.

Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulinresistant rats. Am J Physiol Regul Integr Comp Physiol 289: R486–R494, 2005.

67. Aldhahi, W. and Hamdy, O. Adipokines, inflammation, and the endothelium in diabetes. Curr Diabetes

Rep 3: 293–298, 2003.

68. Peyron-Caso, E., Taverna, M., Guerre-Millo, M., Veronese, A., Pacher, N., Slama, G., and Rizkalla,

S.W. Dietary (n-3) polyunsaturated fatty acids up-regulate plasma leptin in insulin-resistant rats. J

Nutr 132: 2235–2240, 2002.

69. Muurling, M., Mensink, R.P., Pijl, H., Romijn, J.A., Havekes, L.M., and Voshol, P.J. A fish oil diet

does not reverse insulin resistance despite decreased adipose tissue TNF-alpha protein concentration

in ApoE-3*Leiden mice. J Nutr 133: 3350–3355, 2003.



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Vitamin and

9 Antioxidant

Phytochemical Content of

Fresh and Processed Pepper

Fruit (Capsicum annuum)

Luke R. Howard and Robert E.C. Wildman

CONTENTS

I. Introduction ........................................................................................................................165

II. Fruits and Vegetables for Disease Prevention ...................................................................166

III. Ascorbic Acid.....................................................................................................................166

A. Effects of Postharvest Handling and Processing on Ascorbic Acid Content ...........170

IV. Flavonoids ..........................................................................................................................171

A. Postharvest Handling and Effect of Processing on Flavonoid Content ...................173

V. Tocopherols ........................................................................................................................174

A. Effect of Processing on Tocopherol Content of Peppers..........................................174

VI. Carotenoids.........................................................................................................................176

A. Effects of Postharvest Handling and Processing on Carotenoid Content ................180

VII. Capsaicinoids .....................................................................................................................182

A. Effects of Postharvest Handling and Processing ......................................................185

References ......................................................................................................................................185



I. INTRODUCTION

Capsicum species are a New World crop belonging to the Solanacae family. Chiles have been

cultivated for thousands of years, and they are one of the oldest domesticated crops. Most cultivars

grown in the U.S. belong to the species C. annuum and are typically classified according to fruit

shape, flavor, and culinary uses. In addition to C. annuum species, C. frutescens (tabasco) and C.

chinense (habanero) are commonly cultivated and used for culinary and medicinal purposes. The

classification and varieties of peppers grown in the U.S.,1,2 and the production, technology, chemistry, and quality of Capsicum spp., have been reviewed extensively.3–7

Capsicum spp. exhibit great genetic diversity in terms of color, size, shape, and chemical

composition. Researchers have recently recognized that Capsicum fruit also vary greatly in their

content of antioxidant vitamins and phytochemicals. This information may be important for human

health and nutrition as consumers incorporate more peppers into their diets. The goal of this chapter

is to survey the antioxidant vitamin and phytochemical content of different Capsicum species, types,

and cultivars, and to determine the effects of postharvest handling and processing on the levels of

these important phytonutrients.



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II. FRUITS AND VEGETABLES FOR DISEASE PREVENTION

Epidemiological studies indicate that antioxidants present in fruits and vegetables, including βcarotene and vitamins C and E, may be important in prevention of numerous degenerative conditions, including various types of cancer, cardiovascular disease, stroke, atherosclerosis, and cataracts.8–10 Oxidative damage catalyzed by reactive oxygen species (ROS) has been implicated in

over 100 degenerative conditions.11 ROS cause damage to cellular membranes, proteins, and DNA,

which increases the susceptibility of cells to chronic diseases. Oxidative damage in the body is

exacerbated when the balance of ROS exceeds the amount of endogenous antioxidants. The human

body has several enzymatic and nonenzymatic defense systems to regulate ROS in vivo, but these

defense mechanisms are thought to deteriorate with aging. Consumption of fruits and vegetables

that are rich in antioxidant nutrients may afford additional protection against ROS-mediated disorders. Scientists have recently recognized that fruits and vegetables are not only a good source of

antioxidant vitamins but also an excellent source of other essential dietary phytochemicals that can

retard the risk of degenerative diseases.12 The potential health effects of phytochemicals are associated with numerous mechanisms, including prevention of oxidant formation, scavenging of

activated oxidants, reduction of reactive intermediates, induction of repair systems, and promotion

of apoptosis.13

Of interest is how and why fruits and vegetables generate nutraceutical compounds and for

what purpose. With regard to peppers, the presence of different antioxidative enzymes and their

corresponding metabolites in pepper peroxisomes implies that these organelles might be an important pool of antioxidants in fruit cells, where these enzymes could also act as modulators of signal

molecules (O2–, H2O2) during fruit maturation.14 In one study of the peroxisomal fractions of green

and red pepper fruits (Capsicum annuum L., type Lamuyo), the quantity and activity of antioxidant

enzyme systems was generally higher in green than in red fruits.14

In this work, the purification and characterisation of peroxisomes from fruits of a higher plant

was carried out, and their antioxidative enzymatic and nonenzymatic content was investigated.

Green and red pepper fruits (Capsicum annuum L., type Lamuyo) were used in this study. The

analysis by electron microscopy showed that peroxisomes from both types of fruits contained

crystalline cores that varied in shape and size, and the presence of chloroplasts and chromoplasts

in green and red pepper fruits, respectively, was confirmed.



III. ASCORBIC ACID

Capsicum fruit have long been recognized as an excellent source of ascorbic acid, which is a

required nutrient for humans. Svent-Gyorgyi isolated ascorbic acid from paprika fruit in the early

1930s, and subsequently identified the compound in 1933.15 Ascorbic acid has strong reducing

properties due to its enediol structure, which is conjugated with the carbonyl group in a lactone

ring16 (Figure 9.1). In the presence of oxygen, ascorbic acid is degraded to dehydroascorbic acid

(DHA), which still retains vitamin C activity. However, upon further oxidation, the lactone ring of

DHA is destroyed, resulting in formation of 2,3-diketogulonic acid and loss of vitamin activity.

Ascorbic acid is required for collagen formation and prevention of scurvy. Researchers have

postulated a role of ascorbic acid in the prevention of degenerative conditions, including cancer,

heart disease, cataracts, and stimulation of the immune system.17 Prevention of chronic diseases

may be attributed to the ascorbate function as an aqueous reducing agent. Ascorbate can reduce

superoxide, hydroxyl, and other ROS, which may be present in both intracellular and extracellular

matrices. Ascorbate within cells participates as an electron donor, as part of the interaction between

iron and ferritin. Extracellularly, ascorbate may act in concert with tocopherols in lipid membranes,

to quench ROS and prevent lipid peroxidation. Thus, ascorbate may help prevent the oxidation of

low-density lipoprotein (LDL), which is thought to be a major initiating step in the process of

atherosclerosis. The role of ascorbate in cancer prevention may be attributed to its ability to block