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Nutritional Epidemiology

Consumption of Sweetened Beverages and Intakes of Fructose and Glucose Predict Type 2 Diabetes Occurrence¹

² National Public Health Institute, Helsinki FIN 00300, Finland; ³ University of Kuopio, Department of Clinical Nutrition, Kuopio FIN 70211, Finland; and ⁴ Social Insurance Institution, Helsinki FIN 00100 and Turku FIN 20720, Finland

^*To whom correspondence should be addressed. E-mail: jukka.montonen{at}ktl.fi.

	ABSTRACT

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 
The role of intakes of different sugars in the development of type 2 diabetes was studied in a cohort of 4,304 men and women aged 40–60 y and initially free of diabetes at baseline in 1967–1972. Food consumption data were collected using a dietary history interview covering the habitual diet during the previous year. The intakes of different sugars were calculated and divided in quartiles. During a 12-y follow-up, 177 incidents of type 2 diabetes cases were identified from a nationwide register. Combined intake of fructose and glucose was associated with the risk of type 2 diabetes but no significant association was observed for intakes of sucrose, lactose, or maltose. The relative risk between the highest and lowest quartiles of combined fructose and glucose intake was 1.87 (95% [CI] = 1.19, 2.93; P = 0.003). The corresponding relative risks between the extreme quartiles of consumption of food items contributing to sugar intakes were 1.69 (95% [CI] = 1.17, 2.43; P < 0.001) for sweetened berry juice and 1.67 (95% [CI] = 0.98, 2.87; P = 0.01) for soft drinks. Our findings support the view that higher intake of fructose and glucose and sweetened beverages may increase type 2 diabetes risk.

	Introduction

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

Glucose and fructose are natural components of fruits and berries. In addition, a significant proportion of sucrose in sucrose-containing foods, especially beverages, is hydrolyzed into glucose and fructose before the product is consumed. Glucose has a glycemic index of 141 compared with white bread (5) and, accordingly, it has been observed that of sugars, glucose best predicted an increase in blood glucose level (6). Glucose intake predicted an increased risk of type 2 diabetes in a large-scale prospective study in American women (7), but the result was not confirmed in another prospective study (8).

Fructose has been thought to be a safer form of sugar than sucrose due to a lower glycemic response after ingestion. In clinical studies, short-term fructose intake has either improved metabolic control or caused no changes (9,10). However, feeding studies in animals have suggested that fructose intake has a detrimental effect on body weight, plasma glucose, and insulin levels and insulin sensitivity, but the long-term effects of fructose intake in relation to insulin activity and sensitivity in human studies are less clear (11). In a few studies, diets high in fructose have led to reduced insulin sensitivity (12,13) or decreased plasma glucose levels (14,15). Dietary fructose intake was associated with the incidence of type 2 diabetes in a large-scale follow-up study in older women (7), but no significant association was observed in another large-scale cohort of women (8). Cross-sectional analysis based on Nurses' Health Studies I and II showed an association between fructose intake and plasma C-peptide concentration (16). Data on the long-term effects of different sugars on the risk of type 2 diabetes in healthy individuals are sparse and a major need exists for more research in this area, especially on the role of fructose (16). The association between intakes of different sugars and the incidence of type 2 diabetes was studied in a large nationwide cohort of Finns.

	Methods

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 
    Subjects. The Finnish Mobile Clinic Health Examination Survey carried out health examinations in various regions of Finland during the period 1966–1972 (17). A total of 51,522 men and women participated in the survey. Information concerning health was collected by interviews and questionnaires as well as by physiological measurements. Serum samples were taken and stored. A dietary history interview of 10,054 persons was included in the study from 1967 (18). Participants who did not satisfy the age criteria of 40–69 y or reported a daily energy intake of <800 kcal (3347 kJ) or >6,000 kcal (25104 kJ), or who had a history of diabetes were excluded. The final study population consisted of 4304 men and women, of whom 4284 had data available on all of the covariates included. The participants were fully informed about the study and the intended use of the data.

    Baseline measurements. All the participants completed a self-administered questionnaire that was checked at the baseline examination. The questionnaire yielded information on previous and current illnesses, medication use, and lifestyle, such as smoking habits and leisure-time physical activity. Subjects were classified according to smoking status as nonsmokers, ex-smokers, smokers of pipes or cigars only, smokers of <15 cigarettes/d, and smokers of 15 cigarettes/d (19). The participants were asked whether or not they engaged in regular leisure-time physical activity.

Body weight and height were measured in light indoor clothing without shoes and the BMI (kg/m²) was calculated. Casual blood pressure was measured using the auscultatory method. Four hypertension categories were formed on the basis of systolic (SBP)⁵ and diastolic blood pressure (DBP) and antihypertensive medication (19). Persons with SBP 170 mmHg (millimeter of mercury) and DPB 100 mmHg and persons using antihypertensive medication were considered definitely hypertensive. Persons with SBP 160 mmHg and DBP 95 mmHg but not defined as hypertensive were considered to have mild hypertension, and those with SBP <140 mmHg and DBP <90 mmHg were considered normotensive. All persons with intermediate values were considered to have borderline hypertension. The serum cholesterol concentration was determined with an autoanalyzer modification of the Liebermann-Burchard reaction (20).

Known cases of diabetes were identified from information given by the participants and a glucose tolerance test was carried out to diagnose new diabetes at baseline (21,22). All persons with previously known or newly diagnosed diabetes at baseline were excluded from the analyses.

    Dietary assessment. Total habitual food consumption during the previous year was estimated using a dietary history interview (18). Trained interviewers used a questionnaire listing over 100 food items and mixed dishes common to the Finnish diet. Consumption of foods was estimated per day, week, month, or year according to the choice of the respondent. Individual consumption of food items was converted to grams per day. The ingredients of mixed foods were broken down into their components using a recipe file and the intakes of separate food items were calculated per day. The contents of different sugars in foods were estimated using Finnish food composition tables (23) completed with analyzed values for carbohydrates of Finnish foods (24,25). To take into account the dietary patterns beyond the individual dietary intakes, 2 dietary patterns, a prudent pattern characterized by consumption of fruit and vegetables and a conservative pattern characterized by consumption of butter, potatoes, and whole milk, were identified (26). Individual glucose and fructose intakes were calculated as free monosaccharides independent of sucrose. Furthermore, their combined intakes were also calculated, because it is impossible to differentiate their potential associations with risk of diabetes due to the high correlation between their intakes (Pearson r = 0.99; P < 0.001).

Short- and long-term reproducibility of the food consumption data has been reported previously (27). The intraclass correlation coefficients for short-term repeatability were 0.55 for total intake of sugars, 0.40 for fructose, 0.38 for glucose, 0.68 for lactose, 0.61 for sucrose, and 0.57 for maltose. The corresponding long-term repeatability coefficients for 4–7 y were 0.36 for total intake of sugars, 0.28 for both fructose and glucose, 0.55 for lactose, 0.30 for sucrose, and 0.33 for maltose.

Approximately one-half of the sucrose was consumed as a sweetener at the table. The sugar was mainly added to coffee or tea or on top of porridge. The other main sources of sucrose were jams and marmalade, beverages, and fruits and berries, providing nearly 30% of the total sucrose intake. Sweetened berry juice (38%), fruits (23%), and jam and marmalade (12%) represented the major sources of dietary fructose and glucose.

    Incident type 2 diabetes. During a 12-y follow-up, a total of 177 incident cases of type 2 diabetes were identified from a nationwide registry of patients receiving drug reimbursement for hypoglycemic agents, which is maintained by the Social Insurance Institution (28). Participants in our study population were linked to this register using the individual social-security code assigned to each Finnish citizen. The medical certificates of all the cases were checked and all met the WHO diagnostic criteria for type 2 diabetes (29).

    Statistical analysis. Nutrient intakes were adjusted for total energy intake by the residual method described by Willet and Stampfer (30). The associations between dietary variables and diabetes risk are presented as relative risks. Relative risks of type 2 diabetes, with 95% [CI] between quartiles of different food items and nutrients, were calculated using Cox's model (31). The data for honey and syrup consumption were divided into consumers (>0 g/d) and nonconsumers, because the number of consumers was low. Potential confounding factors, including age (continuous variable), sex (2 categories), BMI (quintiles), energy intake (continuous variable), smoking status [never, past, current (pipe or cigar, <15 or 15 cigarettes/d)], geographical area (6 categories), physical activity (regular or no), family history of diabetes (2 categories), prudent dietary pattern (continuous variable) score, and conservative pattern score (continuous variable), were adjusted for in the different multivariate models. Furthermore, a model including potential intermediate factors, such as serum cholesterol and blood pressure and other cardiovascular risk factors such as histories of infarction, angina pectoris, and cardiac failure, was also used. The potential modifying effect of intermediate and other selected factors was studied by including interaction terms in the model. Tests for trends through the quartiles of intake were carried out on the basis of a likelihood ratio test, treating all variables in the model as continuous by entering the quartile medians.

	Results

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Persons who developed type 2 diabetes during the 12-y follow-up were significantly (P for heterogenity < 0.001) older and more obese, more likely to be women nonsmokers and hypertensive and they more often had a family history of diabetes (Table 1). Distribution of the dietary variables did not show major differences between incident cases and noncases with the exception of energy intake (P < 0.001), which was lower in persons who developed type 2 diabetes.

The total sugar intake had a modest, nonsignificant (P for trend = 0.10) association with the incidence of type 2 diabetes (Table 3). Of the individual sugars, the intakes of fructose and glucose as well as their combined intake were significantly associated with the incidence of type 2 diabetes, whereas no association was observed for sucrose, lactose, or maltose. The relative risks between the extreme quartiles of intake were 1.87 (95% [CI] = 1.19, 2.93; P for trend = 0.003) for fructose and glucose combined and 1.56 (95% [CI] = 0.99, 2.46; P for trend = 0.10) for the total intake of sugars when adjusted for age, sex, BMI, energy intake, smoking, geographical area, physical activity, family history of diabetes, and dietary patterns. The inclusion of serum cholesterol, blood pressure, and histories of infarction, angina pectoris, and cardiac failure in the model modestly attenuated the associations observed (Table 3).

Of the food items contributing to sugar intake, greater intakes of sweetened berry juice and soft drinks were associated with the increased risk of type 2 diabetes; jam and marmalade tended to be associated with an increased risk (P for trend = 0.06), and greater consumption of sugar, used as such, suggested a reduced risk (P for trend = 0.08) (Table 4). The relative risks between the extreme quartiles of the consumption were 1.69 (95% [CI] = 1.17, 2.43; P for trend = 0.001) for sweetened berry juice and 1.67 (95% [CI] = 0.98, 2.87; P for trend = 0.01) for soft drinks when adjusted for age, sex, BMI, energy intake, smoking, geographical area, physical activity, family history of diabetes, and dietary patterns. Further adjustment for cardiovascular risk factors such as serum cholesterol, hypertension, and histories of infarction, angina pectoris, and cardiac failure did not affect the results.

	Discussion

TOP ABSTRACT Introduction Methods Results Discussion LITERATURE CITED

 
In this study, higher intakes of combined fructose and glucose predicted an increased risk of type 2 diabetes. The association persisted after adjustment for several potential confounding factors related to lifestyle, dietary patterns, and total sugar intake. Therefore, it is possible that the association of glucose or fructose intake with the development of type 2 diabetes could be ascribed to these monosaccharides per se or factors specifically related to their intake. The association was prominent only in the highest quartile of the intake.

The result of this study is in line with the previous prospective analysis of the data from the Iowa Women's Health Study, in which intakes of glucose and fructose were associated with increased risk of type 2 diabetes (7) and with cross-sectional analysis that showed an association between fructose intake and blood C-peptide level (16). However, no significant association was observed in the prospective analysis of the data from the Women's Health Study (8). A high correlation between glucose and fructose intakes, however, makes it impossible to differentiate their associations with diabetes risk.

Among sugars, glucose has been found to be the best predictor of the insulin response (6). Glucose has high glycemic index compared with white bread (5). The possible effect of glucose on the development of type 2 diabetes is mediated by increased stress to insulin secretion due to high glycemic index. The glycemic index or glycemic load has been associated with diabetes incidence in some large-scale cohort studies (32–35) but not in all (7,8). Despite the lower glycemic index (5), fructose intake may be related to increased risk of type 2 diabetes through several biological mechanisms (11). A higher fructose intake may play a role in an increase in body weight due to the positive energy balance, because fructose ingestion does not increase the production of insulin and leptin, which contribute to the long-term regulation of food intake and energy expenditure (36–38). Positive energy balance leads to obesity that is associated with a higher concentration of nonesterified fatty acids (39), which may reduce insulin sensitivity (40), increase hepatic glucose production (41,42), and have a deleterious effect on the ß cell function (43). Despite the fact that in short-term studies in humans, fructose ingestion did not have a deleterious effect on glucose metabolism and diabetes (44), a reduction in the insulin-binding activity was observed after intake of a large amount of fructose in a small number of normoglycemic men (12) and a diet containing 15% of energy from fructose resulted in significantly higher insulin and glucose responses than diets without fructose after 5 wk (45). Moreover, the long-term feeding of moderate or high amounts of fructose has impaired glucose metabolism and reduced insulin sensitivity in animal studies (46–48).

As a reducing sugar, fructose plays a part in the Maillard reaction with proteins and amino acids to form substituted amino sugars, which undergo further reactions and form advanced glycation end products (AGE) (49). It has been suggested that AGE could be involved in the progression of type 2 diabetes (50) and, in fact, an improvement in insulin sensitivity (51) and reduction in the development of type 2 diabetes (52) have been noted in diabetic animals after AGE have been restricted. Fructose is apparently much more reactive than glucose with respect to glycosylation reactions (53).

Another potential mechanism that may have mediated the effect of glucose or fructose is the low satiety of the liquid foods representing important sugar sources. It has been observed that an excess intake of sugar in liquid form is not compensated by the reduction in food and energy intake and therefore promotes weight gain (54–56). Accordingly, consumption of sweetened berry juice and soft drinks was associated with an increased diabetes risk in our data, which is consistent with recent findings on the consumption of sweetened beverages and fruit punches and diabetes incidence (57).

A modest inverse association has been observed between sucrose intake and diabetes risk in previous studies (7,8). However, no significant association was observed between total sucrose intake and diabetes risk in our study, but added sugar (sucrose) used as such suggested an inverse nonsignificant association with the diabetes risk in our data.

The prospective design was a strength of this study and the collected detailed dietary data enabled us to take into account potential dietary confounders. However, the dietary history method used has limitations that may have caused some misclassification of subjects. These tend to diminish the associations observed between exposure and outcome (58). The result of the dietary history interview is always a subjective assessment of the respondent's own dietary habits. A period of 1 y is a lengthy time to recall. Food models were used to diminish errors in recall and open-ended questions enabled respondents to be more specific in their answers. To minimize possible bias, trained nutrition professionals used a structured questionnaire.

In general, the short-term repeatability of the dietary history method was relatively good (27). However, rather poor repeatability for glucose and fructose hinders the interpretation of the results and the possibility of chance findings increases. The poorer long-term consistency can be partly explained by changes in Finnish dietary habits (59). Changes in food consumption during follow-up tend to weaken the associations observed (58). For this reason, follow-up in this study was limited to 12 y. Because results did not change notably after excluding incidents during the first 4 y, we conclude that patients diagnosed and needing hypoglycemic medication shortly after the baseline investigation did not influence our results.

During the 12-y follow-up, information on cases of diagnosed type 2 diabetes derived from a nationwide register of drug reimbursements. Patients treated by nutritional therapy only were not included in this register. The loss of statistical power due to missing the cases undergoing dietary therapy only may have weakened the associations observed. On the other hand, in many cases, it is likely that diabetic patients undergoing dietary therapy only will later proceed to a phase where drug therapy is needed. Thus, it is probable that the cases included in this study represent a group of patients with a more severe disease of relatively long duration.

The relation between fructose and glucose intakes and the incidence of type 2 diabetes may be an effect of these particular monosaccharides or it may be a result of confounding due to other factors related to them. It is also possible that residual confounding remained after inaccurate measurement of physical activity, smoking status, or blood pressure.

In summary, this study demonstrated an increased incidence of type 2 diabetes in persons with higher intake of fructose and glucose, as well as the consumption of sugar-sweetened beverages, but not in persons with higher intake of sucrose. Further research is needed to reveal the mechanism behind the observations of this study and the few other prospective studies that suggest increased type 2 diabetes risk in persons with higher consumption of sugar-sweetened beverages or intakes of fructose or glucose.

	FOOTNOTES

 
¹ Author disclosures: J. Montonen, R. Järvinen, P. Knekt, M. Heliövaara, and A. Reunanen, no conflicts of interest.

⁵ Abbreviations used: AGE, advanced glycation end product; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Manuscript received 23 January 2007. Initial review completed 14 February 2007. Revision accepted 1 April 2007.

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