Sweeteners and Risk of Obesity and Type 2 Diabetes: The Role of Sugar-Sweetened Beverages
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- Malik, V.S. & Hu, F.B. Curr Diab Rep (2012) 12: 195. doi:10.1007/s11892-012-0259-6
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Temporal patterns over the past three to four decades have shown a close parallel between the rise in added sugar intake and the global obesity and type 2 diabetes (T2D) epidemics. Sugar-sweetened beverages (SSBs), which include the full spectrum of soft drinks, fruit drinks, energy and vitamin water drinks, are composed of naturally derived caloric sweeteners such as sucrose, high fructose corn syrup, or fruit juice concentrates. Collectively they are the largest contributor to added sugar intake in the US diet. Over the past 10 years a number of large observational studies have found positive associations between SSB consumption and long-term weight gain and development of T2D and related metabolic conditions. Experimental studies provide insight into potential biological mechanisms and illustrate that intake of SSBs increases T2D and cardiovascular risk factors. SSBs promote weight gain by incomplete compensation of liquid calories and contribute to increased risk of T2D not only through weight gain, but also independently through glycemic effects of consuming large amounts of rapidly absorbable sugars and metabolic effects of fructose.
KeywordsSugar-sweetened beveragesAdded sugarObesityType 2 diabetesCardiovascular risk
Clinical Trial Acronyms
Coronary Artery Risk Development in Young Adults
Health Professionals Follow-up Study
Nurses’ Health Study
- NHS II
Nurses’ Health Study II.
As the global obesity epidemic continues to worsen, the world is seeing an unprecedented rise in the prevalence of type 2 diabetes (T2D). Excess adiposity, particularly around the central depots, is one of the most well-established risk factors for development of T2D. Temporal trends in the United States show a 10-year lag between the upsurge of obesity and rising rates of T2D . According to World Health Organization estimates, in 2005 approximately 1.6 billion adults were overweight and at least 400 million were obese worldwide, numbers that are projected to reach 2.3 billion and 700 million, respectively, by 2015. Paralleling these trends, in 2010 about 300 million people were estimated to have T2D globally and this number is expected to increase to nearly 450 million by 2030 . The cost of the global diabetes epidemic is staggering both in terms of health care expenditures and quality of life. In 2009, care of T2D and related sequelae led to $113 billion in direct medical costs in the United States (2007 US dollars) . Taken together, these data provide strong rationale for identification of modifiable diet and lifestyle factors for T2D prevention.
In 2009, the American Heart Association released a scientific statement calling for reductions in added sugar intake to 100 to 150 kcal/day for most Americans as a means of reducing obesity and cardiovascular disease (CVD) risk [4•]. The statement identified sugar-sweetened beverages (SSBs) as the primary source of added sugars in the US diet. Over the past 5 years a number of epidemiological studies have found positive associations between SSB consumption and long-term weight gain and development of T2D [5, 6••, 7, 8]. This review discusses temporal trends in SSB intake, recent epidemiological evidence linking SSBs to obesity, T2D and cardiovascular risk, potential biological mechanisms of sweeteners, and implications for clinical practice.
Trends in Added Sugar and SSBs
Dietary sugars either as a naturally occurring component of many foods or as an addition during processing and preparation are ubiquitous in the food environment. Naturally occurring sugars such as fructose, sucrose, and lactose are found intrinsically in fruit, vegetables, and dairy. In contrast, added or extrinsic sugars refer to sugars and syrups that are added to foods and beverages during processing and preparation. SSBs, which include the full spectrum of soft drinks, fruit drinks, energy and vitamin water drinks, are composed of naturally derived caloric sweeteners such as sucrose (50% glucose and 50% fructose), high fructose corn syrup (HFCS; most often 45% glucose and 55% fructose), or fruit juice concentrates.
Time-trend data over the past three to four decades have shown a close parallel between the rise in added sugar intake and the obesity and diabetes epidemics in the United States. National survey data estimated that per capita intake of added sugars increased from 235 kcal/day in the late 1970s to 318 kcal/day in 1995; and HFCS, the primary sweetener used to flavor SSBs, increased from 80 to 132 kcal/day over the same time period . Largely driving this trend was the dramatic increase in consumption of SSBs, which was the greatest single source of calories in the US diet in 1994 to 1996 . Looking specifically at SSB trends, between the late 1970s and 2006, per capita consumption of SSBs increased twofold from 64.4 kcal/day to 141.7 kcal/day, with adolescents and young adults consuming over 200 kcal/day . Similar patterns of SSB consumption are starting to emerge across the globe in developing countries concomitant with rapid rates of urbanization .
SSBs and Obesity
A number of systematic reviews have reported positive associations between intake of SSBs and weight gain or risk of overweight and obesity in the majority of studies in both children and adults [5, 7, 8, 12, 13]. Associations are most consistent in large prospective cohort studies with long durations of follow-up that do not adjust for the potential mediating effect of total energy intake in statistical analyses [5, 7]. Because total energy intake may mediate the association between SSB intake and weight gain, adjusting for total energy intake is equivalent to removing any effect of SSB on body weight that occurs through energy intake, which may explain some of the discrepancy between studies. Three of the largest prospective cohort studies in adults to date have found significant positive associations between daily SSB consumption and weight gain.
In a large cohort of over 50,000 women in the NHS, those who increased their SSB consumption and maintained a high level of intake gained on average 8.0 kg over 8 years, while women who decreased their SSB intake and maintained a low level of intake gained on average 2.8 kg . These findings were later replicated in over 40,000 women in the Black Women’s Health Study  and in a cohort of over 43,000 Chinese adults living in Singapore . Some smaller-scale studies have also found positive associations between SSB consumption and weight gain in either the overall study or in subgroup analyses [5, 13]. Recently, we examined the relationships between changes in lifestyle factors and weight change among 120,877 women and men in our three cohorts (NHS, NHS II, and HPFS) at 4-year intervals. On the basis of increased daily servings of individual dietary components, SSB was most strongly associated with 4-year weight change (1.00 lb) after potato chips (1.69 lb) and potatoes (1.28 lb) [17•]. Evidence from randomized controlled trials (RCTs) is limited, but shows that reducing SSB consumption decreases body weight by reducing energy intake especially among overweight individuals, which supports findings from observational studies. These studies are primarily comprised of short-term feeding trials ranging from 3 to 16 weeks, comparing the effects of consuming non-caloric artificially sweetened beverages with calorically sweetened beverages (sugar, sucrose, HFCS) on weight change [18, 19]. While studies of longer duration are desirable to better characterize long-term weight patterns, they are logistically challenging due to high cost and waning compliance with longer durations of follow-up. However, these short-term studies provide important insight into potential underlying biological mechanisms.
SSBs and Type 2 Diabetes
SSBs and Cardiovascular Risk
A small number of prospective cohort studies have evaluated risk of metabolic syndrome in relation to SSB consumption. Our recent meta-analysis pooled findings from three studies including 19,431 participants and 5803 cases of metabolic syndrome and observed an increased risk of about 20% comparing highest to lowest categories of intake [6••]. Two of these studies also looked at SSB consumption in relation to individual components of metabolic syndrome. Dhingra et al.  found that individuals who consumed ≥ 1 SSB per day had a marginal 18% (RR 1.18; 95% CI, 0.96, 1.44) greater risk of developing hypertension compared to non-consumers after adjusting for baseline hypertension, age, sex, physical activity, smoking, intake of saturated fat, trans fat, fiber, magnesium, total energy, and glycemic index. Results from Nettleton et al.  also found a marginal effect of SSBs on incident hypertension (RR 1.10; 95% CI, 0.87, 1.39) comparing daily consumers to non-consumers. These trends are supported by stronger associations in the NHS and NHS II cohorts where women who consumed ≥ 4 SSBs per day had a 44% and 28% greater risk of developing hypertension, respectively, compared to infrequent consumers . Studies by Dhingra et al.  and Nettleton et al.  also found that daily SSB consumers had a marginally increased risk for developing hypertriglyceridemia compared to infrequent consumers after adjusting for risk factors (RR 1.25, 95% CI, 1.04, 1.51 ; and RR 1.24, 95% CI, 0.98, 1.57 , respectively). In these studies daily SSB consumers also had an increased risk for low high-density lipoprotein cholesterol (RR 1.32; 95% CI, 1.06, 1.64 ; and RR 1.24; 95% CI, 0.95, 1.61 , respectively). In the CARDIA study, higher SSB consumption across quartiles was associated with a number of cardiometabolic outcomes: high waist circumference (RR 1.09; 95% CI, 1.04, 1.14; P for trend, 0.001), high low-density lipoprotein (LDL) cholesterol (RR 1.18; 95% CI, 1.02, 1.35; P for trend = 0.018), high triglycerides (RR 1.06; 95% CI, 1.01, 1.13; P for trend = 0.033), and hypertension (RR 1.06; 95% CI, 1.01, 1.12; P for trend = 0.023) .
Data from short-term trials also provide importance evidence linking SSBs with cardiovascular risk. Raben et al.  found that a sucrose-rich diet consumed for 10 weeks resulted in significant elevations of postprandial glycemia, insulinemia, and lipidemia compared to a diet rich in artificial sweeteners in overweight healthy subjects. A randomized crossover trial among normal weight healthy men found that after 3 weeks, SSBs consumed in small to moderate quantities (600 mL SSB/day containing 40–80 g of sugar) significantly impaired glucose and lipid metabolism and promoted inflammation . Specifically, LDL particle size was reduced for high fructose and high sucrose SSBs and a more atherogenic LDL subclass distribution was seen when fructose and high sucrose–containing SSBs were consumed . Fasting glucose and high-sensitivity C-reactive protein (CRP) increased significantly after fructose, glucose, and sucrose intervention and leptin increased during interventions with SSBs containing glucose . A 10-week intervention comparing effects of sucrose and artificially sweetened food/beverages on markers of inflammation found that serum levels of haptoglobin, transferrin, and CRP were elevated in the sucrose group compared to the sweetener group .
SSBs may affect risk of coronary heart disease (CHD) in a relatively short time of just a few years through effects on inflammation, which influences atherosclerosis, plaque stability, and thrombosis . Few studies have looked at the association between SSB consumption and clinical CHD. Among over 88,000 women in the NHS followed for 24 years, those who consumed ≥ 2 SSBs per day had a 35% (P trend 0.01) increased risk of CHD compared to infrequent consumers after adjusting for risk factors . Additional adjustment for mediating factors such as BMI, total energy, and incident diabetes attenuated the associations but they remained statistically significant, suggesting that the effects of SSBs are not entirely mediated by these factors .
Potential Biological Mechanisms
A number of potential biological mechanisms have been proposed linking SSB intake to T2D and cardiovascular risk through effects on energy balance and adiposity, as well as through independent glycemic effects of rapidly absorbable caloric sweeteners and fructose metabolism.
Liquid Calories and Energy Regulation
The prevailing mechanisms linking SSB intake to weight gain are decreased satiety and incomplete compensatory reduction in energy intake at subsequent meals after consumption of liquid calories . On average SSBs contain 140 to 150 calories and 35 to 37.5 g of sugar per 12 oz serving (equivalent to ~10 teaspoons of sugar). Traditionally, it has been thought that if these calories are added to the typical US diet, without compensation for the additional calories, 1 can of soda per day could lead to a weight gain of 15 lb or 6.75 kg in 1 year. However, this estimation, which uses the 3500 calories per pound rule, does not take into account the dynamic physiological adaptations to altered body weight that lead to changes of both resting metabolic rate as well as the energy cost of physical activity. Rather, based on a dynamic mathematical model that incorporates these factors, adding 1 can of soda per day to the diet would lead to a weight gain of 15 lb over 3 years or 5 lb in 1 year , which is not trivial. Short-term feeding studies comparing SSBs to artificially sweetened beverages in relation to energy intake  and weight change illustrate this point [18, 19, 30, 31]. For example, in studies by Raben et al.  and Reid et al. , after 10 and 4 weeks of active intervention (sucrose vs artificial sweetener), respectively, participants in the sucrose groups showed marginal weight gain and those in the sweetener groups showed marginal weight loss with significant between-group differences [18, 31]. A more recent trial by Raben et al.  comparing sucrose to artificial sweeteners showed that after 10 weeks, there was a significant increase in body weight in the sucrose group (by 1.4 ± 0.6 kg in week 10) compared with the sweetener group (−1.5 ± 0.6 kg in week 10). Additional evidence supporting incomplete compensation for liquid calories has been provided by studies showing greater energy intake and weight gain after isocaloric consumption of beverages compared to solid food [32, 33].These studies argue that sugar or HFCS in liquid beverages may not suppress intake of solid foods to the level needed to maintain energy balance; however, the mechanism responsible for that weaker compensatory response to fluids is largely unknown .
Consumption of SSBs has been shown to induce rapid spikes in blood glucose and insulin levels [25, 35] from high levels of sugars or HFCS, which in conjunction with the large volumes consumed contribute to a high dietary glycemic load (GL). High GL diets are thought to promote weight gain due to the higher postprandial insulin response following ingestion of a high GL meal, which stimulates uptake of glucose by insulin-responsive tissues, leading to a fall in blood glucose concentration and greater suppression of free fatty acids . This depletion of metabolic fuels is thought to induce a rapid hunger response and compensatory overeating as the body attempts to restore energy homeostasis . High GL diets have also been shown to stimulate insulin secretion due to relative postprandial hyperglycemia and increased incretin levels leading to hyperinsulinemia, which over time leads to insulin resistance. Insulin resistance may also occur due to direct effects of hyperglycemia, counterregulatory hormone secretion, and increased serum free fatty acid levels . Diets high in GL may also increase CVD risk through postprandial hyperinsulinemia and insulin resistance leading to dyslipidemia and inflammation and through postprandial hyperglycemia by inducing oxidative stress, which negatively impacts blood pressure, clot formation, and endothelium-dependent blood flow [36, 37]. High GL diets have also been associated with CHD . In addition, the caramel coloring used in cola-type soft drinks is high in advanced glycation end products, which may further increase insulin resistance and inflammation [39, 40]. In a recent report by Stanhope et al. , consumption of fructose-sweetened beverages lowered post-meal glucose and insulin peaks and plasma glycated albumin compared with consumption of glucose-sweetened beverages after 10 weeks, suggesting that it may be the specific effects of fructose, rather than glucose and insulin excursions, that contribute to the adverse effects of consuming SSBs on lipids and insulin sensitivity; however, further confirmatory studies are needed to substantiate this.
Some evidence suggests that consuming fructose, which is a constituent of sucrose and HFCS, in relatively equal amounts may exert additional adverse metabolic effects. The different pathways for metabolism of fructose and glucose are important potential mechanisms. Fructose alone is poorly absorbed, but enhanced by glucose in the gut, thus accounting for the rapid and complete absorption of both fructose and glucose when consumed as sucrose or HFCS. Fructose is preferentially metabolized to lipid in the liver leading to increased hepatic de novo lipogenesis, atherogenic dyslipidemia, and insulin resistance . This was illustrated in a 10-week trial comparing glucose- and fructose-sweetened beverages that found elevated postprandial triacylglycerides, fasting apolipoprotein B (apoB), and LDL in the fructose group as well as increased fasting plasma glucose and insulin levels and decreased insulin sensitivity . Similarly, a more recent trial found that consumption of HFCS-sweetened and fructose-sweetened beverages for 2 weeks at 25% energy increased postprandial triglycerides, and fasting plasma LDL and apoB levels more than glucose . Fructose has also been shown to promote accumulation of visceral adiposity or ectopic fat deposition [43, 45–47], which is associated with cardiometabolic risk. In contrast, some studies have shown greater satiety and lower energy intake after intake of fructose-containing beverages compared with glucose . In addition, Ghanim et al.  did not find evidence of oxidative or inflammatory stress following ingestion of fructose or orange juice, while reactive oxygen species generation and nuclear factor-κB binding were significantly increased after intake of glucose.
Fructose is also the only sugar known to increase serum uric acid levels by increasing ATP degradation to AMP, a uric acid precursor . The production of uric acid in the liver may reduce endothelial nitric oxide, which may partly mediate the association between SSBs and CHD . Hyperuricemia often precedes development of obesity, hyperinsulinemia, and diabetes and findings from animal studies suggest a link with development of metabolic syndrome . Clinical evidence suggests that hyperuricemia and fructose consumption may mediate the association between SSB consumption and hypertension possibly through the development of renal disease, endothelial dysfunction, and activation of the renin-angiotensin system . Intake of SSBs has been associated with hyperuricemia  and risk of developing gout in our cohorts [54, 55].
Given the increasingly widespread use of artificially sweetened beverages for weight management or health reasons, some epidemiologic studies have also evaluated the effect of consuming diet beverages on risk of obesity and related metabolic conditions. In contrast to SSBs, diet beverages are flavored with non-energy–bearing artificial sweeteners such as aspartame, sucralose, saccharin, acesulfame potassium, and neotame . A few studies have reported positive associations between diet soda consumption and weight gain and risk of metabolic syndrome and T2D [21, 22, 57]. However, these observations may be due to reverse causation or residual confounding, since for example diet soda consumption is higher among individuals with T2D compared to those without T2D . Studies in our cohorts with longer durations of follow-up, repeated measures of diet, and adjustment for weight change found only marginal nonsignificant associations between artificially sweetened beverages and T2D [14, 20] and CHD . Diet soda was also associated with weight loss in our study evaluating the effects of changes in diet and lifestyle factors on weight change [17•].
Based on these data, consumption of artificially sweetened beverages is unlikely to promote weight gain or metabolic dysfunction; however, some evidence suggests that the intense sweetness of artificial sweeteners (160–13,000 × sweeter than sucrose)  may condition toward a greater preference for sweets and thus may enhance appetite . Diet soda may also enhance appetite by cephalic phase stimulation, although this area remains controversial . Consumers of diet soda may also use this choice as a rationale for consuming other higher-calorie foods leading to weight gain . Further studies are needed to evaluate the metabolic consequences of artificial sweeteners.
Implications for Clinical Care
Bradford Hill criteria for causality applied to evidence evaluating SSB consumption and risk of T2D
Bradford Hill criteria
SSB consumption and risk of T2D
1) Strength of association
Significant positive association
RR: 1.26 (CI, 1.12, 1.41) for 1–2 servings/day
Consistent data from large prospective cohort studies
SSB has been shown to increase risk of related metabolic conditions and unrelated conditions such as dental caries and reductions in bone mineral density
Prospective studies have established temporality
5) Biological gradient (dose–response)
Increase of 1 SSB/day associated with about 15% increased risk of T2D
RR: 1.15 (CI, 1.11, 1.20)
6) Biological plausibility
Evidence regarding incomplete compensation for liquid calories, glycemic effects of consuming large amounts of rapidly absorbable sugars, and metabolic effects of fructose provide biological plausibility
7) Experimental evidence
RCTs with clinical T2D as an end point are logistically difficult; however, experimental evidence from studies of biomarkers of T2D and cardiovascular risk provide support
Selection of healthy alternatives to SSBs has thus become an important question. Unlike SSBs, water does not contain liquid calories and some evidence has shown associations between increased water consumption and satiety and lower energy intake [66–68]. Although fruit juice contains some vitamins and nutrients they contain a relatively high amount of natural sugars and should therefore be consumed in moderation. Previous studies have shown associations between juice intake and weight gain  and T2D . A number of studies have shown that regular consumption of coffee and tea can have favorable effects on T2D and CVD risk [70, 71], possibly because of their high polyphenol content, making them healthy options provided that caloric sweeteners and whiteners are used sparingly. Replacement of one serving of SSB with 1 cup of coffee was associated with a 17% reduction in risk of T2D . Consumption of dairy, particularly low fat, has been associated with reduced risk of T2D [72, 73], hypertension , and CHD , suggesting that low-fat milk may be a reasonable substitute for SSB but this has to be weighed against the potential risk of some cancers linked to dairy intake [76–78]. Diet sodas may be an acceptable alternative to SSBs as they provide few to no calories but little is known about the long-term health consequences of consuming artificial sweeteners over a lifetime.
Consumption of SSBs has increased markedly across the globe in recent decades, tracking positively with growing burdens of obesity and T2D. These beverages are currently the largest source of added sugar intake in the US diet. Epidemiological evidence has shown strong and consistent associations between SSB intake and risk of T2D and experimental studies have provided important insight into potential biological mechanisms. SSBs are thought to promote weight gain by incomplete compensation for liquid calories at subsequent meals and may increase risk of T2D independent of obesity as a potential contributor to a high dietary GL leading to insulin resistance, impaired β-cell function, dyslipidemia, and inflammation. Fructose from HFSC or sucrose may promote accumulation of visceral adipose tissue and induce additional adverse effects on lipids due to enhanced hepatic de novo lipogenesis and increase risk of hypertension from production of uric acid. Limiting intake of SSBs is one simple change that if implemented could have a measurable impact on weight control and risk of T2D and other metabolic diseases in the general population.
No potential conflicts of interest relevant to this article were reported.