Journal of the American College of Nutrition, Vol. 17, No. 4, 317-321 (1998)
Published by the American College of Nutrition
Nutritional Factors Adversely Influencing the Glucose/Insulin System
Meira Fields, PhD, FACN
USDA, ARS, Beltsville Human Nutrition Research Center, BARC-East, Beltsville, Maryland
Address reprint requests to: Meira Fields, PhD, FACN, USDA, ARS, BHNRC, NRFL, Building 307, Room 330, BARC-East, Beltsville, Maryland 20705
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ABSTRACT
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For the majority of people, particularly if they do not smoke, the food they eat is the largest controllable factor determining their long-term health. The disproportionate consumption of foods high in fat, especially high in saturated fat, and high in simple sugars at the expense of foods high in complex carbohydrate and unsaturated fat has the potential of inducing abnormal metabolic processes in a normal healthy individual and to promote chronic degenerative diseases. Some of the effects of individual macronutrients such as fat, refined sugars and alcohol in promoting abnormalities in glucose/insulin system are presented. These nutrients were chosen because they also have the ability to alter oxidative state of the individual, which in turn could affect the glucose/insulin system. This review focuses on the role of dietary nutrient interactions in influencing the glucose/insulin system through the generation of reactive oxygen species. The importance of dietary macronutrient interaction with micronutrients such as copper and iron and the potential it has in affecting the glucose/insulin system is addressed.
Key words: refined sugars, fructose, fat, alcohol, copper, iron, insulin, glucose
Key teaching points:
• Diets high in fat, alcohol and refined sugars are associated with numerous adverse effects that promote abnormalities in a glucose/insulin system.
• These effects include insulin resistance, reduced activities of antioxidant enzymes, impaired copper and iron homeostasis, and increased xanthine oxidase activity.
• Low activities of antioxidant enzymes and hepatic iron retention can be responsible for cellular toxicity and peroxidative damage and are thought to be involved in the development of abnormalities of glucose/insulin system.
• Reduction of liver iron decreases reactive oxygen species which in turn ameliorates the glucose/insulin system.
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INTRODUCTION
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Normal healthy people living in industrialized societies such as the United States are likely to develop during the course of their lives some form of a complex chronic and/or degenerative disease such as noninsulin-dependent diabetes mellitus (NIDDM), obesity, hypertension, or cardiovascular disease. These diseases are thought to be influenced by more than a single gene or environmental factor. Genes influencing complex disease traits generally induce some susceptibility to the disorder, and as such may not lead to a disease unless other genes and/or environmental factors are also present. Thus, genes alone may not be sufficient for disease expression.
Environmental factors such as dietary components are known to influence the prevalence of degenerative diseases. Indeed, in order to decrease risk factors associated with degenerative diseases, recommendations have been made regarding modifications of the present US diet. These recommendations include a decrease in the consumption of total fat, saturated fat, cholesterol, salt, simple sugars, and an increase in the consumption of polyunsaturated fat, complex carbohydrate, and fiber [1–5]. If a diet has the potential of inducing abnormal metabolic processes in a normal healthy individual, then it has the potential of preventing and ameliorating chronic diseases.
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DIETARY FAT
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High dietary fat, overweight and obesity are positively associated with diabetes [6–12]. Intakes of total fats and saturated fatty acids remain above the recommended levels for a large proportion of the population. Although total energy from a fat intake declined from 41% in 1977–78 to 34% in 1995, the intake of saturated fat remained the same. About 1/3 of adults and 1/5 of the adolescents in the US are overweight [4,5].
Numerous mechanisms have been shown to be responsible for the effect of dietary fat on glucose/insulin system. In both muscle and adipose tissue, a high-fat diet resulted in decreased insulin receptor number, but no change in receptor affinity. High-fat diet has been shown to be responsible for decreased insulin-stimulated glucose transport and depressed intracellular glucose metabolism. Fat intake affects insulin sensitivity and hepatic glucose output [13,14]. The type of fat and degree of saturation also play an important role. Saturated fat and cholesterol are positively associated with fasting and postprandial glucose levels [6–8]. Fatty acid composition of membranes is dependent on the fatty acid composition of the diet. Diets high in polyunsaturated fatty acids result in increased insulin receptor number but decreased receptor affinity [15]. Saturated fat is responsible for decreased insulin binding [15]. Saturated fat, however, could exert its indirect effects on the glucose/insulin system by mechanisms involving oxidative stress. Increased production and/or ineffective scavenging of reactive oxygen species may play a critical role in tissue injury. It has been suggested that free radical related processes are altered in diabetes [16]. The pancreas is highly vulnerable to oxidative injury, because islet ß-cells are relatively deficient in enzyme activity to scavenge reactive oxygen radicals [17]. Saturated fat has been shown to be responsible for elevation of hepatic iron retention [18–21]. Under certain redox environments iron has the potential of generating reactive oxygen species leading to oxidative stress, cellular toxicity and DNA damage [22,23]. Hepatic iron retention could be responsible for abnormalities of glucose metabolism. Indeed, hemochromatosis which is associated with hepatic iron overload has been implicated in diabetes [24,25].
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ALCOHOL
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When the issue of alcohol consumption is discussed, it is important to consider the acute and chronic effects of alcohol separately [26,27]. In general, numerous adverse effects can arise from alcohol consumption. The primary chronic health-hazard associated with alcohol use is liver disease, cirrhosis, fibrosis and necrosis, which contribute significantly to illness as well as death [27–29]. The definite role that alcohol plays in carbohydrate metabolism is difficult to establish because of confounding factors such as body fat distribution, gender, age, and smoking habits [26,27]. In addition, diets that are high in fat further increase the susceptibility of the liver to alcohol-induced damage [29]. Liver disease is associated with abnormalities of glucose tolerance and insulin resistance similar to those seen in patients suffering from diabetes mellitus [30]. A chronic alcohol intake also promotes generation of superoxide free radicals, hydrogen peroxide and hydroxyl radicals [31]. It has been suggested that ethanol consumption increases hepatic iron stores [31]. Free radicals, however, can be derived directly from ethanol and acetaldehyde, and could play a role in alcohol-induced liver disease [26,32]. Iron, a catalyst in many oxidative reactions, has the potential to induce tissue damage. Regardless of the mechanism responsible for damage caused by alcohol, increased risk of diabetes has been shown in some studies, but not in others [27,33,34]. It is interesting to note that in diabetic patients, alcohol has been shown to result in acute hypoglycemia [34].
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CARBOHYDRATES AND SIMPLE AND REFINED SUGARS
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The intake of different carbohydrates in a diet results in inconsistent results regarding glycemic response [35–41]. It is usually accepted that simple sugars affect glucose metabolism and diabetes detrimentally [36–39]. In contrast, the intake of starches and polysaccharides have a beneficial effect, since these carbohydrates are associated with fiber intake [41].
Many dietary components are involved in diet and health relationships. Chief among them is the high intake of refined sugars. The consumption of nonalcoholic beverages such as soft drinks has increased 68% and fruit juice consumption has increased 24% since 1972 [2–4]. These drinks contain mainly high-fructose corn syrup and refined sugars [42]. In the US, the consumption of cane sugar plus high-fructose corn syrup has increased from 105 pounds per capita in 1985–86 to 127 in 1995–96. The consumption of caloric sweeteners expressed as pounds per capita rose from 128 in 1985–86 to 149 in 1995–96 [42]. In both humans and experimental animals, the high consumption of refined sugars has been shown to have deleterious effects on glucose metabolism [35,36,43–45].
Fructose consumption is responsible for insulin resistance and abnormal glucose tolerance [46–49]. It is also responsible for development of fatty liver [50]. However, abnormalities in glucose metabolism do not occur only at the levels of beta cells of the pancreas, they could occur also in the liver. The liver plays an important role in the maintenance of glucose homeostasis by controlling the balance between hepatic glucose production and glucose utilization by the peripheral tissue. The liver is also the major organ that metabolizes and regulates fructose [50–53]. It is also responsible for controlling the homeostasis of copper and iron.
Although the metabolism of glucose and fructose are similar, fructose metabolism induces numerous abnormalities. Fructose consumption induces fatty liver [50–53] which in turn could eventually lead to necrosis, fibrosis and impaired liver functions. In addition, fructose metabolism has the ability to induce generation of reactive oxygen species due to increased activity of xanthine oxidase [50–53] and generation of glyceraldehyde, an inducer of free radicals. The liver may be exposed to oxidative stress following the consumption of fructose.
In addition to contributing to metabolic abnormalities, the consumption of fructose has been reported to affect homeostasis of numerous trace elements. Fructose has been shown to increase iron absorption in humans and experimental animals [54,55]. Fructose intake decreases the activity of the copper enzyme superoxide dismutase (SOD) and reduces the concentration of serum and hepatic copper [56,57]. In addition, fructose consumption is responsible for inducing the sorbitol pathway [58]. Sorbitol, an endogenous alcohol, has the capability of chelating copper, making copper unavailable for utilization [59]. Experimental animals fed fructose have nondetectable levels of ceruloplasmin, a copper-transporting protein in plasma [56]. The reduction of copper is accompanied by a spontaneous increased hepatic iron concentration, which in turn has the capability of generating reactive oxygen species. Furthermore, fructose consumption is responsible for the reduction of activity of selenoenzyme glutathione peroxidase (GSH-Px), an enzyme responsible for protection against reactive oxygen species [57]. These effects of fructose are further aggravated with copper deficiency [57]. The combination of hepatic iron overload, inadequate copper status, and insufficient protection against free radicals (reduced activities of SOD and GSH-Px), with fructose intake is responsible for generation of reactive oxygen species [60]. It is interesting to note that many metal ions have "insulin-like" activities [61,62]. These include copper, zinc, vanadium, nickel, and chromium. Their presence stimulates insulin binding, glucose oxidation, lipogenesis, and glycogenesis. Their deficiencies could be responsible for impaired insulin functions. Abnormalities in glucose/insulin system when fructose is consumed could result from the coexistence of few conditions: i.e., reduced copper, elevated iron, fatty liver and generation of reactive oxygen species.
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IRON AND GLUCOSE/INSULIN SYSTEM
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Iron overload is associated with abnormalities of glucose homeostasis. Hemochromatosis, thalassemia, high ferritin, and aplastic anemia have been shown to be associated with abnormal glucose tolerance, insulin resistance and diabetes [24,25,63–65]. Treatment of patients suffering from high ferritin diabetes and from hemochromatosis with iron chelators or venesection corrected abnormalities associated with diabetes [24,25]. Copper deficiency is also associated with hepatic iron retention. Iron is a strong oxidant which has the ability to generate reactive oxygen species. The pancreas is highly susceptible to a free radical insult due to limited antioxidant defense system compared with the liver [17]. The ability of the pancreas to secrete insulin in rats fed a diet containing fructose and an inadequate amount of copper was impaired [66]. This diet was also responsible for abnormal glucose tolerance following an oral glucose load [67].
The consumption of a fructose-based diet, low in copper, resulted in generation of free radicals associated with hepatic iron retention [60]. No free radicals were detected in livers of rats fed a copper-deficient, starch-based diet [60]. In order to prevent abnormalities to the pancreas, the concentration of hepatic iron had to be reduced. This was achieved by either chelation [60] or by feeding a diet that was low in iron [68]. The prevention of iron retention restored the ability of the pancreas to secrete insulin and corrected abnormalities associated with glucose tolerance [69,70].
The numerous studies reviewed herein illustrate the potential that dietary nutrient interactions has on the generation of reactive oxygen species in healthy rats with no known predisposition for obesity, diabetes and cardiovascular disease. It should be borne in mind that 30% and 60% of adults use supplements of iron and ascorbic acid, respectively [71]. More than 50% of individuals who use iron supplements consume 5 to 10 times the RDA for iron. Mean intakes of supplemental ascorbic acid approach 10 times the RDA for ascorbic acid. Both iron and ascorbic acid are copper antagonists. The intake of copper by humans is marginal or deficient [72]. The additive effects of iron and ascorbic acid on copper status may be important in view of the marginal copper intake and the widespread use of iron and ascorbic acid supplements.
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CONCLUSIONS
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Normal healthy people living in industrialized societies are likely to develop during the course of their lives some form of a degenerative disease that will affect their glucose/insulin system. Abnormalities of this system have the potential of inducing diabetes, obesity and cardiovascular disease. Prevention or amelioration of abnormalities in glucose/insulin system should be of high priority in order to improve the quality of life and reduce health care cost. Diet has the potential of promoting and preventing chronic diseases. Little is known of the potential that dietary nutrient interaction has in promoting or preventing these abnormalities.
Diets consumed in industrialized societies including the US, are relatively high in simple sugars, total fat and saturated fat. These dietary components have been known to affect the glucose/insulin system. These diets are also low in copper. The use of supplements in the US is extensive. Many contain ascorbic acid and iron. Numerous other supplements are being taken by individuals who are not knowledgeable of their need or understand their role in dietary nutrient interactions. Major considerations should be taken when formulating dietary recommendations and giving advice, since interactions among nutrients determine their bioavailability, which in turn can be responsible for promoting or preventing chronic diseases.
Received March 1, 1997.
Accepted April 1, 1998.
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ABSTRACT
INTRODUCTION
