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November 2002, Volume 56, Number 11, Pages 1049-1071
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Glycemic index in chronic disease: a review
L S Augustin1,2,a,b, S Franceschi1,4,b, D J A Jenkins2,3,b, C W C Kendall2,3,b and C La Vecchia5,6,b

1Servizio di Epidemiologia, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, Italy

2Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Canada

3Clinical Nutrition and Risk Factor Modification Center, St Michael's Hospital, Toronto, Canada

4Field and Intervention Studies Unit, International Agency for Research on Cancer, Lyon, France

5Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy

6Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milano, Italy

Correspondence to: L S Augustin, 150 College St no. 340, Toronto, Ontario, M5S 3E2 Canada. E-mail:

aGuarantor: L Augustin.

bContributors: SF and LA were responsible for the concept of writing a comprehensive review on the topic of the glycemic index in chronic disease. LA was responsible for writing the review. DJ and CK contributed with their expertise on glycemic index, coronary heart disease and diabetes. CLV and SF contributed with their expertise on cancer and epidemiology. All authors read the report and made suggestions.


Aim: The intent of this review is to critically analyze the scientific evidence on the role of the glycemic index in chronic Western disease and to discuss the utility of the glycemic index in the prevention and management of these disease states.

Background: The glycemic index ranks foods based on their postprandial blood glucose response. Hyperinsulinemia and insulin resistance, as well as their determinants (eg high energy intake, obesity, lack of physical activity) have been implicated in the etiology of diabetes, coronary heart disease and cancer. Recently, among dietary factors, carbohydrates have attracted much attention as a significant culprit, however, different types of carbohydrate produce varying glycemic and insulinemic responses. Low glycemic index foods, characterized by slowly absorbed carbohydrates, have been shown in some studies to produce beneficial effects on glucose control, hyperinsulinemia, insulin resistance, blood lipids and satiety.

Method: Studies on the short and long-term metabolic effects of diets with different glycemic indices will be presented and discussed. The review will focus primarily on clinical and epidemiological data, and will briefly discuss in vitro and animal studies related to possible mechanisms by which the glycemic index may influence chronic disease.

European Journal of Clinical Nutrition (2002) 56, 1049-1071. doi:10.1038/sj.ejcn.1601454


glycemic index; glycemic load; diabetes; coronary heart disease; obesity; cancer


Until recently carbohydrates have been classified as 'simple' and 'complex' based on their degree of polymerization; however, their effects on health may be better described on the basis of their physiological effects (ie ability to raise blood glucose), which depend both on the type of constituent sugars (eg glucose, fructose, galactose) and the physical form of the carbohydrate (eg particle size, degree of hydration). This classification is referred to as the glycemic index (GI). The GI is a quantitative assessment of foods based on postprandial blood glucose response (Jenkins et al, 1981, 1984), expressed as a percentage of the response to an equivalent carbohydrate portion of a reference food (white bread or glucose; Wolever et al, 1991). Carbohydrate foods consumed in isoglucidic amounts produce different glycemic responses (Jenkins et al, 1981) depending on the nature of the food and type and extent of food processing. The principle is that the slower the rate of carbohydrate absorption the lower the rise of blood glucose and the lower the GI value. Several health benefits exist for reducing the rate of carbohydrate absorption by means of a low GI diet. These include: reduced insulin demand, improved blood glucose control, and reduced blood lipid levels, all factors that may play important roles in the prevention or management of several chronic Western diseases including diabetes, coronary heart disease (CHD) and possibly certain cancers.

High GI foods are characterized by fast-release carbohydrate and higher blood glucose levels, resulting in greater insulin demand. Hyperinsulinemia is a characteristic condition of insulin resistance and could be seen as a way of coping with reduced insulin sensitivity which has per se the purpose of maintining circulating glucose levels. For the purpose of this review the two terms 'insulin resistance' and 'hyperinsulinemia' will be combined since they are often observed concomitantly.

A similarity has been noted between the lifestyle risk factors for insulin resistance (eg obesity, lack of physical activity, high intakes of refined carbohydrates) and the major chronic Western diseases, suggesting the hypothesis that hyperinsulinemia may be one of the promoting factors for these conditions (McKeown-Eyssen, 1994; Giovannucci, 1995). Epidemiological evidence suggests direct associations between GI (expressed as glycemic load, a measure of quality as well as quantity of total carbohydrate intake and thus an indirect measure of dietary insulin demand) and risk of diabetes (Salmeron et al, 1997a,b) as well as CHD (Liu et al, 2000) and obesity (Ludwig et al, 1999; Table 1). Evidence is also emerging of a possible link with cancers of the colon (Franceschi et al, 2001) and breast (Augustin et al, 2001; Table 1).

This review will focus on the GI and its relation to the etiology and clinical management of diabetes, CHD, obesity and the prevention of cancer.

Glycemic index and the slow-release carbohydrate

The rate of hydrolysis of food in the gastrointestinal tract and the rate of gastric emptying determine the absorption rate which, in turn, determines the extent and duration of the glucose rise after a meal. Circulating insulin levels are determined directly by beta-cell stimulation by absorbed products of digestion (ie glucose and amino acids) and indirectly by their action on incretins (eg gut inhibitory peptide) released from gut cells. Neural and endocrine stimuli also play a role. The system is therefore responsive to the amount of carbohydrate and its rate of absorption.

The dietary GI provides an indication of the rate at which carbohydrate foods are digested (Jenkins et al, 1981; Englyst et al, 1999). It allows ranking of foods from those which give rise to the highest blood glucose and insulin responses (high glycemic food) to those associated with the lowest blood glucose and insulin responses (low GI foods). The reference food is white bread with a GI set at 100 (Table 2). Low-GI foods can therefore be viewed as a dietary tool to reduce glucose absorption rate and insulin output (Table 3). The implications of prolonging absorption time (Table 4) may be important in the etiology of chronic disease and will be discussed in relation to the major chronic conditions.

Factors affecting the rate of glucose absorption from starchy food and therefore the GI value include (1) the nature of the food and (2) the type and extent of food processing (Table 5). The former includes the ratio of amylose to amylopectin present in the raw food (Behall et al, 1988) and the type of monosaccharide components, the amount and type of dietary fiber (Jenkins et al, 1978), the presence of large amounts of fat or protein (Nuttall et al, 1984; Wolever et al, 1985; Collier et al, 1986; Bornet et al, 1987), antinutrients such as phytic acid, lectins and tannins (Yoon et al, 1983; Thompson et al, 1984; Rea et al, 1985) and nutrient-starch interactions in carbohydrate-containing foods, such as in wheat products (Jenkins et al, 1987a). Extrusion, flaking, grinding, canning, storing and cooking of the carbohydrate-containing foods can affect the particle size and the integrity of the starch granules (Jenkins et al, 1988a) and plant cell walls (Ellis et al, 1991), making the carbohydrate portion more accessible to digestive enzymes (Wolever, 1990; Collins et al, 1981).

Fat and protein may modify the glycemic response to a carbohydrate food by slowing gastric emptying (Welch et al, 1987) and increasing insulin secretion, respectively (Nuttall et al, 1984; Gannon et al, 1988). However, it has been shown that neither fat nor protein in the amounts found in most foods (with the exception of peanuts and most nuts) significantly alters the glycemic response (Wolever et al, 1994). Protein levels of 30 g and fat levels of 50 g per 50 g of available carbohydrate may decrease the GI (Wolever et al, 1994).

Thus far more than 500 foods have been tested for assessment of their GI, and values are summarized in GI tables (Foster-Powell & Brand Miller, 1995). Low GI foods include vegetables, fruit, legumes and wholegrain breads such as pumpernickel, while high-GI foods include most refined grain products such as white bread, potatoes and rice (Table 2). The GI tables may have various applications, for instance in designing diets aimed at long-term blood glucose control, as some researchers have found that the GI may be applied not only to single foods but also to mixed meals (Wolever et al, 1985; Chew et al, 1985; Collier et al, 1986; Bornet et al, 1987; Le Floch et al, 1991). The GI of mixed meals has also been shown to correlate positively with the insulinemic index (a measure of postprandial insulin rise; Bornet et al, 1987). However, the debate on the clinical utility of the GI concept has not been resolved. Some investigators have criticized the usefulness of the GI in mixed meals, suggesting the GI of each component of a meal cannot predict the glycemic response to that meal (Coulston et al, 1987). Despite the authors' conclusions, their study indeed showed that mixed meals based on high- and low-GI foods produce completely different glycemic effects (Figure 1 in Coulston et al, 1987). The discrepancies between studies may be explained partly by methodological differences, principally the method of calculation of the glycemic response area (eg total area above and below baseline vs area above baseline), the method of blood sampling (arterial vs venous blood) and the length of the study (ie the time between the meal and the last glycemic measurement; Wolever et al, 1991). When using the same methodology the GI of mixed meals can be predicted consistently by calculating the mean GI value of their components weighted by the carbohydrate content of each component and by the fact that the correlation between the GI of mixed meals and the mean GI value for their components ranges from 0.84 to 0.99 (Wolever & Jenkins 1986, Wolever et al, 1991; Truswell, 1992).

The glycemic index in diabetes

Relatively few prospective studies assessed the association of GI and type 2 diabetes risk (Salmeron et al, 1997a,b). Salmeron and collegues have looked at this and found that diets with a high GI increased the risk of type 2 diabetes by 37% (highest vs lowest quintiles) after correcting for known risk factors, in a cohort of over 42 000 men during a 6 y follow-up (Salmeron et al, 1997a). Similar results were observed in the Nurses cohort (n=65 173), where a positive association betweeen type 2 diabetes and glycemic load (GL) was also shown (the product of the average dietary GI and total carbohydrate intake and therefore a measure of total insulin demand; Salmeron et al, 1997b). The GI and GL were not associated with type 2 diabetes in the Iowa Women's Health Study (Meyer et al, 2000). This study, however, included an elderly cohort which could introduce a selection bias.

The link between high GI and high GL diets and diabetes may relate to glucose peaks and increased insulin demand. High GI foods lead to rapid rises in blood glucose and insulin levels. Hyperinsulinemia, in turn, may downregulate insulin receptors and therefore reduce insulin efficiency, resulting in insulin resistance (Virkamaki et al, 1999). This condition may act in a vicious circle by increasing blood glucose concentrations and insulin secretion as shown in Figure 1. Insulin resistance is a risk factor for type 2 diabetes (Reaven, 1993; Nijpels, 1998). Also, poor glucose control has been shown to result in a greater incidence of long term macrovascular and microvascular complications in both type 1 and 2 diabetic patients (The Diabetes Control and Complications Trial Research Group, 1993; UK Prospective Diabetes Study Group, 1998; Stratton et al, 2000). Each 1% reduction in mean hemoglobin-A1c (HbA1c) was associated with a 21% reduction in risk for severe end points related to diabetes (eg mortality, myocardial infarction, heart failure, stroke, amputation, retinopathy, cataract extraction; Stratton et al, 2000).

Low-GI foods tend to delay glucose absorption thereby resulting in reduced peak insulin concentrations and overall insulin demand. Several studies have found improvements in glycemic control with low-GI diets. In a group of 32 patients with CHD fed a low-GI diet for 4 weeks, significant improvements in insulin sensitivity were reported as suggested by lower insulin requirements necessary to handle a standard glucose load and by the enhanced insulin-induced glucose uptake in adipocytes (Frost et al, 1996). Low-GI diets have been shown in other studies to reduce blood glucose levels and urinary C-peptide output, as a measure of insulin secretion, also in healthy subjects (Burke et al, 1982; Jenkins et al, 1987b). Low-GI diets also improved glycemic control in diabetic patients, as indicated by reductions in glycosylated proteins (serum fructosamine or HbA1c) in 10 of the 14 studies that measured these variables (Table 6). It should be noted that changes in HbA1c levels tend to be seen after 3 months of dietary intervention. In most of these studies diets were balanced for macronutrient intake and on average they resulted in a 20% difference of dietary GI. One study achieved a 31% GI difference between the test and control group by altering the structure of the starchy food by using the same foods processed differently (eg whole vs milled grain or seeds, whole vs ground beans, parboiled rice vs sticky rice), thereby avoiding alterations in the proportions of macronutrients, micronutrients and phytochemicals. In this trial a decrease in both fasting glucose and insulin levels was achieved in the low GI group (between- and within-group differences), as well as significant reductions in fructosamine levels (within-group difference; Jarvi et al, 1999). Generally, cross-sectional data appear to support the results of clinical trials (Wolever et al, 1999, Buyken et al, 2001).

A cross-sectional study on 272 type 1 diabetic patients found a significant positive correlation between HbA1c and dietary GI, as assessed by a 3-day food record (Wolever et al, 1999).

The health benefits of a low-GI diet is also supported by a number of investigations on meal frequency which was used as a model for a reduced rate of carbohydrate absorption. Increasing meal frequency in isocaloric diets in diabetic and non-diabetic subjects has been shown to reduce postprandial glucose rise (Jenkins et al, 1992, Bertelsen et al, 1993; Jones et al, 1993), daily insulin levels (Jenkins et al, 1992; Bertelsen et al, 1993; Jones et al, 1993) and 24 h urinary C-peptide output (Jenkins et al, 1989,1992). Increasing meal frequency is now included in the recommendations given for the management of diabetes by the American Diabetes Association (1994). While the use of the GI is not universally accepted, several health organizations throughout the world now recommend consuming low-GI foods in the management of type 2 diabetes (European Association for the Study of Diabetes, 1995; Buchhorn, 1997) and as part of the healthy diet recommended to the general population (FAO/WHO report, 1998).

Two main mechanisms of action could be involved in the regulation of insulin sensitivity and glucose levels by low-GI diets: (1) free fatty acid levels; and (2) oxidative stress. In general, rapidly absorbed carbohydrates stimulate a large insulin rise, followed by a rapid blood glucose fall, often below baseline values. This could result in a counter-regulatory response with the release of free fatty acids, creating an insulin-resistant environment (Piatti et al, 1991; Boden et al, 1991) and reduced glucose tolerance. Ingestion of a slow release carbohydrate food (eg uncooked cornstarch) at bedtime was shown to produce a substantial suppression of nocturnal free fatty acid levels and postprandial improvements in breakfast glucose levels possibly due to reduced nocturnal lipolysis (Axelsen et al, 1997,1999a). A slow-release carbohydrate food taken in the evening can also prevent nocturnal hypoglycemia in patients with insulin-dependent diabetes mellitus (Axelsen et al, 1999b).

Oxidative stress defined as a disturbance in the balance between free radical production and antioxidant capacity, may play a major role in the micro- and macro-angiopathic complications of diabetes (Baynes, 1991). Diabetes has been associated with enhanced oxidative stress in several studies (Cominacini et al, 1994; Tsai et al, 1994; Beaudeux et al, 1995), although not in all (Jenkins et al, 1996; Sanchez-Quesada et al, 1996) and with reduced blood levels of antioxidants (Maxwell et al, 1997; Ceriello et al, 1998b). Recent findings suggest that metabolic processes following a meal may increase oxidative stress (Ceriello et al, 1999; Rao & Agarwal, 1999). A direct link has been found between postprandial glycemia and the induction of oxidative stress (Ceriello et al, 1998a,1999) that can be reversed by antioxidants (Paolisso et al, 1993,1994; Sharma et al, 2000). In this respect, possible mechanisms of action of low-GI diets include reduction of: (i) glucose toxicity, ie the effect of high glucose levels in depressing pancreatic function through free radical damage of pancreatic beta cells; and (ii) glycosylation of proteins and key enzymes responsible for metabolic processes (advanced glycosylation end products¾AGE, Paolisso et al, 1992; Ceriello, 2000). No studies thus far have tested the effects of various GI isocaloric diets on oxidative stress in diabetic patients or healthy individuals.

The glycemic index in coronary heart disease

Epidemiological evidence suggests that low-GI diets may decrease the risk of CHD independently (Liu et al, 2000) and as part of a healthy lifestyle (Stampfer et al, 2000). One study looked at the relationship between GL and CHD in a cohort of 75 521 women followed for 10 y (Liu et al, 2000). A direct association emerged after adjusting for known and suspected risk factors (OR=1.98; CI 1.41-2.77, highest vs lowest quintile). These findings were not confirmed by the Zutphen Elderly Study which, however, included a very small GI range and an elderly cohort, thereby intro-ducing a possible element of selection bias (van Dam et al, 2000).

The possible beneficial effects of a low-GI diet in the prevention of CHD may be explained by improvements in blood lipid profiles, insulin levels, thrombolitic factors and endothelial function.

Hyperlipidemia is a risk factor for CHD and it is one of the most common metabolic dysfunctions associated with diabetes, a disease responsible for a two-fold increase in mortality due to vascular disease (Stamler et al, 1993; Lotufo et al, 2001). Long-term studies, aimed at determining the metabolic effects of isocaloric macronutrient-balanced diets with high- vs low-GI foods, have been shown to significantly reduce serum cholesterol and triglyceride levels in hyperlipidemic and diabetic patients (Jenkins et al, 1987c; Wolever et al, 1992a,b). Significant reductions were seen in total cholesterol (-8.8%), low-density lipoprotein cholesterol (LDL-C; -9.1%) and triglyceride (-19.3%) with no change in high-density lipoprotein cholesterol (HDL-C; Jenkins et al, 1987c). Total cholesterol reductions of 7% were also found in diabetic patients (Wolever et al, 1992a,b). More recently Jarvi et al (1999) were able to obtain lipid reductions comparable to those of statins (20-30% from baseline), after 3 weeks on a low-GI diet.

Studies on high meal frequency (eg nibbling vs gorging) have been conducted to simulate slow absorption and thus to mimic the effects of a low-GI diet. The 'nibbling' vs 'gorging' paradigm has shown that increasing meal frequency (from 3 to >9 meal/day) reduced total and LDL cholesterol, apolipoprotein-B and serum uric acid levels in healthy subjects, after a period of 2 weeks (Arnold et al, 1993; Jenkins et al, 1989, 1995; Jones et al, 1993). Significant lipid reductions in total and LDL cholesterol (0.23, 0.16 mmol/l, respectively) were also reported in the Rancho Bernardo trial on more than 2000 men and women aged 50-89 y, when meal frequency was increased from 1-2 meals per day to 4 meals per day (Edelstein et al, 1992).

There have been concerns that high carbohydrate intakes at the expense of fat, particularly monounsaturated fat (Coulston et al, 1989; Mensink and Katan, 1987; Garg et al, 1994) could result in a rise in triglycerides and very-low-density lipoproteins and a suppression of HDL levels, which could translate into a higher risk of heart disease (Gordon et al, 1989; Stampfer et al, 1996; Vega & Grundy, 1996; Hokanson & Austin, 1996). However, not all carbohydrate-rich diets may produce the same effects on HDL levels, as low-GI diets may confer a more favorable lipid profile compared with high-GI diets. Lowering the dietary GI by at least 12 points reduced triglycerides by approximately 9% in 10 out of 11 studies (Brand Miller, 1994) and recent data showed that a high carbohydrate diet made of low-GI foods significantly increased HDL levels by 5.4% compared to an isocaloric high carbohydrate/high GI diet (Luscombe et al, 1999). In addition, cross-sectional data (Frost et al, 1999; Ford & Liu, 2001) showed that dietary GI was inversely related to HDL cholesterol levels, which in turn were inversely related to triglycerides, and that GI was a stronger predictor of serum HDL levels than dietary fat (Frost et al, 1999). Other investigators have shown that the unwanted HDL reductions seen with some high carbohydrate diets may be transient (Heilbronn et al, 1999).

The proposed mechanisms for lipid modulation by low-GI foods compared to high GI foods may include: (1) lower insulin-stimulated HMG-CoA reductase activity (the rate-limiting enzyme in cholesterol synthesis; Rodwell et al, 1976), as a result of a reduced rate of carbohydrate absorption; (2) impaired bile acid and cholesterol reabsorption from the ileum due to the typically high fibre content of low-GI foods (Kritchevsky & Story 1974; Jenkins et al, 1993); (3) inhibition of hepatic cholesterol synthesis by the short chain fatty acid propionate, a by-product of colonic fermentation (Illman et al, 1988; Wolever et al, 1988; Wright et al, 1990); (4) reduced inflammatory response. Some evidence suggests a possible role of insulin in stimulating acute-phase proteins (O'Riordain et al, 1995; Thompson et al, 1991) which have been directly related to intra-abdominal fat and inversely related to insulin-stimulated glucose disposal (Sites et al, 2002). HDL is considered a negative acute-phase protein (Malle et al, 1993) and has been found to be negatively associated to C-reactive protein (CRP) and acute and chronic inflammatory states (Bausserman et al, 1988; Rossner, 1978; Hardardottir et al, 1994). HDL may reduce the inflammatory response by binding to stimulated T cells thus blocking their interaction with monocytes and consequently inhibiting TNF-alpha and IL-1beta (Hyka et al, 2001). A possible mechanism could therefore be that lower glucose raises after low-GI foods may reduce the inflammatory response and raise HDL levels, when compared to high-GI foods.

Regulating insulin levels may be important not only in diabetic patients, but also in healthy subjects as hyperinsulinemia has been directly associated with CHD in previously healthy populations (Ducimetiere et al, 1980; Pyorala et al, 1985; Despres et al, 1996). Hyperinsulinemia has recently been found to moderately increase cardiovascular mortality in middle-age men (Lakka et al, 2000) and insulin resistance, a risk factor for CHD (Reaven, 1993) has been shown to respond to manipulations of the dietary GI (Frost et al, 1998). Patients with a history of CHD were randomized to either a low- or a high-GI diet (15% GI difference). After the 4 week treatment period an oral glucose tolerance test was performed following an overnight fast and a fat biopsy was obtained to assess in vitro glucose uptake in adipocytes. Less insulin was needed to handle a standard glucose challenge and increased insulin-stimulated glucose uptake was observed in the low-GI group, hence suggesting an improvement in insulin resistance (Frost et al, 1996).

Finally, when looking at thrombolytic factors Jarvi et al (1999) showed a significant reduction of 54% in plasminogen activator inhibitor-1, a marker of increased coagulation, after 3 weeks on a low-GI diet compared to a high-GI diet where energy, macro- and micro-nutrients were balanced in all subjects. Although the mechanisms need to be elucidated some evidence suggests that hyperglycemia and hyperinsulinemia may lead to impaired fibrinolysis and thrombosis as shown by clinical (Calles-Escandon et al, 1998) and correlational studies (Juhan-Vague et al, 1989; Meigs et al, 2000), thereby increasing the risk of CHD (Gerstein & Yusuf, 1996; Ruige et al, 1998).

In relation to endothelial function there is some evidence for a role of hyperglycemia in endothelial cell dysfunction possibly through increased generation of oxygen free radicals (Tesfamariam & Cohen 1992; Graier et al, 1996; Cosentino et al, 1997). Endothelium-dependent vasodilation impaired by dietary glucose ingestion seemed to be restored by consumption of antioxidant vitamins (Levine et al, 1996; Title et al, 2000; Skyrme-Jones et al, 2000). Diabetic patients (type 1 and 2) tend to be more prone to endothelial dysfunction (eg decreased endothelium-dependent vasodilation) and to have higher levels of oxidative stress than healthy populations (Clarkson et al, 1996; Williams et al, 1996; Akkus et al, 1996; Santini et al, 1997; Ceriello et al, 1998b) and in healthy individuals postprandial hyperglycemia appears to result in increased oxidative stress (Koska et al, 1997; Ceriello et al, 1998a; Kawano et al, 1999).

Also, fasting and postprandial glucose levels were related to CHD in a metaregression analysis of 20 studies including almost 100 000 people, followed for at least 12 y (Coutinho et al, 1999).

The glycemic index in obesity

Obesity is a risk factor for several chronic diseases including NIDDM, CHD and some types of cancer (Must et al, 1999). The prevalence of overweight (body mass index (BMI)>25 kg/m2) and obesity (BMI>30 kg/m2) are estimated to be 63 and 55% among American middle-aged men and women, respectively (Must et al, 1999), and the increase in prevalence of obesity in the last two decades is 8% (Kuczmarski et al, 1994).

Of the dietary factors, fat has been considered by some the main culprit (Astrup & Raben, 1992; Golay & Bobbioni, 1997); however, at the same time as the prevalence of overweight increased there has been a reduction in fat intake in the United States from 42 to 34% of total energy (Lenfant & Ernst, 1994; Nicklas, 1995), with a concomitant increase in carbohydrate intake. In highly industrialized countries the major sources of carbohydrates are refined foods which tend to be quickly absorbed and have high GI values.

Generally, low-GI foods are associated with greater satiety compared to high-GI foods or meals (Haber et al, 1977; Leathwood & Pollet, 1988; Rodin et al, 1988; Holt et al, 1992; Holt & Miller, 1994; Van Amelsvoort & Weststrate, 1992; Liljeberg et al, 1999). Recently Ludwig et al (1999) have studied the effect of high-, medium- or low-GI breakfast meals on subsequent ad-libitum food intake in obese teenage boys. They observed reductions in energy intake of 53 and 81% in the medium- and low-GI groups, respectively, compared to the high-GI group, 5 h after breakfast. These results suggest that in isoenergetic meals, slowly digested carbohydrate-rich foods may allow a sense of satiety to last longer than rapidly digested foods. The characteristic effects of high-GI foods, such as fast carbohydrate absorption, large blood glucose and hormonal (insulin/glucagon) fluctuations, together with reduced satiety, could favour overnutrition in the long run (Haber et al, 1977). In particular, the hypoglycemic undershoot, a characteristic effect of high-GI foods, may induce hunger. This may be explained by high-insulin and low-glucagon levels, triggered by high-GI foods, inducing glucose storage, inhibiting lipolysis and consequently reducing glucose availability for metabolic oxidation (hypoglycemic undershoot). This metabolic state could be seen as a fasting state and would trigger glucagon release and hunger signals. Low-GI foods, however, tend to maintain glucose and insulin at a moderate level avoiding the hypoglycemic state. Also, low-GI foods that are rich in dietary fiber may produce a distention of the gastrointestinal tract which may further explain the enhanced satiety level. Cholecystokinin (CCK), a gut peptide that induces satiety, is thought to be directly affected by gastric volume. Meal GI has been found inversely proportional to CCK response and satiety (Holt et al, 1992), suggesting a possible role of gastric volume and of bulky foods in maintenance of appetite suppression.

Long-term studies on the impact of low-GI diets in the management and prevention of obesity are, however, necessary in order to confirm the promising short-term trials.

Glycemic index and cancer

The amount of evidence on the relationship between GI and cancer is scant at present. Three epidemiological studies have looked at this and found direct associations for colorectal and breast cancer (Slattery et al, 1997; Franceschi et al, 2001; Augustin et al, 2001).

However, several lines of evidence point to a possible role of the GI in the development of cancer. McKeown-Eyssen (1994) and Giovannucci (1995) hypothesized that hyperinsulinemia/insulin resistance may promote colorectal cancer and possibly other types of cancers related to Western lifestyle (Bruning et al, 1992). High intakes of energy and refined carbohydrates, low intake of vegetables, fruit and dietary fiber, lack of physical activity, obesity, diabetes, hyperinsulinemia and high levels of insulin-like growth factors (IGFs) have been implicated in the etiology of various types of cancer (Giovannucci, 1999). Evidence supporting a possible role of the GI or the GL in cancer etiology is still limited and will be discussed in this present review by briefly presenting in vitro, animal and human studies, including dietary (eg carbohydrates) and non-dietary factors (eg diabetes, growth factors) that may influence the risk of cancer through the insulin hypothesis.

Colorectal cancer

The influence of the GI or GL has been little studied in relation to colorectal cancer. One case-control study suggests a direct association between dietary GI and colon cancer risk of the proximal site, after adjusting for age, BMI, physical activity, use of aspirin or other non-steroidal anti-inflammatory drugs, family history of colorectal cancer, non-carbohydrate energy intake, dietary calcium and fiber (Slattery et al, 1997). Dietary GI as well as GL (an indirect measure of dietary insulin demand) were assessed in a large case-control study and found to be directly associated with colorectal cancer risk (OR for GI, highest vs lowest quintile=1.7; and for GL, OR=1.8). The results were adjusted for sociodemographic factors, physical activity, number of daily meals, and intakes of fiber, alcohol and energy. ORs were especially elevated for cancer of the colon (1.9 for GI and 2.0 for GL; Franceschi et al, 2001). These data suggest the more refined the carbohydrates in the habitual diet, the greater the risk for cancer of the colorectum.

Less convincing evidence however comes from animal studies where differences in dietary GI did not affect the growth of aberrant crypt foci, a preneoplastic marker of colon cancer (Corpet et al, 1998). Also, high-GI diets did not seem to stimulate colon carcinogenesis in an animal model although the investigators found a possible protective effect of pasta which reduced intestinal adenoma incidence when compared to high sucrose and glucose diets (Caderni et al, 1997).

Carbohydrates are among dietary factors that influence both glucose and insulin levels and also appear related to colorectal cancer risk. The main carbohydrate classes studied are starch (or polysaccharides) and sugar. Epidemiological observations report a direct association between starch or polysaccharide intake and colorectal cancer although some did not achieve statistical significance (Tuyns et al, 1987; Haenszel et al, 1980; Slattery et al, 1988; Zaridze et al, 1993; Franceschi et al, 1998; Macquart-Moulin et al, 1986). However, when the end point was colorectal adenomatous polyp, a precursor of colorectal cancer, high carbohydrate intake resulted in a lower risk in both cohort (Giovannucci et al, 1992) and case-control studies (Hoff et al, 1986; Macquart-Moulin et al, 1987; Benito et al, 1993; Neugut et al, 1993; Sandler et al, 1993). In two studies the association was found only in women (Neugut et al, 1993; Sandler et al, 1993). A positive association of sugar intake with colorectal cancer risk has been observed in the majority of cohort and case-control studies that have looked at this relationship (Table 7). Adjustments for energy intake and other possible confounders such as body weight, socio-economic status, smoking and family history of the disease were not possible in all studies. Of the seven studies that did include these adjustments (Bostick et al, 1994; Macquart-Moulin et al, 1986,1987; La Vecchia et al, 1993; Centonze et al, 1994; Franceschi et al, 1997; Slattery et al, 1997), six (Bostick et al, 1994; Macquart-Moulin et al, 1987; La Vecchia et al, 1993; Centonze et al, 1994; Franceschi et al, 1997; Slattery et al, 1997) found a significant increase in risk of colorectal cancer with high sugar consumption, with odd ratios (ORs) ranging from 1.4 to 2.8 for the highest quartile or quintile of intake. The picture is further complicated when food groups were analysed. Starch-rich foods such as rice in Japan (Wynder et al, 1969), rice, cereal dishes and potatoes in Southern Europe (Macquart-Moulin et al, 1986; Franceschi et al, 1997) were found to be directly associated with colorectal cancer risk.

The slightly conflicting results may be partly due to the primary type of carbohydrate consumed by the population under study. In some countries the main sources of carbohydrate may be unrefined bread (eg a low-GI bread such as pumpernickel), while in others it may be high-GI foods such as potatoes or white bread. These foods elicit different glycemic and insulinemic responses and thus could affect the risk of colorectal cancer differently.

Other evidence from non-dietary factors is pointing to a possible promoting role of insulin in colon carcinogenesis. A link between cancer and diabetes mellitus has been suspected for more than 100 y and until the 1920s hyperglycemia was used as a marker in cancer screening (Freund, 1885; Trinkler, 1890; Boas, 1903; Schafer, 1934; Marble, 1934; Ellinger & Landsman, 1944). Type 2 diabetes, a condition resulting from long-term exposure to high insulin levels, has been found to increase significantly colorectal and colon cancer risk by 43 and 49%, respectively, in the cohort of women from the Nurses' Health Study (Hu et al, 1999). Similar associations have been reported by several other investigators (Adami et al, 1991; O'Mara et al, 1985; Hardell et al, 1996; La Vecchia et al, 1991,1997; Wideroff et al, 1997), albeit not all (Ragozzino et al, 1982; Green & Jensen, 1985; Kune et al, 1988; Steenland et al, 1995; Tables 8 and 9). In summary, these studies suggest a 10-40% increase in risk of colorectal cancer in diabetic patients. Most of the associations appear to be moderately positive, stronger for males than females and for colon than rectal cancer. The associations were not explained by potential confounding factors including BMI and physical activity (La Vecchia et al, 1997).

When diabetic populations were followed in prospective studies the increase in colorectal cancer risk was approximately 34% in men and 20% in women (Weiderpass et al, 1997a; Will et al, 1998) compared to the general population, and it was stronger for colon than rectal cancer, confirming the above findings. However, the progression of colorectal cancer did not seem to be worsened by diabetes (Will et al, 1998).

Another way of investigating the insulin-colon cancer hypothesis is by assessing the association between blood glucose levels after glucose challenge and subsequent colorectal cancer mortality. After 12 y follow-up, Levine et al (1990) found a positive association in men but not in women. These results, however, were not confirmed by Smith et al (1992), who conducted a similar study with a larger cohort and a longer follow-up (18-20 y). More recently Schoen et al (1999) found a two-fold increased risk in colorectal cancer after 77 months of follow-up in subjects with high baseline fasting glucose levels and high glucose and insulin levels 2 h after glucose challenge (relative risk, RR=1.8, 2.4, 2.0, respectively). In this study no associations were found with diabetes although the number of diabetic subjects was very limited (n=23). Further evidence for a possible role of hyperinsulinemia in colorectal cancer is given by a small case-control study where direct associations were found between two risk factors for hyperinsulinemia, plasma triglycerides and glucose, and risk of carcinoma in situ (Yamada et al, 1998).

Epidemiological studies have found a positive association between colon cancer risk and various determinants of hyperinsulinemia/insulin resistance, particularly obesity and physical inactivity (Vena et al, 1987; Severson et al, 1989; Ballard-Barbash et al, 1990; Potter et al, 1993; Giovannucci et al, 1995; Schoen et al, 1999).

Is there a link between high glucose, high insulin levels and increased risk of cancer? Mechanistic studies have been pointed at insulin-like growth factors (IGFs). Insulin acts as a growth factor for colonic mucosal cells and it has been shown to possess promoting effects in in vitro and in animal cancer studies (Koenuma et al, 1989; Watkins et al, 1990; Bjork et al, 1993; Tran et al, 1996). Insulin has the ability to stimulate IGFs which are important mitogens, necessary for the cell to progress from G1 to the S phase of the cell cycle (Aaronson, 1991). Ninety-five percent of IGF-1 circulates bound to IGF binding protein-3 (IGFBP-3), which controls the availability of free IGF-1 by modulating its access to the IGF-1 receptor (Jones & Clemmons, 1995; Collett-Solberg & Cohen 1996). IGF-1 promotes cell growth by stimulating tyrosine-specific protein kinase activity both in its own receptors as well as in the insulin receptors. Insulin has been shown to have moderate affinity to the IGF receptors, particularly the IGF-1 receptor (Ullrich et al, 1986). IGF-1 has also anti-apoptotic (Baserga, 1995; Remacle-Bonnet et al, 2000) and angiogenic properties (Warren et al, 1996), two attributes that may favour tumor development. IGFBPs (mainly IGFBP-3 and IGFBP-1) appear to have the opposite effects to IGF-1 (Giovannucci, 1999).

An indirect mechanism postulated for the tumor initiating action of IGFs may include interactions with genetic factors since growth factors are known to activate k-ras proteins (Bos, 1998), which are responsible for promoting cell growth. When mutated, k-ras proteins lose their ability to become inactive and their hyperactivity may increase the risk of generating tumor cells.

Insulin and IGF-1 receptors have been found in both normal and malignant cells of the colonic mucosa and have been shown to stimulate proliferation of human colorectal cells (Lahm et al, 1992; McKeown-Eyssen, 1994).

Circulating levels of IGF-1 were related to colorectal cancer risk in a case-control study, after adjustment for known dietary and non-dietary risk factors (Manousos et al, 1999). Similarly, two other cohort studies have shown a strong positive association between IGF-1 and colorectal cancer among men of different age groups (Ma et al, 1999) and between IGF-1 and intermediate-late stage adenomas as well as colorectal cancer among women, where a more than two-fold increased risk was found (Giovannucci et al, 2000). In these two cohorts a negative association was observed for IGFBP-3 which reduced risk by 72% in men when the highest quintile was compared to the lowest (Ma et al, 1999) and in women for both colorectal adenoma and cancer (highest vs lowest tertile). Also, high levels of IGF-1 and low levels of IGFBP-3 have been shown to be directly associated with colorectal adenomas (RR=4.39; 95% CI 1.31-14.7) and to predict adenoma progression, suggesting that both factors could be related to future colorectal cancer risk (Renehan et al, 2001).

Other growth factor-related studies suggest a link between IGF-1 and colorectal carcinogenesis. Tall individuals (Hebert et al, 1997) and those with acromegaly, characterized by elevated levels of growth hormone and IGF-1 (Ron et al, 1992), show an increased risk of colorectal cancer.

Nutrition is a major regulator of IGF-1 (Underwood, 1996). Fasting results in a decrease while overnutrition results in an increase in IGF-1 levels although the exact nature of the dose-response relationship between food intake and levels of IGFs in circulation remains to be determined. In a clinical trial high carbohydrate/high-GI diets increased IGF-1 levels compared to low carbohydrate diets in obese subjects (Prewitt et al, 1992). The opposite was shown in a small cross-sectional study in Greece where an independent and negative association was found between circulating IGF-1 levels and energy from carbohydrates (Kaklamani et al, 1999). The Mediterranean diet, however, is known to contain several food items with low GI values and it is possible that the dietary GL in this Greek population was lower than in a typical Western diet used in the clinical study by Prewitt et al (1992).

Breast cancer

Only one study thus far has reported on the association between dietary GI or GL and risk of breast cancer (Augustin et al, 2001). Direct associations with breast cancer risk emerged for GI (OR=1.4 for highest vs lowest quintile; 95% CI 1.1-1.6) and GL (OR=1.3; 95% CI 1.1-1.6) after correcting for known risk factors. Interestingly, high-GI foods, such as white bread, increased the risk of breast cancer (OR=1.3; 95% CI 1.1-1.6) while the intake of pasta, a medium-low-GI food, did not influence risk (OR=1.0; 95% CI 0.8-1.2).

Dietary factors have been shown to play a role in breast cancer. Of the macronutrients that affect the GI starch intake has been directly associated with breast cancer risk in a case-control study after adjustment for confounding factors such as age, energy intake and alcohol consumption (Franceschi et al, 1996). Similar results were obtained by Ingram et al, (1991) while others did not show a significant relation (Rohan et al, 1988; Zaridze et al, 1991). Total carbohydrate intake in general was not associated with breast cancer risk (Table 10), although one study showed a significantly positive association (Franceschi et al, 1996) and another showed a negative association (Wakai et al, 2000). One of the possible explanations for these apparently opposing results could be the different type of carbohydrates used as the staple food in the two different population (Italian and Indonesian, respectively). High-GI foods as white bread and crackers are the main starch consumed by the Italian population representing 39% of total starch intake, followed by pasta and rice which together account for 25% (Favero et al, 1997). Starch identified as a food group (eg white bread or refined cereal dishes) has also been found to increase risk of breast cancer in most epidemiological studies (Iscovich et al, 1989; Franceschi et al, 1995; Favero et al, 1998), although some have found no association (Toniolo et al, 1989; Rohan et al, 1993) and in one study from the Netherlands an inverse association emerged (van't Veer et al, 1990). However, in this study the cereal products represented also the main source of dietary fiber suggesting these were not refined cereals. Associations of sugar intake/confectionery with breast cancer have been reported in at least eight studies; two were direct ( Franceschi et al, 1995; Favero et al, 1998), one inverse after adjustment for macronutrient energy (Zaridze et al, 1991), while the remaining showed no consistent association (Rohan et al, 1988; Iscovich et al, 1989, Ewertz & Gill 1990; Ingram et al, 1991; Levi et al, 1993, Franceschi et al, 1996; Table 10).

The European intervention study (DIANA project) has shown that after 4.5 months on a diet rich in low-GI foods postmenopausal women showed reduced levels of circulating estradiol and testosterone, two hormones associated with breast cancer in postmenopausal women (Berrino et al, 2001). It should be noted, however, that this randomized controlled trial also included other dietary manipulations (eg soy foods) which could have partly accounted for the results.

Endocrine factors associated with diabetes may influence the growth of neoplastic breast cells. Frequency of breast cancer seems to be increased in diabetic women (Talamini et al, 1997) and women with impaired glucose tolerance (Muck et al, 1975). A large case-control study on 2569 women with breast cancer and 2588 controls (median age 55 y) showed an increased risk of breast cancer with diabetes mellitus in post-menopausal women after allowance for common risk factors such as parity and BMI (OR=1.5, 95% CI=1.1-2.0; Talamini et al, 1997). In a large retrospective cohort study of 80 005 diabetic women, a 30% increased risk of breast cancer emerged in diabetics compared with the incidence rates of the general Swedish population (Weiderpass et al, 1997b). No significant association was found in another study that included over 41 000 women aged 55-69 y during a 10 y follow-up (Sellers et al, 1998). In the Iowa Study of over 31 000 women, diabetes worsened breast cancer prognosis while it seemed to affect risk only in women with a history of breast cancer; however, obesity was found to account for most of this association (Folsom et al, 2000).

Hyperisulinemia/insulin resistance has been hypothesized to play a role in breast cancer development (Kaaks, 1996). Insulin may act as a mitogen in a dose-dependent manner in breast cancer cells through the insulin receptor. Positive associations of insulin with breast cancer were observed in 99 premenopausal non-diabetic women diagnosed with node-negative invasive carcinoma of the breast (first stage) compared to 99 age-matched controls with benign breast disease (Del Giudice et al, 1998). The odds ratio between the highest and lowest quintile of insulin levels was 2.83 (95% CI=1.22-6.58) after adjusting for dietary and other risk factors such as obesity. Another study showed that serum C-peptide levels, a measure of insulin secretion, were significantly increased in 223 cases with stage I and II breast cancer (38-75 y) compared to 441 age-matched controls (RR=2.9, 95% CI=1.7-5.1, highest vs lowest quartile, C-peptide difference of 1.7 µg/l; Bruning et al, 1992). These results were independent of adiposity and body fat distribution. However, in the Malmo Preventive Project, when looking at fasting blood glucose and blood glucose levels after an oral glucose challenge no relationship was found with breast cancer in peri- and postmenopausal women (Manjer et al, 2001).

Obesity, in particular central obesity, is one of the major risk factors for insulin resistance and hyperinsulinemia and is positively associated with breast cancer risk in postmenopausal women (Sellers et al, 1992; Hunter & Willett, 1993; Ballard-Barbash & Swanson, 1996; Trentham-Dietz et al, 1997; Galanis et al, 1998). Central obesity was directly associated with breast cancer independently of BMI in at least two studies (Folsom et al, 1990; Kaaks et al, 1998). Two possible reasons for these associations could be related to hormonal factors: (i) estrogen synthesis from androstenedione, which occurs mainly in adipose tissue, is increased with greater body fat; and (ii) obesity leads often to a status of hyperinsulinemia with the potential consequences on estrogen and insulin-like growth factors previously mentioned. The latter point is supported by epidemiological evidence showing an inverse correlation between obesity and sex hormone binding globulin (Madigan et al, 1998; Newcomb et al, 1995).

Estrogen has long been shown as a promoting agent in breast cancer and several risk factors for breast cancer such as nulliparity, late age at first pregnancy and late natural menopause are also associated with life-long exposure to sex hormones. The most active form of estrogen is free, unbound estradiol. The influence of estrogens on the breast is related to estrogen receptors which may be activated, among others, by insulin-like growth factors (Yee & Lee, 2000). Sustained high insulin levels may increase the risk of breast cancer by at least two possible routes: (1) suppression of sex hormone-binding globulin (SHBG) thereby rendering free circulating estradiol more available for action at the tissue level; (2) suppression of IGFBP-I, thus increasing free IGF-1 levels (Plymate et al, 1990; Nestler et al, 1991).

In vitro and animal studies have shown mitogenic and anti-apoptotic effects of IGFs in mammary cell lines (Bhalla et al, 2000; Helle & Lonning, 1996; Pilichowska et al, 1997; Foekens et al, 1989; Huff et al, 1986, Ng et al, 1997). Transgenic mice overexpressing growth hormone have a higher frequency of breast cancer (Bates et al, 1995; Hadsell et al, 1996) and disruption of the IGF-1 gene seems to prevent breast tumor formation by viral oncogens (Sell et al, 1993). Human mechanistic studies of the effect of estrogen antagonist drugs on breast carcinogenesis have shown a direct link with IGF-1. Tamoxifen is used in the prevention and therapy of breast cancer and has been found to reduce serum levels of IGF-1 and raise IGFBP-1 in postmenopausal breast cancer patients (Ho et al, 1998). This has been proposed as one of the mechanisms through which the antiestrogenic drug tamoxifen and more recently fenretinide, a vitamin A analog, may inhibit growth of mammary tumor cells (Ho et al, 1998; Kelloff et al, 1999).

Epidemiologic evidence is suggesting a possible role of IGFs in promoting and IGFBPs in suppressing breast carcinogenesis. Higher levels of IGF-1 were associated with breast cancer both in pre- and post-menopausal women in one study (Peyrat et al, 1993) and only in premenopausal women in two other studies (Bruning et al, 1995; Bohlke et al, 1998) where lower levels of IGFBP-3 were also found in premenopausal cases compared to controls. No associations were observed for these variables and breast cancer in postmenopausal women in two other investigations (Bruning et al, 1995; Hankinson et al, 1997) and in one study on premenopausal women (Del Giudice et al, 1998), although in the latter the control group chosen, potentially at high risk. In a small case-control study IGF-1 and IGFBP-3 were found, respectively, directly and indirectly associated with premenopausal ductal carcinoma in situ (Bohlke et al, 1998). Similar results were obtained in a nested case-control study based on the American Nurses Cohort where the positive association between plasma IGF-1 levels and breast cancer risk reached significance in premenopausal women younger than 50 and the relative risk increased after adjustment for plasma IGFBP-3 concentrations (Hankinson et al, 1998). Most of these studies did not include analysis on free IGF-1 which may be the most active fraction of total IGF-1, except in one small case-control study (Li et al, 2001) where a significant positive association was found with breast cancer risk (OR=6.31).

As for colorectal cancer, other growth factor related studies may support a role of IGFs in breast cancer. Acromegaly increased the risk by four-fold (Nabarro, 1987) with a two-fold increase in mortality from breast cancer (Orme et al, 1996). Also height has been directly associated with breast cancer (van den Brandt et al, 1997). Although modest, positive associations have been found between height and breast cancer in several prospective studies where approximately two-fold increase in risk was observed with a difference in height of 15 cm (de Ward et al, 1974; Swanson et al, 1988; van den Brandt et al, 1997) or with 8 cm increment (Tornberg et al, 1988, Tretli, 1989; Vatten & Kvinnsland 1990, 1992; Manjer et al, 2001).

Prostate cancer

Some evidence suggests a promoting effect of refined carbohydrates in prostate carcinogenesis. Diets rich in fat, refined sugars and excess calories, all factors that favour the development of hyperinsulinemia, increase risk of prostate cancer (Talamini et al, 1992; Franceschi, 1994). Conversely, a low-fat/high-fiber diet plus daily exercise has been shown to decrease insulin and increase SHBG levels in obese men (Tymchuk et al, 1998).

Androgens are necessary hormones for the development and progression of prostate cancer. Testosterone is regulated by SHBG and also by insulin and insulin-like growth factors (Plymate et al, 1988; Singh et al, 1990; Pasquali et al, 1995; Katsuki et al, 1996). As with breast cancer, insulin may increase prostate cancer risk by suppressing SHBG levels. Insulin has also been shown to act as a mitogen in prostate adenocarcinoma cell lines (Polychronakos et al, 1991; Kimura et al, 1996). Insulin-like growth factors, particularly the IGF-1 family, have mitogenic and antiapoptotic activity in normal as well as in transformed prostate epithelial cells (Cohen et al, 1991; Rajah et al, 1997) and stimulate prostate growth in rodents (Torring et al, 1997). Epidemiological studies have shown a positive correlation between IGF-1 levels and prostate cancer risk (Chan et al, 1998; Mantzoros et al, 1997; Wolk et al, 1998). A four-fold increased risk was observed in the highest quartile of IGF-1 levels compared to the lowest level in a nested case-control study of 152 paired subjects (Chan et al, 1998). The results were independent from baseline prostate-specific antigen levels and remained statistically significant after adjusting for potential confounders such as weight, height, BMI, lycopene, androgen receptors and plasma hormone levels. The design of the study allowed the inference that high levels of circulating IGF-1 were not a consequence of disease progression as suggested also by other investigators who found no association between IGFs and prostate cancer stage (Wolk et al, 1998). IGFBPs have also been considered in relation to prostate cancer, particularly IGFBP-3 in epidemiological studies (Chan et al, 1998; Wolk et al, 1998). Most investigators have reported an inverse association between IGFBP-3 and prostate cancer risk (Chan et al, 1998; Thrasher et al, 1996; Kanety et al, 1993), although others have found no association (Wolk et al, 1998).

A possible role of IGFs in prostate carcinogenesis is also suggested by mechanistic studies on Suramin, a drug used in the treatment of advanced prostate cancer, which was shown to suppress IGF-levels (Miglietta et al, 1993; Sartor et al, 1994).

Furthermore, height, as a surrogate of growth factors and IGF activity, has been shown to be positively associated with prostate cancer risk in two cohort studies (Andersson et al, 1997; Giovannucci et al, 1997) and in a case-control study where a moderate direct association was observed with advanced prostate cancer (Norrish et al, 2000).

It is not yet clear whether diabetes may be a risk factor for prostate cancer. Some epidemiological studies have shown a 34% lowered risk (Giovannucci et al, 1998), while in another there was a 56% increased risk only in men with a diagnosis of diabetes of 5 y or more (Will et al, 1999).

Obesity is also directly associated with prostate cancer (Gann et al, 1995). Compared to normal weight (BMI<23 kg/m2), men moderately overweight (BMI=23-28 kg/m2) showed a two-fold elevated risk while severely overweight men (BMI>28 kg/m2) showed a four-fold greater risk of prostate cancer after correcting for confounding factors (Talamini et al, 1986).

Although scant, some evidence points towards a role of insulin in prostate carcinogenesis. At present no studies have been conducted on the relationship between dietary GI or GL risk of prostate cancer.


Low-GI diets include foods such as beans, vegetables, pasta, parboiled rice and wholegrain breads and they may have clinical implications in the prevention and management of chronic Western diseases, particularly type 2 diabetes, CHD and possibly cancer. High and low GI diets may be a better measure for assessing the physiological effects of dietary carbohydrates than the traditional 'simple' and 'complex' carbohydrate definition. Overall, GL may be a better measure of the association between dietary carbohydrate and disease in epidemiological studies.

The literature suggests that the low-fat/high-carbohydrate diets advocated by health organizations in Western countries could be further improved by switching from high-GI to low-GI food choices. When introduced ad-libitum in the diet, low-GI foods would often confer an array of advantages with their low energy density and discrete content of dietary fiber, vitamins, minerals and phytochemicals. Studies looking at dietary (eg carbohydrates) and non-dietary factors (eg diabetes, growth factors) in relation to cancer may suggest an important role of insulin in carcinogenesis. There may be a place for low-GI diets in disease prevention and management particularly in populations characterized by already high incidences of obesity, insulin resistance and glucose intolerance; however, more studies are necessary to confirm the possible role of high glucose and insulin in disease development in order to rule out any possible confounding factor and to better understand potential mechanisms of action.


The authors wish to thank Mrs Luigina Mei for editorial assistance.


Aaronson S. (1991). Growth factors and cancer. Science, 254: 1146-1153. MEDLINE

Adami HO, McLaughlin MJ, Ekbom A et al. (1991). Cancer risk in patients with diabetes mellitus. Cancer Causes Control, 2: 307-314. MEDLINE

Akkus I, Kalak S, Vural H, Caglayan O, Menekse E, Can G, Durmus B. (1996). Leukocyte lipid peroxidation, superoxide dismutase, glutathione peroxidase and serum and leukocyte vitamin C levels of patients with type II diabetes mellitus. Clin. Chim. Acta, 244: 221-227.

American Diabetes Association. (1994). Position Statement. Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care, 17: 519-522.

Andersson SO, Wolk A, Bergstrom R et al. (1997). Body size and prostate cancer: a 20-year follow-up among 135006 Swedish construction workers. J. Natl Cancer Inst., 89: 385-389. MEDLINE

Arnold LM, Ball MJ, Duncan AQ, Mann J. (1993). Effect of isoenergetic intake of three or nine meals on plasma lipoproteins and glucose metabolism. Am. J. Clin. Nutr., 57: 446-451.

Astrup A, Raben A. (1992). Obesity: an inherited metabolic deficiency in the control of macronutrient balance? Eur. J. Clin. Nutr., 46: 611-620.

Augustin LS, Dal Maso L, La Vecchia C, Parpinel M, Negri E, Vaccarella S, Kendall CKW, Jenkins DJA, Franceschi S. (2001). Dietary glycemic index and glycemic load in breast cancer risk: a case-control study. Ann. Oncol., 12: 1533-1538.

Axelsen M, Lonnroth P, Arvidsson Lenner R, Smith U. (1997). Suppression of the nocturnal free fatty acid levels by bedtime cornstarch in NIDDM subjects. Eur. J. Clin. Invest., 27: 157-163.

Axelsen M, Wesslau C, Lonnroth P, Arvidsson Lenner R, Smith U. (1999a). Bedtime uncooked cornstarch supplement prevents nocturnal hypoglycaemia in intensively treated type 1 diabetes subjects. J. Intern. Med., 245: 229-236.

Axelsen M, Arvidsson Lenner R, Lonnroth P, Smith U. (1999b). Breakfast glycaemic response in patients with type 2 diabetes: effects of bedtime dietary carbohydrates. Eur. J. Clin. Nutr., 53: 706-710.

Ballard-Barbash R, Swanson CA. (1996). Body weight: estimation of risk for breast and endometrial cancers. Am. J. Clin. Nutr., 63: ((Suppl)) 437S-441S.

Ballard-Barbash R, Schatzkin A, Albanes D et al. (1990). Physical activity and risk of large bowel cancer in the Framingham Study. Cancer Res., 50: 3610-3613.

Baserga R. (1995). The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res., 55: 249-252. MEDLINE

Bates P, Fisher R, Ward A, Richardson L, Hill DJ, Graham CF. (1995). Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF II). Br. J. Cancer, 72: 1189-1193. MEDLINE

Bausserman LL, Bernier DN, McAdam KP, Herbert PN. (1988). Serum amyloid A and high density lipoproteins during the acute phase response. Eur. J. Clin. Invest., 18: 619-626.

Baynes JW. (1991). Role of oxidative stress in development of complications in diabetes. Diabetes, 40: 405-412. MEDLINE

Beaudeux J-L, Guillausseau P-J, Peynet J, Flourie F, Assayag M, Tielmans D, Warnet A, Rousselet F. (1995). Enhanced susceptibility of low-density lipoprotein to in vitro oxidation in type 1 and type 2 diabetic patients. Clin. Chim. Acta, 239: 131-141.

Behall KM, Scholfield DJ, Canary J. (1988). Effect of starch structure on glucose and insulin responses in adults. Am. J. Clin. Nutr., 47: 428-432.

Benito E, Obrador A, Stiggelbout A et al. (1990). A population-based case-control study of colorectal cancer in Majorca I. Dietary factors. Int. J. Cancer, 45: 69-76. MEDLINE

Benito E, Cabeza E, Moreno V, Obrador A, Bosch FX. (1993). Diet and colorectal adenomas: a case-control study in Majorca. Int. J. Cancer, 55: 213-219.

Berrino F, Bellati C, Secreto G, Camerini E, Pala V, Panico S, Allegro G, Kaaks R. (2001). Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol. Biomarkers Prev., 10: 25-33.

Bertelsen J, Christiansen C, Thomsen C et al. (1993). Effect of meal frequency on blood glucose, insulin, and free fatty acids in NIDDM subjects. Diabetes Care, 16: 4-7.

Bhalla V, Joshi K, Vohra H, Singh G, Ganguly NK. (2000). Effect of growth factors on proliferation of normal, borderline and malignant breast epithelial cells. Exp. Mol. Pathol., 68: 124-132.

Bidoli E, Franceschi S, Talamini R et al. (1992). Food consumption and cancer of the colon and rectum in north-eastern Italy. Int. J. Cancer, 50: 223-229. MEDLINE

Bjork J, Nilsson J, Hultcrantz R, Johansson C. (1993). Growth-regulatory effects of sensory neuropeptides, epidermal growth factor, insulin, and somatostatin on the non transformed intestinal epithelial cell line IEC-6 and the colon cancer cell line HT 29. Scand. J. Gastroenterol., 28: 879-884.

Boas J. (1903). Ueber Carcinom und Diabetes. Berlin Klin. Wschr., 40: 243-247.

Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. (1991). Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J. Clin. Invest., 88: 960-966.

Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS. (1998). Insulin-like growth factor-1 in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology, 9: 570-573.

Bornet FRJ, Costagliola D, Rizkalla SW, Blayo A, Fontvieille AM et al. (1987). Insulinemic and glycemic indexes of six starch-rich foods taken alone and in a mixed meal by type 2 diabetics. Am. J. Clin. Nutr., 45: 588-595.

Bos JL. (1998). All in the family? New insights and questions regarding interconnectivity of Ras Rap1 and Ral. EMBO J., 17: 6776-6782. Article MEDLINE

Bostick RM, Potter JD, Kushi LH et al. (1994). Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in lowa women (United States). Cancer Causes Control, 5: 38-52.

Brand JC, Colagiuri S, Crossman S, Allen A, Roberts DC, Truswell AS. (1991). Low glycemic index foods improve long term glycemic control in non-insulin-dependent diabetes mellitus. Diabetes Care, 14: 95-101. MEDLINE

Brand Miller JC. (1994). The importance of glycemic index in diabetes. Am. J. Clin. Nutr., 59: ((Suppl)) 747S-752S. MEDLINE

Bristol JB, Emmett PM, Heaton KW, Williamson RC. (1985). Sugar, fat, and the risk of colorectal cancer. Br. Med. J. (Clin. Res. Edn), 291: 1467-1470.

Bruning PF, Bonfrer JMG, van Noord PAH, Hart AAM, De Jong-Bakker M, Nooijen WJ. (1992). Insulin resistance and breast-cancer risk. Int. J. Cancer, 52: 511-516. MEDLINE

Bruning PF, van Doorn J, Bonfrer JMG, van Noord PAH, Korse CM, Linders TC, Hart AAM. (1995). Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. Int. J. Cancer, 62: 266-270. MEDLINE

Buchhorn D. (1997). Adjusted carbohydrate exchange: Food exchanges for diabetes management corrected with glycemic index. Aust J. Nutr. Dietet., 54: 65-68.

Burke BJ, Hartog M, Heaton KW, Hooper S. (1982). Assessment of the metabolic effects of dietary carbohydrate and fibre by measuring urinary excretion of C-peptide. Hum. Nutr. Clin. Nutr., 36: 373-380.

Buyken AE, Toeller M, Heitkamp G, Karamanos B, Rottiers R, Muggeo M, Fuller JH. (2001). Glycemic index in the diet of European outpatients with type 1 diabetes: relations to glycated hemoglobin and serum lipids. Am. J. Clin. Nutr., 73: 574-581.

Caderni G, Luceri C, Lancioni L, Giannini A, Fazi M, Brighenti F, Cresci A, Orpianesi C, Dolara P. (1997). Modification of azoxymethane intestinal carcinogenesis in rats by feeding sucrose boluses, pasta and glucose. Nutr. Cancer, 28: 146-152.

Calle-Pascual AL, Gomez V, Leon E, Bordiu E. (1988). Foods with a low glycemic index do not improve glycemic control of both type 1 and type 2 diabetic patients after one month of therapy. Diabetes Metab. (Paris), 14: 629-633.

Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. (1998). Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes, 47: 290-293.

Centonze S, Boeing H, Leoci C, Guerra V, Misciangna G. (1994). Dietary habits and colorectal cancer in a low risk area. Results from a population-based case-control study in Southern Italy. Nutr. Cancer, 21: 233-246. MEDLINE

Ceriello A. (2000). Oxidative stress and glycemic regulation. Metabolism, 49: 27S-29S.

Ceriello A, Bortolotti N, Crescentini A, Motz E, Lizzio S, Russo A, Ezsol Z, Tonutti L, Taboga C. (1998a). Antioxidant defences are reduced during the oral glucose tolerance test in normal and non-insulin-dependent diabetic subjects. Eur. J. Clin. Invest., 28: 529-533.

Ceriello A, Bortolotti N, Motz E, Crescentini A, Lizzio S, Russo A, Tonutti L, Taboga C. (1998b). Meal-generated oxidative stress in type 2 diabetic patients. Diabetes Care, 21: 1529-1533.

Ceriello A, Bortolotti N, Motz E, Pieri C, Marra M, Tonutti L, Lizzio S, Feletto F, Catone B, Taboga C. (1999). Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism, 48: 1503-1508.

Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al. (1998). Plasma insulin-like growth factor-1 and prostate cancer risk: a prospective study. Science, 279: 563-566. Article MEDLINE

Chew I, Brand JC, Thorburn AW, Truswell AS. (1985). Plasma glucose and insulin resonses to mixed meals. Proc. Nutr. Soc. Aust., 10: 194.

Clarkson P, Celermajer DS, Donald AE, Sampson M, Sorensen KE, Adams M, Yue DK, Betteridge DJ, Deanfield JE. (1996). Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J. Am. Coll. Cardiol., 28: 573-579. MEDLINE

Cohen P, Peehl DM, Lamson G, Rosenfeld RG. (1991). Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J. Clin. Endocrinol. Metab., 73: 401-407. MEDLINE

Cohn C. (1964). Feeding patterns and some aspects of cholesterol metabolism. Fed. Proc., 23: 76-81.

Collett-Solberg PF, Cohen P. (1996). The role of the insulin-like growth factor binding proteins and the IGFBP proteases in modulation IGF action. Endocrinol. Metab. Clin. N. Am., 25: 591-614.

Collier GR, Wolever TMS, Wong GS, Josse RG. (1986). Prediction of glycemic response to mixed meals in noninsulin-dependent diabetic subjects. Am. J. Clin. Nutr., 44: 349-352.

Collier GR, Giudici S, Kalmusky J et al. (1988). Low glycaemic index starchy foods improve glucose control and lower serum cholesterol in diabetic children. Diab. Nutr. Metab., 1: 11-19.

Collins P, Williams C, MacDonald I. (1981). Effect of cooking on serum glucose and insulin responses to starch. Br. Med. J., 282: 1032-1033.

Cominacini L, Garbin U, Pastorino AM, Fratta Pasini A, Campagnola M, De Santis A, Davoli A, Lo Cascio V. (1994). Increased susceptibility of LDL to in vitro oxidation in patients with insulin-dependent and non-insulin-dependent diabetes mellitus. Diabetes Res., 26: 173-184.

Corpet DE, Peiffer G, Tache S. (1998). Glycemic index, nutrient density, and promotion of aberrant crypt foci in rat colon. Nutr. Cancer, 32: 29-36.

Cosentino F, Hishikawa K, Katusic ZS, Luscher TF. (1997). High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation, 96: 25-28. MEDLINE

Coulston AM, Hollenbeck CB, Swislolocki MD, Reaven GM. (1987). Effect of source of dietary carbohydrate on plasma glucose and insulin responses to mixed meals in subjects with NIDDM. Diabetes Care, 10: 395-400.

Coulston AM, Hollenbeck CB, Swislolocki MD, Reaven GM. (1989). Persistence of hypertriacylglycerolemic effect of low-fat high-carbohydrate diets in NIDDM patients. Diabetes Care, 12: 94-101.

Coutinho M, Gerstein HC, Wang Y, Yusuf S. (1999). The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 y. Diabetes Care, 22: 233-240. MEDLINE

Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ. (1998). Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res. Treat., 47: 111-120.

Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. (1996). Hyperinsulinemia as an independent risk factor for ischemic heart disease. New Engl. J. Med., 334: 952-957. MEDLINE

de Waard F, Baanders-van Halewijn EA. (1974). A prospective study in general practice on breast-cancer risk in postmenopausal women. Int. J. Cancer, 14: 153-160.

Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. (1980). Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia, 19: 205-210. MEDLINE

Edelstein SL, Barrett-Connor EL, Wingard DL, Cohn BA. (1992). Increased meal frequency associated with decreased cholesterol concentrations; Rancho Bernardo, CA, 1984-1987. Am. J. Clin. Nutr., 55: 664-669. MEDLINE

Ellinger F, Landsman H. (1944). Frequency and course of cancer in diabetics. NY State J. Med., 44: 259-265.

Ellis PR, Dawoud FM, Morris ER. (1991). Blood glucose, plasma insulin and sensory responses to guar-containing wheat breads: effects of molecular weight and particle size of guar gum. Br. J. Nutr., 66: 363-379. MEDLINE

Englyst KN, Englyst HN, Hudson GJ, Cole TJ, Cummings JH. (1999). Rapidly available glucose in foods: an in vitro measurement that reflects the glycemic response. Am. J. Clin. Nutr., 69: 448-454. MEDLINE

European Association for the Study of Diabetes. (1995). Recommendations for the nutritional management of patients with diabetes mellitus. Diab. Nutr. Metab., 8: 186-189.

Ewertz M, Gill C. (1990). Dietary factors and breast cancer risk in Denmark. Int. J. Cancer, 46: 779-784.

FAO/WHO Expert Report. Carbohydrates in human nutrition. Report of a Joint FAO/WHO Expert Consultation, Rome, 14-18 April, 1997. FAO Food and Nutrition Paper 66. Rome (1998).

FAO/WHO Report. (1998). Carbohydrate in human nutrition. Report of a Joint FAO/WHO Expert Consultation FAO Food Nutr. Pap., 66: 1-140.

Favero A, Salvini S, Russo A, Parpinel M, Negri E, Decarli A, La Vecchia C, Giacosa A, Franceschi S. (1997). Sources of macro- and micronutrients in Italian women: results from a food frequency questionnaire for cancer studies. Eur. J. Cancer Prev., 6: 277-287.

Favero A, Parpinel M, Franceschi S. (1998). Diet and risk of breast cancer: major findings from an Italian case-control study. Biomed. Pharmacother., 52: 109-115.

Foekens JA, Portengen H, Janssen M, Klijn JGM. (1989). Insulin-like growth factor-1 receptors and insulin-like growth factor 1 like activity in human primary breast cancer. Cancer, 63: 2139-2147. MEDLINE

Folsom AR, Kaye SA, Princeas RJ, Potter JD, Gapstur SM, Wallace RC. (1990). Increased incidence of carcinoma of the breast associated with abdominal adiposity in postmenopausal women. Am. J. Epidemiol., 131: 794-803. MEDLINE

Folsom AR, Kushi LH, Anderson KE, Mink PJ, Olson JE, Hong CP, Sellers TA, Lazovich D, Prineas RJ. (2000). Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study. Arch. Intern. Med., 160: 2117-2128. MEDLINE

Fontvieille AM, Acosta M, Rizkalla SW et al. (1988). A moderate switch from high to low glycaemic-index foods for 3 weeks improves the metabolic control of type I (IDDM) diabetic subjects. Diab. Nutr. Metab., 1: 139-143.

Fontvieille AM, Rizkalla SW, Penformis A, Acosta M, Bornet FRJ, Slama G. (1992). The use of low glycaemic index foods improves metabolic control of diabetic patients over five weeks. Diabet. Med., 9: 444-450.

Ford ES, Liu S. (2001). Glycemic index and serum high-density lipoprotein cholesterol concentration among US adults. Arch. Intern. Med., 161: 572-576.

Foster-Powell K, Brand Miller J. (1995). International tables of glycemic index. Am. J. Clin. Nutr., 62: 871S-893S. MEDLINE

Franceschi S. (1994). Fat and prostate cancer. Epidemiology, 5: 271-273.

Franceschi S, Favero A, La Vecchia C et al. (1995). Influence of food groups and food diversity on breast cancer risk in Italy. Int. J. Cancer, 63: 785-789.

Franceschi S, Favero A, Decarli A, Negri E, La Vecchia C, Ferraroni M, Russo A, Salvini S, Amadori D, Conti E, Montella M, Giacosa A. (1996). Intake of macronutrients and risk of breast cancer. Lancet, 347: 1351-1356. MEDLINE

Francheschi S, Favero A, La Vecchia C, Negri E, Conti E, Montella M, Giacosa A, Nanni O, Decarli A. (1997). Food groups and risk of colorectal cancer in Italy. Int. J. Cancer, 72: 56-61. Article MEDLINE

Franceschi S, La Vecchia C, Russo A, Favero A, Negri E, Conti E, Montella M, Filiberti R, Amadori D, Decarli A. (1998). Macronutrient intake and risk of colorectal cancer in Italy. Int. J. Cancer, 76: 321-324. Article MEDLINE

Franceschi S, Dal Maso L, Augustin L, Negri E, Parpinel M, Boyle P, Jenkins DJ, La Vecchia C. (2001). Dietary glycemic load and colorectal cancer risk. Ann. Oncol., 12: 173-178.

Freund E. (1885). Zur Diagnose des Carcinoms. Wien Med. Blat., 8: 268-269.

Frost G, Wilding J, Beecham J. (1994). Dietary advice based on the glycaemic index improves dietary profile and metabolic control in type 2 diabetic patients. Diabet. Med., 11: 397-401.

Frost G, Keogh B, Smith D, Akinsanya K, Leeds A. (1996). The effect of low-glycemic carbohydrate on insulin and glucose response in vivo and in vitro in patients with coronary heart disease. Metabolism, 45: 669-672. MEDLINE

Frost GS, Keogh BE, Smith D, Leeds AR, Dornhorst A. (1998). Reduced adipocyte insulin sensitivity in Caucasian and Asian subjects with coronary heart disease. Diabet. Med., 15: 1003-1009.

Frost G, Leeds AA, Dore' CJ, Madeiros S, Brading S, Dornhorst A. (1999). Glycaemic index as a determinant of serum HDL-cholesterol concentration. Lancet, 353: 1045-1048.

Galanis DJ, Kolonel LN, Lee J et al. (1998). Anthropometric predictors of breast cancer incidence and survival in a multi-ethnic cohort of female residents of Hawaii. United States. Cancer Causes Control, 9: 217-224. MEDLINE

Gann PH, Daviglus ML, Dyer AR, Stamler J. (1995). Heart rate and prostate cancer mortality: results of a prospective analysis. Cancer Epidemiol. Biomarkers Prev., 4: 611-616.

Gannon MC, Nuttall FQ, Neil BJ, Westphal SA. (1988). The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects. Metabolism, 37: 1081-1088.

Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen YD, Grundy SM, Huet BA et al. (1994). Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. JAMA, 271: 1421-1428. MEDLINE

Gerstein HC, Yusuf S. (1996). Dysglycaemia and risk of cardiovascular disease. Lancet, 347: 949-950.

Giacco R, Parillo M, Rivellese AA, Lasorella G, Giacco A, D'Episcopo L, Riccardi G. (2000). Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care, 23: 1461-1466.

Gilbertson HR, Brand-Miller JC, Thorburn AW, Evans S, Chondros P, Werther GA. (2001). The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes. Diabetes Care, 24: 1137-1143.

Giovannucci E. (1995). Insulin and colon cancer. Cancer Causes Control, 6: 164-179.

Giovannucci E. (1999). Insulin-like growth factor-1 and binding protein-3 and risk of cancer. Horm. Res., 51: ((Suppl 3)) 34-41.

Giovannucci E, Stampfer MJ, Colditz G, Rimm EB, Willett WC. (1992). Relationship of diet to risk of colorectal adenoma in men. J. Natl Cancer Inst., 84: 91-98.

Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. (1995). Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann. Inern. Med., 122: 327-334.

Giovannucci E, Rimm EB, Stampfer MJ et al. (1997). Height, body weight, and risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev., 6: 557-663.

Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. (1998). Diabetes mellitus and risk of prostate cancer (United States). Cancer Causes Control, 9: 3-9.

Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE. (2000). A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol. Biomarkers Prev., 9: 345-349.

Golay A, Bobbioni E. (1997). The role of dietary fat in obesity. Int. J. Obes. Relat. Metab. Disord., 21: S2-S11. MEDLINE

Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. (1989). High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation, 79: 8-15. MEDLINE

Graier WF, Simecek S, Kukovetz WR, Kostner GM. (1996). High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. Diabetes, 45: 1386-1395.

Green A, Jensen OM. (1985). Frequency of cancer among insulin-treated diabetic patients in Denmark. Diabetologia, 28: 128-130.

Haber GB, Heaton KW, Murphy D, Burroughs LF. (1977). Depletion and disruption of dietary fibre. Effects on satiety, plasma-glucose, and serum-insulin. Lancet, 2: 679-682. MEDLINE

Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM. (1996). Targeted expression of des (1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression. Endocrinology, 137: 321-330. MEDLINE

Haenszel W, Locke FB, Segi M. (1980). A case-control study of large bowel cancer in Japan. J. Natl Cancer Inst., 64: 17-22.

Hankinson S, Pollak M, Michaud D, Willett W, Speizer Fthe Nurses' Health Study Research Group. (1997). A prospective assessment of plasma insulin-like growth factor levels and breast cancer risk. Am. J. Epidemiol., 145: S72.

Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. (1998). Circulating concentrations of insulin-like growth factor-1 and risk of breast cancer. Lancet, 351: 1393-1396. Article MEDLINE

Hardardottir I, Grunfeld C, Feingold KR. (1994). Effects of endotoxin and cytokines on lipid metabolism. Curr. Opin. Lipidol., 5: 207-215. MEDLINE

Hardell L, Fredrikson M, Axelson O. (1996). Case-control study on colon cancer regarding previous disease and drug intake. Int. J. Oncol., 8: 439-444.

Hebert PR, Ajani U, Cook NR, Lee I-M, Chan KS, Hennekens CH. (1997). Adult height and incidence of cancer in male physicians (United States). Cancer Causes Control, 8: 591-597.

Heilbronn LK, Noakes M, Clifton PM. (1999). Effect of energy restriction, weight loss, and diet composition on plasma lipids and glucose in patients with type 2 diabetes. Diabetes Care, 22: 889-895.

Helle SI, Lonning PE. (1996). Insulin-like growth factors in breast cancer. Acta Oncol., 35: ((Suppl 5)) 19-22.

Ho GH, Ji CY, Phang BH, Lee KO, Soo KC, Ng EH. (1998). Tamoxifen alters levels of serum insulin-like growth factors and binding proteins in postmenopausal breast cancer patients: a prospective paired cohort study. Ann. Surg. Oncol., 5: 361-367.

Hoff G, Moen IE, Trygg K et al. (1986). Epidemiology of polyps in the rectum and sigmoid colon. Evaluation of nutritional factors. Scand. J. Gastroenterol., 21: 199-204.

Hokanson JE, Austin MA. (1996). Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J. Cardiovasc. Risk., 3: 213-219. MEDLINE

Holt SH, Miller JB. (1994). Particle size, satiety and the glycaemic response. Eur. J. Clin. Nutr., 48: 496-502. MEDLINE

Holt S, Brand J, Soveny C, Hansky J. (1992). Relationship of satiety to postprandial glycaemic, insulin and cholecystokinin responses. Appetite, 18: 129-141.

Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, Speizer FE, Giovannucci E. (1999). Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J. Natl Cancer Inst., 91: 542-547.

Huff KK, Kaufman D, Gabbay KH, Spencer EM, Lippman ME, Dickson RB. (1986). Secretion of an insulin-like growth factor-1-related protein by human breast cancer cells. Cancer Res., 46: 4613-4619.

Hunter DJ, Willett WC. (1993). Diet, body size and breast cancer. Epidemiol. Rev., 15: 110-132. MEDLINE

Hyka N, Dayer JM, Modoux C, Kohno T, Edwards CK III, Roux-Lombard P, Burger D. (2001). Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood, 97: 2381-2389. Article MEDLINE

Illman RJ, Topping DL, McIntosh GH, Trimble RP, Storer GB, Taylor MN, Cheng BQ. (1988). Hypocholesterolemic effects of dietary propionate: studies in whole animals and perfused rat liver. Ann. Nutr. Metab., 32: 95-107.

Ingram DM, Nottage E, Roberts T. (1991). The role of diet in the development of breast cancer: a case-control study of patients with breast cancer, benign epithelial hyperplasia and fibrocystic disease of the breast. Br. J. Cancer, 64: 187-191.

Iscovich JM, Iscovich RB, Howe J et al. (1989). A case-control study of diet and breast cancer in Argentina. Int. J. Cancer, 44: 770-777.

Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO. (1999). Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low-glycemic index diet in type 2 diabetic patients. Diabetes Care, 22: 10-18. MEDLINE

Jenkins AJ, Dlein RL, Chassereau CN, Hermayer KL, Lopes-Virella MF. (1996). LDL from patients with well-controlled IDDM is not more susceptible to in vitro oxidation. Diabetes, 45: 762-767.

Jenkins DJA, Wolever TMS, Leeds AR et al. (1978). Dietary fibers, fiber analogues, and glucose tolerance: importance of viscosity. Br. Med. J., 1: 1392-1394. MEDLINE

Jenkins DJA, Wolever TMS, Taylor RH et al. (1981). Glycemic index of foods: a physiological basis for carbohydrate exchange. Am. J. Clin. Nutr., 34: 362-366. MEDLINE

Jenkins DJA, Wolever TMS, Jenkins AL, Josse RG, Wong GS. (1984). The glycemic response to carbohydrate foods. Lancet, 2: 388-391.

Jenkins DJA, Thorne MJ, Wolever TMS, Jenkins AL, Rao AV, Thompson LU. (1987a). The effect of starch-protein interaction in wheat on the glycemic response and rate of in vitro digestion. Am. J. Clin. Nutr., 45: 946-951.

Jenkins DJA, Wolever TMS, Collier GR et al. (1987b). Metabolic effects of a low-glycemic-index diet. Am. J. Clin. Nutr., 46: 968-975. MEDLINE

Jenkins DJA, Wolever TMS, Kalmusky J, Giudici S, Giordano C, Patten R, Wong GS et al. (1987c). Low-glycemic index diet in hyperlipidemia: use of traditional starchy foods. Am. J. Clin. Nutr., 46: 66-71. MEDLINE

Jenkins DJA, Wesson V, Wolever TMS et al. (1988a). Wholemeal versus wholegrain breads: proportion of whole or cracked grain and the glycaemic response. Br. Med. J., 297: 958-960.

Jenkins DJA, Wolever TMS, Buckley G et al. (1988b). Low glycemic index starchy foods in the diabetic diet. Am. J. Clin. Nutr., 48: 248-254.

Jenkins DJA, Wolever TMS, Vuksan V et al. (1989). Nibbling versus gorging: metabolic advantages of increased meal frequency. New Engl. J. Med., 321: 929-934. MEDLINE

Jenkins DJ, Wolever TM, Ocana AM, Vuksan V, Cunnane SC, Jenkins M, Wong GS, Singer W, Bloom SR, Blendis LM et al. (1990). Metabolic effects of reducing rate of glucose ingestion by single bolus versus continuous sipping. Diabetes, 39: 775-781.

Jenkins DJA, Ocana A, Jenkins AL et al. (1992). Metabolic advantages of spreading the nutrient load: effects of meal frequency in non-insulin-dependent diabetes. Am. J. Clin. Nutr., 55: 461-467.

Jenkins DJA, Wolever TMS, Rao AV, Hegele RA, Mitchell SJ, Ransom TPP, Boctor DL et al. (1993). Effect on blood lipids of very high intakes of fiber in diets low in saturated fat and cholesterol. New Engl. J. Med., 329: 21-26.

Jenkins DJA, Khan A, Jenkins AL et al. (1995). Effect of nibbling versus gorging on cardiovascular risk factors: serum uric acid and blood lipids. Metabolism, 44: 549-555.

Jenkins DJ, Jenkins AL. (1995). Nutrition principles and diabetes. A role for "lente carbohydrate"? Diabetes Care, 18: 1491-1498. MEDLINE

Jenkins DJ, Axelsen M, Kendall CWC, Augustin LSA, Vuksan V, Smith U. (2000). Dietary fiber, lente carbohydrates and the insulin resistant diseases. Br. J. Nutr., 83: S157-S163.

Jones JI, Clemmons DR. (1995). Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev., 16: 3-34. MEDLINE

Jones PJ, Leitch CA, Pederson RA. (1993). Meal frequency effects of plasma hormone concentrations and cholesterol synthesis in humans. Am. J. Clin. Nutr., 57: 868-874.

Juhan-Vague I, Alessi MC, Joly P et al. (1989). Plasma plasminogen activator inhibitor-1 in angina pectoris: influence of plasma insulin and acute-phase response. Arteriosclerosis, 9: 362-367.

Kaaks R. (1996). Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control, 7: 605-625.

Kaaks R, Van Noord PA, DenTonkelaar I et al. (1998). Breast cancer incidence in relation to height, body-fat distribution in the Dutch 'DOM' cohort. Int. J. Cancer, 76: 647-651. Article MEDLINE

Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS. (1999). Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J. Clin. Oncol., 17: 3291-3298.

Kanety H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C et al. (1993). Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J. Clin. Endocrinol. Metab., 77: 229-233.

Katsouyanni K, Willett W, Trichopoulos D, Boyle P, Trichopoulou A, Vasilaros S, Papadiamantis J, MacMahon B. (1988). Risk of breast cancer among Greek women in relation to nutrient intake. Cancer, 61: 181-185.

Katsouyanni K, Trichopoulou A, Stuver S, Garas Y, Kritselis A, Kyriakou G, Stoikidou M, Boyle P, Trichopoulos D. (1994). The association of fat and other macronutrients with breast cancer: a case-control study from Greece. Br. J. Cancer, 70: 537-541.

Katsuki A, Sumida Y, Murashima S, Fujii M, Ito K et al. (1996). Acute and chronic regulation of serum sex hormone-binding globulin levels by plasma insulin concentrations in male non-insulin-dependent diabetes mellitus patients. J. Clin. Endocrinol. Metab., 81: 2515-2519.

Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. (1999). Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J. Am. Coll. Cardiol., 34: 146-154.

Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Boone CW, Malone WA, Hawk ET, Lieberman R, Lawrence JA, Kopelovich L, Ali I, Viner JL, Sigman CC. (1999). Progress in cancer chemoprevention. Ann. NY Acad. Sci., 889: 1-13.

Kessler II. (1970). Cancer mortality among diabetics. J. Natl Cancer Inst., 44: 673-686.

Kimura G, Kasuya J, Giannini S, Honda Y, Mohan S, Kawachi M et al. (1996). Insulin-like growth factor (IGF) system components in human prostate cancer cell-lines: LNCaP, DU145, and PC-3 cells. Int. J. Urol., 3: 39-46.

Koenuma M, Yamori T, Tsuruo T. (1989). Insulin and insulin-like growth factor 1 stimulate proliferation of metastatic variants of colon carcinoma 26. Jpn. J. Cancer Res., 80: 51-58.

Kono S, Honjo S, Todoroki I, Nishiwaki M, Hamada H, Nishikawa H, Koga H, Ogawa S, Nakagawa K. (1998). Glucose intolerance and adenomas of the sigmoid colon in Japanese men (Japan). Cancer Causes Control, 9: 441-446.

Koska J, Syrova D, Blazicek P, Marko M, Grna DJ, Kvetnansky R, Vigas M. (1997). Activity of antioxidant enzymes during hyperglycemia and hypoglycemia in healthy subjects. Ann. NY Acad. Sci., 82: 575-579.

Kritchevsky D, Story JA. (1974). Binding of bile salts in vitro by nonnutritive fiber. J. Nutr., 104: 458-462.

Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. (1994). Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA, 20: 205-211.

Kune GA, Kune S, Watson LF. (1988). Colorectal cancer risk, chronic illnesses, operations and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res., 48: 4399-4404.

Lafrance L, Rabasa-Lhoret R, Poisson D, Ducros F, Chiasson JL. (1998). Effects of different glycaemic index foods and dietary fibre intake on glycaemic control in type 1 diabetic patients on intensive insulin therapy. Diabet Med., 15: 972-978.

Lahm H, Suardet L, Laurent PL et al. (1992). Growth regulation and co-stimulation of human colorectal cancer cell lines by insulin-like growth factor I, II and transforming growth factor alpha. Br. J. Cancer, 65: 341-346.

Lakka HM, Lakka TA, Tuomilehto J, Sivenius J, Salonen JT. (2000). Hyperinsulinemia and the risk of cardiovascular death and acute coronary and cerebrovascular events in men. Arch. Intern. Med., 160: 1160-1168.

La Vecchia C, Negri E, Decarli A et al. (1988). A case-control study of diet and colorectal cancer in Northern Italy. Int. J. Cancer, 41: 492-498.

La Vecchia C, D'Avanzo B, Negri E, Franceschi S. (1991). History of selected diseases and the risk of colorectal cancer. Eur. J. Cancer, 27: 582-586.

La Vecchia C, Franceschi S, Dolora P, Bidoli E. (1993). Refined sugar intake and the risk of colorectal cancer in humans. Int. J. Cancer, 55: 386-389.

La Vecchia C, Negri E, Franceschi S, D'Avanzo B, Boyle P. (1994). A case-control study of diabetes mellitus and cancer risk. Br. J. Cancer, 70: 950-953. MEDLINE

La Vecchia C, Negri E, Decarli A, Franceschi S. (1997). Diabetes mellitus and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev., 6: 1007-1010.

Leathwood P, Pollet P. (1988). Effects of slow release carbohydrates in the form of bean flakes on the evolution of hunger and satiety in man. Appetite, 10: 1-11. MEDLINE

Le Floch JP, Baudin E, Escuyer P, Wirquin E, Yomtov B, Perlemuter L. (1991). Reproducibility of glucose and insulin responses to mixed meal in type II diabetic patients. Diabetes Care, 14: 138-140.

Le Marchand L, Wilkens LR, Kolonel LN et al. (1997). Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res., 57: 4787-4794.

Lenfant C, Ernst N. (1994). Daily dietary fat and total food-energy intakes¾Third National Health and Nutrition Examination Survey, Phase 1, 1988-1991. Morbid. Mortal. Weekly Rep., 43: 116-117.

Levi F, La Vecchia C, Gulie C et al. (1993). Dietary factors and breast cancer risk in Vaud, Switzerland. Nutr. Cancer, 19: 327-335.

Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF Jr, Vita JA. (1996). Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation, 93: 1107-1113.

Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J. (1990). Post-load plasma glucose and cancer mortality in middle-aged men and women. 12-year follow-up findings of the Chicago Heart Association Detection Project in Industry. Am. J. Epidemiol., 131: 254-262.

Li BD, Khosravi MJ, Berkel HJ, Diamandi A, Dayton MA, Smith M, Yu H. (2001). Free insulin-like growth factor-1 and breast cancer risk. Int. J. Cancer, 91: 736-739.

Liljeberg HG, Akerberg AK, Bjorck IM. (1999). Effect of the glycemic index and content of indigestible carbohydrates of cereal-based breakfast meals on glucose tolerance at lunch in healthy subjects. Am. J. Clin. Nutr., 69: 647-655. MEDLINE

Liu S, Willett WC, Stampfer MJ, Hu FB, Franz M, Sampson L, Hennekens CH, Manson JE. (2000). A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am. J. Clin. Nutr., 71: 1455-1461. MEDLINE

Lotufo PA, Gaziano JM, Chae CU, Ajani UA, Moreno-John G, Buring JE, Manson JE. (2001). Diabetes and all-cause and coronary heart disease mortality among US male physicians. Arch. Intern. Med., 161: 242-247.

Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, Roberts SB. (1999). High glycemic index foods, overeating, and obesity. Pediatrics, 103: E26.

Lund Nilsen TI, Vatten LJ. (2001). Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinemia hypothesis. Br. J. Cancer, 84: 417-422.

Luscombe ND, Noakes M, Clifton PM. (1999). Diets high and low in glycemic index versus high monounsaturated fat diets: effects on glucose and lipid metabolism in NIDDM. Eur. J. Clin. Nutr., 53: 473-478. Article MEDLINE

Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ. (1999). Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J. Natl Cancer Inst., 91: 620-625. MEDLINE

Macquart-Moulin G, Riboli E, Cornee J et al. (1986). Case-control study on colorectal cancer and diet in Marseilles. Int. J. Cancer, 38: 183-191.

Macquart-Moulin G, Riboli E, Cornee J, Charnay B, Berthezene P, Day N. (1987). Colorectal polyps and diet: a case-control study in Marseille. Int. J. Cancer, 40: 179-188.

Madigan MP, Troisi R, Potischman N et al. (1998). Serum hormone levels in relation to reproductive and lifestyle factors in post-menopausal women (United States). Cancer Causes Control, 9: 199-207. MEDLINE

Malle E, Steinmetz A, Raynes JG. (1993). Serum amyloid A (SAA): an acute phase protein and apolipoprotein. Atherosclerosis, 102: 131-146.

Manjer J, Kaaks R, Riboli E, Berglund G. (2001). Risk of breast cancer in relation to anthropometry, blood pressure, blood lipids and glucose metabolism: a prospective study within the Malmo Preventive Project. Eur. J. Cancer. Prev., 10: 33-42.

Manousos O, Day NE, Trichopoulos D, Gerovassilis F, Tzonou A, Polychronopoulou A. (1983). Diet and colorectal cancer: a case-control study in Greece. Int. J. Cancer, 32: 1-5.

Manousos O, Souglakos J, Bosetti C et al. (1999). IGF-1 and IGF-1I in relation to colorectal cancer. Int. J. Cancer, 83: 15-17.

Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO. (1997). Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br. J. Cancer, 76: 1115-1118. MEDLINE

Marble A. (1934). Diabetes and cancer. New Engl. J. Med., 211: 339-349.

Maxwell SR, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GH, Jones AF, Barnett AH. (1997). Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur. J. Clin. Invest., 27: 484-490.

McKeown-Eyssen G. (1994). Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol. Biomarkers Prev., 3: 687-695.

Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D'Agostino RB, Wilson PW. (2000). Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA, 283: 221-228.

Mensink RP, Katan MB. (1987). Effect of monounsaturated fatty acids versus complex carbohydrates on high-density lipoproteins in healthy men and women. Lancet, 1: 122-125. MEDLINE

Meyer KA, Kushi LH, Jacobs DR, Slavin J, Sellers TA, Folsom AR. (2000). Carbohydrates, dietary fiber, and incident type 2 diabetes in older women. Am. J. Clin. Nutr., 71: 921-930.

Miglietta L, Barreca A, Repetto L, Costantini M, Rosso R, Boccardo F. (1993). Suramin and serum insulin-like growth factor levels in metastatic cancer patients. Anticancer Res., 13: 2473-2476.

Miller AB, Howe GR, Jain M, Craib KJ, Harrison L. (1983). Food items and food groups as risk factors in a case-control study of diet and colorectal cancer. Int. J. Cancer, 32: 155-161.

Muck BR, Trotnow S, Hommel G. (1975). Cancer of the breast, diabetes and pathological glucose tolerance. Arch. Gynak., 220: 73-81.

Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. (1999). The disease burden associated with overweight and obesity. JAMA, 282: 1523-1529. MEDLINE

Nabarro JD. (1987). Acromegaly. Clin. Endocrinol. (Oxf)., 26: 481-512.

Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG. (1991). A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 72: 83-89.

Neugut AI, Garbowski GC, Lee WC, Murray T, Nieves JW, Forde KA, Treat MR, Waye JD , Fenoglio Preiser C. (1993). Dietary risk factors for the incidence and recurrence of colorectal adenomatous polyps: a case-control study. Ann. Intern. Med., 118: 91-95.

Newcomb PA, Klein R, Klein BE et al. (1995). Association of dietary and life-style factors with sex hormones in postmenopausal women. Epidemiology, 6: 318-321.

Ng ST, Zhou J, Adesanya OO, Wang J, LeRoith D, Bondy CA. (1997). Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nat. Med., 3: 1141-1144. MEDLINE

Nicklas TA. (1995). Dietary studies of children: the Bogalusa Heart Study experience. J. Am. Diet. Assoc., 95: 417-418.

Nijpels G. (1998). Determinants for the progression from impaired glucose tolerance to non-insulin-dependent diabetes mellitus. Eur. J. Clin. Invest., 28: ((Suppl 2)) 8-13.

Norrish AE, McRae CU, Holdaway IM, Jackson RT. (2000). Height-related risk factors for prostate cancer. Br. J. Cancer, 82: 241-245.

Nuttall FQ, Mooradian AD, Gannon MC, Billington C, Krezowscki P. (1984). Effect of protein ingestion on the glucose and insulin response to a standardized oral glucose load. Diabetes Care, 7: 465-470.

O'Mara BA, Byers T, Schoenfeld E. (1985). Diabetes mellitus and cancer risk: a multisite case-control study. J. Chron. Dis., 38: 435-441.

O'Riordain MG, Ross JA, Fearon KC, Maingay J, Farouk M, Garden OJ, Carter DC. (1995). Insulin and counterregulatory hormones influence acute-phase protein production in human hepatocytes. Am. J. Physiol., 269: ((2 Pt 1)) E323-330.

Orme SM, McNally RJ, Cartwright RA, Belchetz PE. (1996). Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J. Clin. Endocrinol. Metab., 83: 2730-2734.

Paolisso G, Giugliano D, Pizza G, Gambardella A, Tesauro P, Varricchio M, D'Onofrio F. (1992). Glutathione infusion potentiates glucose-induced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care, 15: 1-7.

Paolisso G, D'Amore A, Giugliano D et al. (1993). Pharmacological doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am. J. Clin. Nutr., 57: 650-656.

Paolisso G, D'Amore A, Balbi V et al. (1994). Plasma vitamin C affects glucose homeostasis in healthy subjects and non¾insulin-dependent diabetics. Am. J. Physiol., 266: E261-E268.

Pasquali R, Casimirri F, De Iasio R, Mesini P, Boschi S et al. (1995). Insulin regulates testosterone and sex hormone binding-globulin concentrations in adult normal-weight and obese men. J. Clin. Endocrinol. Metab., 80: 654-658.

Peters RK, Pike MC, Garabrant D, Mack TM. (1992). Diet and colon cancer in Los Angeles County, California. Cancer Causes Control, 3: 457-473. MEDLINE

Peyrat JP, Bonneterre J, Hecquet B, Vennin P, Louchez MM, Fournier C, Lefebvre J, Demaille A. (1993). Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer. Eur. J. Cancer, 29A: 492-497. MEDLINE

Piatti PM, Monti LD, Pacchioni M, Pontiroli AE, Pozza G. (1991). Forearm insulin- and non-insulin-mediated glucose uptake and muscle metabolism in man: role of free fatty acids and blood glucose levels. Metabolism, 40: 926-933.

Pickle LW, Greene MH, Ziegler RG, Toledo A, Hoover R, Lynch HT, Fraumeni JF Jr. (1984). Colorectal cancer in rural Nebraska. Cancer Res., 44: 363-369.

Pilichowska M, Kimua N, Fujiwara H, Nagura H. (1997). Immunohistochemical study of TGF-alpha, TGF-beta1, EGFR and IGF-1 expression in human breast carcinoma. Mod. Pathol., 10: 969-975. MEDLINE

Plymate SR, Matej LA, Jones RE, Friedl KE. (1988). Inhibition of sex hormone binding-globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J. Clin. Endocrinol. Metab., 67: 460-464. MEDLINE

Plymate SR, Hoop RC, Jones RE, Mtej LA. (1990). Regulation of sex hormone-binding globulin production by growth factors. Metabolism, 39: 967-970.

Polychronakos C, Janthly U, Lehoux JG, Koutsilieris M. (1991). Mitogenic effects of insulin and insulin-like growth factors on PA-III rat prostate adenocarcinoma cells: characterization of the receptors involved. Prostate, 19: 313-321.

Potter JD, Slattery ML, Bostick RM, Gapstur SM. (1993). Colon cancer: a review of the epidemiology. Epidemiol. Rev., 15: 499-545.

Prewitt TE, Unterman TG, Glick R, Cole TG, Schmeisser D, Bowen PE, Langenberg P. (1992). Insulin-like growth factor I and low-density-lipoprotein cholesterol in women during high- and low-fat feeding. Am. J. Clin. Nutr., 55: 381-384.

Pyorala K, Savolainen E, Kaukola S, Haapakoski J. (1985). Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9 1/2-year follow-up of the Helsinki policemen study population. Acta. Med. Scand., 701: 38-52.

Ragozzino M, Melton LJ III, Chu C-P, Palumbo PJ. (1982). Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. J. Chron. Dis., 35: 13-19.

Rajah R, Valentinis B, Cohen P. (1997). Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53 and IGF-1 independent mechanism. J. Biol. Chem., 272: 12181-12188. MEDLINE

Rao AV, Agarwal S. (1999). Role of lycopene as antioxidant carotenoid in the prevention of chronic diseases: a review. Nutr. Res., 19: 305-323.

Rea RL, Thompson LU, Jenkins DJA. (1985). Lectins in foods and their relation to starch digestibility. Nutr. Res., 5: 919-929.

Reaven GM. (1993). Role of insulin resistance in human disease (syndrome X): an expanded definition. A. Rev. Med., 44: 121-131.

Remacle-Bonnet MM, Garrouste FL, Heller S, Andre F, Marvaldi JL, Pommier GJ. (2000). Insulin-like growth factor-1 protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. Cancer Res., 60: 2007-2017. MEDLINE

Renehan AG, Painter JE, Atkin WS, Potten CS, Shalet SM, O'Dwyer ST. (2001). High-risk colorectal adenomas and serum insulin-like growth factors. Br. J. Surg., 88: 107-113.

Rodin J, Reed D, Jamner L. (1988). Metabolic effects of fructose and glucose: implications for food intake. Am. J. Clin. Nutr., 47: 683-689.

Rodwell VW, Nordstrom JL, Mitschelen JJ. (1976). Regulation of HGM-CoA reductase. Adv. Lipid. Res., 14: 1-76.

Rohan TE, McMichael AJ, Baghurst PA. (1988). A population-based case-control study of diet and breast cancer in Australia. Am. J. Epidemiol., 128: 478-489.

Rohan TE, Howe GR, Friedenreich CM et al. (1993). Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study. Cancer Causes Control, 4: 29-37. MEDLINE

Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni JF Jr. (1992). Acromegaly and gastrointestinal cancer. [Published erratum appears in Cancer 1992; 69: 549.]. Cancer, 68: 1673-1677.

Rossner S. (1978). Further studies on serum lipoproteins in connective tissue diseases. Atherosclerosis, 31: 93-99.

Ruige JB, Assendelft WJ, Dekker JM, Kostense PJ, Heine RJ, Bouter LM. (1998). Insulin and risk of cardiovascular disease: a meta-analysis. Circulation, 97: 996-1001.

Salmeron J, Ascherio A, Rimm EB et al. (1997a). Dietary fiber, glycemic load, and risk of NIDDM in men. Diabetes Care, 20: 545-550. MEDLINE

Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. (1997b). Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. JAMA, 277: 472-477. MEDLINE

Sanchez-Quesada JL, Perez A, Caixas A, Ordonmez-Llanos J, Carreras G, Payes A, Gonzalez-Sastre F, de Leiva A. (1996). Electronegative low density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control. Diabetologia, 39: 1469-1476.

Sandler RS, Lyles CM, Peipins LA, McAuliffe CA, Woosley JT, Kupper LL. (1993). Diet and risk of colorectal adenomas: macronutrients, cholesterol and fiber. J. Natl Cancer Inst., 85: 884-891.

Santini SA, Marra G, Giardina B, Cotroneo P, Mordente A, Martorana GE, Manto A, Ghirlanda G. (1997). Defective plasma antioxidant defenses and enhanced susceptibility to lipid peroxidation in uncomplicated IDDM. Diabetes, 46: 1853-1858.

Sartor O, Cooper MR, Khleif SN, Myers CE. (1994). Suramin decreases circulating levels of insulin-like growth factor-1. Am. J. Med., 96: 390.

Schafer O. (1934). Carcinom und Diabetes (Inaugural Dissertation). Druckerei-Verlag Hans Rosler, Augsburg.

Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman M, Tracy RP, Dobs A, Savage PJ. (1999). Increased blood glucose and insulin, body size, and incident colorectal cancer. J. Natl Cancer Inst., 91: 1147-1154.

Seely S, Horrobin DF. (1983). Diet and breast cancer: the possible connection with sugar consumption. Med. Hypotheses, 11: 319-327.

Sell C, Rubini M, Rubin R, Liu J-P, Efstratiadis A, Baserga R. (1993). Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc. Natl Acad. Sci. USA, 90: 11217-11221. MEDLINE

Sellers TA, Kushi LH, Potter JD, Kaye SA, Nelson CL, McGovern PG et al. (1992). Effect of family history, body-fat distribution, and reproductive factors on the risk of postmenopausal breast cancer. New Engl. J. Med., 326: 1323-1329.

Sellers TA, Anderson KE, Olson JE, Folsom AR. (1998). Family histories of diabetes mellitus and breast cancer and incidence of postmenopausal breast cancer. Epidemiology, 9: 102-105.

Severson RK, Nomura AMY, Grove JS, Stemmermann GN. (1989). A prospective analysis of physical activity and cancer. Am. J. Epidemiol., 130: 522-529. MEDLINE

Sharma A, Kharb S, Chugh SN, Kakkar R, Singh GP. (2000). Evaluation of oxidative stress before and after control of glycemia and after vitamin E supplementation in diabetic patients. Metabolism, 49: 160-162.

Singh A, Hamilton-Fairley D, Koistinen R, Seppala M, James VHT et al. (1990). Effects of insulin-like growth factor-type I (IGF-1) and insulin on the secretion of sex hormone-binding globulin and IGF-1 binding protein (IBP-I) by human hepatoma cells. J. Endocrinol., 124: R1-R3.

Sites CK, Toth MJ, Cushman M, L'Hommedieu GD, Tchernof A, Tracy RP, Poehlman ET. (2002). Menopause-related differences in inflammation markers and their relationship to body fat distribution and insulin-stimulated glucose disposal. Fertil. Steril., 77: 128-135.

Skyrme-Jones RA, O'Brien RC, Berry KL, Meredith IT. (2000). Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. J. Am. Coll. Cardiol., 36: 94-102.

Slattery ML, Schumacher MC, Smith KR et al. (1988). Physical activity, diet and risk of colon cancer in Utah. Am. J. Epidemiol., 128: 989-999.

Slattery ML, Benson J, Berry TD, Duncan D, Edwards SL, Caan BJ, Potter JD. (1997). Dietary sugar and colon cancer. Cancer Epidemiol. Biomark. Prev., 6: 677-685.

Smith GD, Egger M, Shipley MJ, Marmot MG. (1992). Post-challenge glucose concentration, impaired glucose tolerance, diabetes and cancer mortality in men. Am. J. Epidemiol., 136: 1110-1114.

Stamler J, Vaccaro O, Neaton JD, Wentworth D. (1993). Diabetes, other risk factors, and 12-yr cardiovascular mortality in men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care, 16: 434-444. MEDLINE

Stampfer MJ, Krauss RM, Ma J et al. (1996). A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA, 276: 882-888. MEDLINE

Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. (2000). Primary prevention of coronary heart disease in women through diet and lifestyle. New Engl. J. Med., 343: 16-22.

Steenland K, Nowlin S, Palu S. (1995). Cancer incidence in the National Health and Nutrition Examination Survey I follow-up data: diabetes, cholesterol, pulse, and physical activity. Cancer Epidemiol. Biomarkers Prev., 4: 807-811. MEDLINE

Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. (2000). Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. Br. Med. J., 321: 405-412.

Swanson CA, Jones DY, Schatzkin A, Brinton LA, Ziegler RG. (1988). Breast cancer risk assessed by anthropometry in the NHANES I epidemiological follow-up study. Cancer Res., 48: 5363-5367.

Talamini R, La Vecchia C, Decarli A, Negri E, Franceschi S. (1986). Nutrition, social factors and prostatic cancer in a Northern Italian population. Br. J. Cancer, 53: 817-821.

Talamini R, Franceschi S, La Vecchia C, Serraino D, Barra S, Negri E. (1992). Diet and prostatic cancer: a case-control study in northern Italy. Nutr. Cancer, 18: 277-286.

Talamini R, Franceschi S, Favero A, Negri E, Parazzini F, La Vecchia C. (1997). Selected medical conditions and risk of breast cancer. Br. J. Cancer, 75: 1699-1703. MEDLINE

Tesfamariam B, Cohen RA. (1992). Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am. J. Physiol., 263: H321-H326.

The Diabetes Control and Complications Trial Research Group. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl. J. Med., 329: 977-986.

Thompson D, Harrison SP, Evans SW, Whicher JT. (1991). Insulin modulation of acute-phase protein production in a human hepatoma cell line. Cytokine, 3: 619-626.

Thompson LU, Yoon JH, Jenkins DJA, Wolever TMS, Jenkins AL. (1984). Relationship between polyphenol intake and blood glucose response of normal and diabetic individuals. Am. J. Clin. Nutr., 39: 745-751.

Thrasher JB, Tennant MK, Twomey PA, Hansberry KL, Wettlaufer JN, Plymate SR. (1996). Immunohistochemical localization of insulin-like growth factor binding proteins 2 and 3 in prostate tissue: clinical correlations. J. Urol., 155: 999-1003.

Title LM, Cummings PM, Giddens K, Nassar BA. (2000). Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J. Am. Coll. Cardiol., 36: 2185-2191.

Toniolo P, Riboli E, Protta F, Charrel M, Cappa AP. (1989). Calorie-providing nutrients and risk of breast cancer. J. Natl Cancer Inst., 81: 278-286.

Tornberg SA, Holm LE, Carstensen JM. (1988). Breast cancer risk in relation to serum cholesterol, serum beta-lipoprotein, height, weight, and blood pressure. Acta Oncol., 27: 31-37.

Torring N, Vinter-Jensen L, Pedersen SB, Sorensen FB, Flyvbjerg A, Nexo E. (1997). Systemic administration of insulin-like growth factor I (IGF-1) causes growth of the rat prostate. J. Urol., 158: 222-227.

Tran TT, Medline A, Bruce RW. (1996). Insulin promotion of colon tumors in rats. Cancer Epidemiol. Biomarkers Prev., 5: 1013-1015.

Trentham-Dietz A, Newcomb PA, Storer BE et al. (1997). Body size and risk of breast cancer. Am. J. Epidemiol., 145: 1011-1019. MEDLINE

Tretli S. (1989). Height and weight in relation to breast cancer morbidity and mortality: a prospective study of 570,000 women in Norway. Int. J. Cancer, 44: 23-30. MEDLINE

Trinkler N. (1890). Ueber die diagnostische Verwertung des Gehaltes an Zucker und reducirender Substanz im Blute vom Menschen bei verschiedenen Krankheiten. Zbl. Med. Wissen, 28: 498-499.

Truswell AS. (1992). Glycaemic index of foods. Eur. J. Clin. Nutr., 46: ((Suppl 2)) S91-S101.

Tsai EC, Hirsch IB, Brunzell JD, Chait A. (1994). Reduced plasma peroxyl radical trapping capacity and increased susceptibility of LDL to oxidation in poorly controlled IDDM. Diabetes, 43: 1010-1014. MEDLINE

Tuyns AJ, Haelterman M, Kaaks R. (1987). Colorectal cancer and the intake of nutrients: oligosaccharides are a risk factor, fats are not. A case-control study in Belgium. Nutr. Cancer, 10: 181-196.

Tymchuk CN, Tessler SB, Aronson WJ, Barnard RJ. (1998). Effects of diet and exercise on insulin, sex hormone-binding globulin, and prostate-specific antigen. Nutr. Cancer, 31: 127-131. MEDLINE

UK Prospective Diabetes Study Group. (1998). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDA 33). Lancet, 352: 837-852.

Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E et al. (1986). Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J., 5: 2503-2512. MEDLINE

Underwood LE. (1996). Nutritional regulation of IGF-1 and IGFBPs. J. Pediat. Edocrinol. Metab., 9: 303-312.

van Amelsvoort JM, Weststrate JA. (1992). Amylose-amylopectin ratio in a meal affects postprandial variables in male volunteers. Am. J. Clin. Nutr., 55: 712-718. MEDLINE

van Dam RM, Visscher AW, Feskens EJ, Verhoef P, Kromhout D. (2000). Dietary glycemic index in relation to metabolic risk factors and incidence of coronary heart disease: the Zutphen Elderly Study. Eur. J. Clin. Nutr., 54: 726-731.

van den Brandt PA, Dirx MJ, Ronckers CM, van den Hoogen P, Goldbohm RA. (1997). Height, weight change, and postmenopausal breast cancer risk: The Netherlands Cohort Study. Cancer Causes Control, 8: 39-47. MEDLINE

van't Veer P, Kalb CM, Verhoef P et al. (1990). Dietary fiber, beta-carotene and breast cancer: results from a case-control study. Int. J. Cancer, 45: 825-828.

Vatten LJ, Kvinnsland S. (1990). Body mass index and risk of breast cancer. A prospective study of 23,826 Norwegian women. Int. J. Cancer, 45: 440-444.

Vatten LJ, Kvinnsland S. (1992). Prospective study of height, body mass index and risk of breast cancer. Acta Oncol., 31: 195-200.

Vega GL, Grundy SM. (1996). Hypoalphalipoproteinemia (low high density lipoprotein) as a risk factor for cornary heart disease. Curr. Opin. Lipid., 7: 209-216.

Vena JE, Graham S, Zielezny M et al. (1987). Occupational exercise and risk of cancer. Am. J. Clin. Nutr., 45: 318-327. MEDLINE

Virkamaki A, Ueki K, Kahn C. (1999). Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. Review. J. Clin. Invest., 103: 931-943. MEDLINE

Wakai K, Dillon DS, Ohno Y, Prihartono J et al. (2000). Fat intake and breast cancer risk in an area where fat intake is low: a case-control study in Indonesia. Int. J. Epidemiol., 29: 20-28.

Warren R, Yuan H, Matli M, Ferrara N, Donner D. (1996). Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma. J. Biol. Chem., 271: 29483-29488.

Watkins LF, Lewis FR, Levine AE. (1990). Characterization of the synergistic effects of insulin and transferrin and the regulation of their receptors on a human colon carcinoma cell line. Int. J. Cancer, 45: 372-375.

Weiderpass E, Gridley G, Nyren O, Ekbom A, Persson I, Adami HO. (1997a). Diabetes mellitus and risk of large bowel cancer. J. Natl Cancer Inst., 89: 660-661.

Weiderpass E, Gridley G, Persson I, Nyren O, Ekbom A, Adami HO. (1997b). Risk of endometrial and breast cancer in patients with diabetes mellitus. Int. J. Cancer, 71: 60-63.

Welch IM, Bruce C, Hill SE, Read NW. (1987). Duodenal and ileal lipid suppresses postprandial blood glucose and insulin responses in man: possible implications for the dietary management of diabetes mellitus. Clin. Sci. (Lond), 72: 209-216.

Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, Borch-Johnsen K, Olsen JH. (1997). Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J. Natl Cancer Inst, 89: 1360-1365.

Will JC, Galuska DA, Vinicor F, Calle EE. (1998). Colorectal cancer: another complication of diabetes mellitus? Am. J. Epidemiol., 147: 816-825.

Will JC, Vinicor F, Calle EE. (1999). Is diabetes mellitus associated with prostate cancer incidence and survival? Epidemiology, 10: 313-318.

Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. (1996). Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J. Am. Coll. Cardiol., 27: 567-574.

Wolever TMS. (1990). The glycemic index. In: Aspects of Some Vitamins, minerals and Enzymes in Health and Disease, ed. GH Borne. World Review Nutrition Diet Vol. 62, pp 120-185, Basel; Karger.

Wolever TMS, Jenkins DJA. (1986). The use of the glycemic index in predicting the blood glucose response to mixed meals. Am. J. Clin. Nutr., 43: 167-172. MEDLINE

Wolever TMS, Nuttell FQ, Lee R et al. (1985). Prediction of the relative blood glucose response of mixed meals using the white bread glycemic index. Diabetes. Care, 8: 418-428.

Wolever TMS, Brighenti F, Jenkins DJA. (1988). Serum short chain fatty acids after rectal infusion of acetate and propionate in man. J. Clin. Nutr. Gastroenterol., 3: 42-49.

Wolever TMS, Jenkins DJA, Jenkins AL, Josse RG. (1991). The glycemic index: methodology and clinical implications. Am. J. Clin. Nutr., 54: 846-854. MEDLINE

Wolever TMS, Jenkins DJA, Vuksan V, Jenkins AL, Wong GS, Josse RG. (1992a). Beneficial effect of low-glycemic index diet in overweight NIDDM subjects. Diabetes Care, 15: 562-564. MEDLINE

Wolever TMS, Jenkins DJA, Vuksan V, Jenkins AL, Buckley GC, Wong GS, Josse RG. (1992b). Beneficial effect of a low-glycaemic index diet in type 2 diabetes. Diabetes. Med., 9: 451-458.

Wolever TMS, Katzman-Relle L, Jenkins AL, Vuksan V, Josse RG, Jenkins DJA. (1994). Glycaemic index of 102 complex carbohydrate foods in patients with diabetes. Nutr. Res., 14: 651-669.

Wolever TM, Hamad S, Chiasson JL, Josse RG, Leiter LA, Rodger NW, Ross SA, Ryan EA. (1999). Day-to-day consistency in amount and source of carbohydrate associated with improved blood glucose control in type 1 diabetes. J. Am. Coll. Nutr., 18: 242-247.

Wolk A, Mantzoros CS, Andersson SO, Bergstrom R, Signorello LB, Lagiou P et al. (1998). Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. J. Natl Cancer Inst., 90: 911-915. MEDLINE

Wright RS, Anderson JW, Bridges SR. (1990). Propionate inhibits hepatocyte lipid synthesis. Proc. Soc. Exp. Biol. Med., 195: 26-29.

Wynder EL, Kajitani T, Ishikawa S, Dodo H, Takano A. (1969). Environmental factors of cancer of the colon and rectum. II. Japanese epidemiological data. Cancer, 23: 1210-1220.

Yamada K, Araki S, Tamura M, Sakai I, Takahashi Y, Kashihara H, Kono S. (1998). Relation of serum total cholesterol, serum triglycerides and fasting plasma glucose to colorectal carcinoma in situ. Int. J. Epidemiol., 27: 794-798.

Yee D, Lee AV. (2000). Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J. Mammary Gland Biol. Neoplasia, 5: 107-115.

Yoon JH, Thompson LU, Jenkins DJA. (1983). The effect of phytic acid on in vitro rate of starch digestibility and blood glucose response. Am. J. Clin. Nutr., 38: 835-842.

Zaridze D, Lifanova Y, Maximovitch D, Day NE, Duffy SW. (1991). Diet, alcohol consumption and reproductive factors in a case-control study of breast cancer in Moscow. Int. J. Cancer, 48: 493-501.

Zaridze D, Filipchenko V, Kustov V et al. (1993). Diet and colorectal cancer: results of two case-control studies in Russia. Eur. J. Cancer, 29A: 112-115.


Figure 1 Potential mechanism for the relationship between high glycemic index foods and insulin resistance. (Adapted from Jenkins et al, 2000).


Table 1 Relationship between dietary glycemic index and chronic disease in epidemiological studies

Table 2 Glycemic indices of some common foods

Table 3 Factors that can reduce the rate of glucose absorption and insulin levels

Table 4 Possible effects of prolonging carbohydrate absorption time

Table 5 Factors that infuence the glycemic response and the glycemic index

Table 6 Effect of low GI foods on glycosylated proteins in type 1 and 2 diabetes

Table 7 Relationship between carbohydrate intake and colorectal cancer risk

Table 8 Relation between diabetes mellitus, colorectal cancer and adenoma: case-control studies

Table 9 Relationship between diabetes mellitus and colorectal cancer: cohort studies

Table 10 Relationship between carbohydrate intake and breast cancer risk

Received 13 March 2002
November 2002, Volume 56, Number 11, Pages 1049-1071
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