Max Lafontan, PhD, is director of research, Unité Inserm 858, Institut de Médecine Moléculaire de Rangueil, and Université Paul Sabatier, Toulouse, France.
The author is not receiving any funding for research investigations from Danone Waters but has received consulting fees from a paid advisory board for the review.
Dr Lafontan has received speaker and consultancy honorarium from Danone Waters R&D.
Correspondence: Max Lafontan, PhD, Unité Inserm 858, Institut de Médecine Moléculaire de Rangueil, 1 Avenue Jean Poulhès, BP84225, 31432 Toulouse cedex 04, France (firstname.lastname@example.org).
The present overview will be limited to the analysis of the putative impact of sugar inclusion in beverages on health, obesity, and diabetes risk. Mechanisms of action and physiological end points will be highlighted to clarify the differences existing in the health impact of various kinds of sugars.
Sugars, Heterogeneity, Basic Biology, Major Metabolic Impacts and Health-Related Questions
The term sugars (carbohydrates) includes a large family of monosaccharides and disaccharides, which are naturally present in (or added to) food or beverages. Sugar is the most common word for saccharose (sucrose); it represents 75% of added sugars, whereas glucose syrup represents only 25% in France. The most commonly used sweetener in the United States is high-fructose corn syrup (55% fructose and 45% glucose). The mean sugar content of sugar-sweetened beverages (SSBs) commonly used in the United States is 10 g/100 g (ranging from 4.5 to 16 g/100 g). Sugar-sweetened beverages represent the major source of dietary fructose, as provided in various forms including carbonated soft drinks, juice-based beverages, 100% juices, flavored milk, gourmet coffees, and liquid meal replacement mixtures for weight loss. Fructose is also included in solid foods (pastries, desserts, and a number of processed foods). The introduction of high-fructose corn syrup in the 1970s in the United States has resulted in a 30% increase in total fructose intake in the last 20 years. It is associated with a remarkable increase in the rates of obesity and diabetes.1-3
Glycemic Index, Glycemic Load, and Feeding
The glycemic index (GI) is the method of indexing the glycemic response to a fixed amount of available carbohydrate from a test food, to the same amount of available carbohydrate from a standard food consumed by the same subject. Initially, the standard "food" was glucose, now it is white bread. The glycemic load (GL) is a ranking system integrating sugar content and portion size; it is the product of the GI and total carbohydrates in the food portion. Detailed data on GI and GL are reported by Foster-Powell et al.4 Foods with high GI are suspected to be the dietary factor that promotes repeated insulin release and contributes to the settlement of chronic diseases in patients at risk. Drinking SSBs when eating food contributes to a high GI of the overall diet.
Glucose and Fructose Possess Strikingly Different Metabolic Fates
Main alimentary polysaccharide hydrolysis generates glucose, fructose, and galactose, which are absorbed by the intestinal cells and delivered into circulation. Glucose and fructose have different metabolic fates in terms of absorptive processes, metabolic effects, and actions on leptin, ghrelin, and insulin secretion. Growing evidence suggests direct and opposite actions of glucose and fructose on hypothalamic neurons and food intake.
The site, rate, and extent of carbohydrate digestion and absorption from the gut are keys to understanding the many roles of carbohydrates. Glucose and galactose are absorbed via a Na+/glucose cotransporter (SGLT1), whereas fructose is absorbed further down the duodenum by a non-Na+-dependent process (Glut 5 transporter). The gastrointestinal system plays an important role in the neuroendocrine regulation of food intake. Recent mechanisms governing sugars and other nutrient sensing and peptide secretion by enteroendocrine cells have been discovered. Novel taste-like pathways exist in the enteroendocrine cells, which express several G protein-coupled receptors identified as taste receptors similar to those previously found in the taste buds on the tongue.5 Several enteroendocrine cell types throughout the gut express T1R2/3 sweet taste G protein-coupled receptors, T2R-family bitter receptors, and/or the taste-specific G protein Gαgustducin.6 The combination of T1R2+3 recognizes natural sugars such as sucrose and glucose and also artificial sweeteners such as saccharin and acesulfame K.7
Glucose is an energy-providing substrate; glucose consumption by muscle considerably increases during physical exercise. Glucose oxidized during physical activity comes from glycogen stores in the liver and muscles and from ingested carbohydrates. Oxidation of other hexoses (eg, fructose and galactose) is lower than that of glucose. They must be transformed into glucose by the liver before utilization by skeletal muscle. Glucose need depends on the type of exercise, its intensity and duration, age, sex, and the level of physical training of the subjects. Nutrition recommendations for men and women performing exercise must be adapted to their individual needs according to the exercise performed.
Outside its role as an energy-providing substrate in numerous tissues, glucose is also an important signaling molecule. Glucose is involved in the regulation of the expression of genes regulating glycolysis and lipogenesis via a pathway involving a new transcription factor (ie, carbohydrate regulatory element binding protein).8 Fructose metabolism has unique characteristics; it is largely metabolized in the liver (50%-70%), with the rest being metabolized by the kidneys and adipocytes. Fructose possesses beneficial effects at low concentrations (hepatic glucose uptake) while exerting a number of deleterious effects when chronically consumed in excess (hepatic steatosis, insulin resistance, inflammation, and hyperuricemia).9
Glucose sensing is an important function of the brain.10 Two populations of glucose-sensing neurons have been identified in hypothalamic areas: those that are excited (ie, increased electrical activity) and those that are inhibited (ie, decreased activity). They are triggered at different glucose concentrations. Unlike glucose, which suppresses food intake, fructose increases food intake when metabolized by the central nervous system. Fructose has the opposite effect of glucose on the AMP activated kinase/malonyl-CoA signaling system and thereby feeding behavior. Thus, increased fructose metabolism within the brain increases food intake and obesity risk.11
Sugars and Sweetness Are Important in Establishing Lifelong Food Habits
It is important to understand the early factors that determine choice and ingestion, when designing strategies to enhance the health of infants, children, and adults. Early experiences set the stage for later food choices, and they are important in establishing lifelong food habits.12 Different brain regions are responsive to sweetness intensity and pleasantness perceptions in humans.13 Psychological and behavioral components of sweetness are very complex. Full development of this question is considered to be outside the present review.
Glucose, Insulin Secretion, and Glucotoxicity
High dietary GI and GL have been associated with an increased risk of developing type 2 diabetes mellitus in large prospective studies.14 The foods that were the most consistently associated with increased risk of type 2 diabetes are white rice, white bread, potatoes, and SSBs. Type 2 diabetes is a complex syndrome of polygenic nature; the genetic susceptibility of the pancreas β cells determines the risk of developing the disease. Increased plasma glucose and free fatty acids may exert, in the long term, toxic influences on β-cell function. When glucose is in excess, instead of flowing uniquely and normally through oxidative phosphorylation, metabolites overflow into alternative pathways causing oxidative stress and leading to β-cell dysfunction.15
Comments on the Obesity Epidemic
Adipocyte number is settled early in life during childhood and adolescence. An increasing number of nations face childhood obesity problems. Obese children are at a high risk of becoming irreversibly obese adults. Most obese adults have been obese since childhood, with less than 10% of children with normal weight going on to develop adult obesity. By contrast, more than three-fourths of obese children go on to become obese adults. Obesity has its genesis in childhood. Interventional focus should be placed in early life.16 Risk factors and causes of obesity in children include a number of parameters (ie, genetic, antenatal life, auxologic parameters at birth, early postnatal development, socioeconomic conditions of the parents, physical activity, dieting, etc).
Increased lipid storage in already developed fat cells (adipocytes) is thought to be the most important event of fat mass expansion. Adipocyte number is a major determinant for the fat mass in adults. As previously suspected in the 1970s, a recent study has confirmed that the number of adipocytes existing in adulthood is set during childhood and adolescence. The number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. A tight regulation of fat cell numbers occurs during adulthood.17 Thus, it is clear that an excess number of fat cells represent an important element of the future of fat mass status. The number of adipocytes for lean and obese individuals is set before the age of 20 years. Adipocyte number is subject to little variation during adulthood; changes are limited to variations in cell size. Even after significant weight loss in adulthood and reduced adipocyte volume, the adipocyte number remains the same.
Glucose uptake is essential for triacylglycerol synthesis in human fat cells. Glucose uptake by fat cells operates under the control of the Glut 4 glucose transporter. Insulin stimulates fatty acids and glucose uptake and activates lipoprotein lipase activity and triglyceride synthesis.18 It is easily understandable that whenever insulin release is potently stimulated by high GI food or SSB intake, a potent signal for fat storage will be provided to the fat cell by insulin. Erratic and/or frequent intake of SSBs could represent a risk of fat storage in patients at risk of developing obesity, depending on their activity level. Cumulative daily imbalances in energy intake affect body fat mass.19 If intake exceeds expenditure by 2% daily (ie, <1 can of SSBs) for a year, the result would be an increase of 75 312 kJ, or approximately 2.3 kg. A major program to control childhood obesity must be established at all the levels of health care delivery. The necessary measures include education of the public regarding the risk factors for childhood obesity: (1) limit consumption of sucrose- and fructose-containing drinks and foods with high carbohydrate and fat contents, (2) assume correct hydration by water drinking, and (3) promote exercise programs at home and at school.
What Do Epidemiological Studies Tell Us: Interest and Limits of Cross-sectional, Longitudinal, and Intervention Studies?
Overweight among children has increased dramatically during the past 2 decades and is reaching epidemic proportions. The obesity epidemic is a crisis that requires action before all the scientific evidence is settled. A number of questions have been raised concerning the putative impact of SSBs on health and obesity epidemics. Energy intake is positively associated with consumption of soft drinks.20 For example, mean adjusted energy intake was 7656 kJ/d for school-aged children who were not consumers of SSBs, compared with 8443 kJ/d for children who consumed an average of 250 mL of soda per day.21
Influential global reports have asserted that SSBs play a key role in the etiology of overweight and obesity.22,23 Cross-sectional studies are the most common. A number of comprehensive scientific reviews of the evidence have tended to be cautious, less straightforward, and with a number of controversies that cannot be detailed here. A recent systematic review and meta-analysis have concluded that the strength of the relationship was near zero and contested some previous positive results.24 However, this meta-analysis was open to criticisms. Concerning longitudinal studies, half of a group of 18 showed a significant positive result between SSB intake and body mass index; the effect appears to be rather small. The effects of potential confounding factors from other components of the diet, physical activity, and other lifestyle factors are not sufficiently assessed in the majority of such studies, as recently discussed.25
Intervention trials represent the best level of evidence to test a hypothesis. Avoidance of SSBs may help to prevent further weight gain in overweight children or obese subjects.26,27 The relative effects of dietary sugars (glucose vs fructose) were compared during a 10-week consumption period. Overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. It was demonstrated that dietary fructose specifically increases hepatic de novo lipogenesis, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.28 Results of intervention trials are promising, although they remain quite rare, difficult to settle, and expensive.
Conclusions and Future Trends
Despite the large number of studies on the role of sugar intake in beverages on overweight and health, definitive conclusions are not easily drawn from studies. Publication biases have been highlighted recently.25 Industry-funded studies tend to reveal smaller effects than other studies. Cross-sectional studies are the most abundant types of studies but they cannot establish cause-effect relationships and are rarely conclusive. The effects observed in longitudinal studies are often seen in the studies of smaller size, but could be affected by modification of other aspects of diet and lifestyle. It is necessary to be careful with industry-funded studies, which have a tendency to reveal smaller effects.
The recent results of an intervention study provide the best arguments to infer causality. It is expected that this kind of intervention approach will be expanded in the future in the different populations of the planet because nutritional habits and sugar composition of SSBs could differ noticeably. Intervention trials must be developed to delineate the doses of SSBs promoting adverse changes of plasma lipids and a decrease in insulin sensitivity in different populations at risk for health problems. More studies of adequate duration must also be performed among children and in overweight consumers of SSBs. When considering weight changes and obesity-related questions related to SSB consumption, it is important to take into account population differences and genetic parameters. Lifestyle influences (eg, other components of the diet and physical activity) must also be considered in the studies.
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