The role of fructose transporters in diseases linked to excessive fructose intake

Abstract

Fructose intake has increased dramatically since humans were hunter-gatherers, probably outpacing the capacity of human evolution to make physiologically healthy adaptations. Epidemiological data indicate that this increasing trend continued until recently. Excessive intakes that chronically increase portal and peripheral blood fructose concentrations to >1 and 0.1 mm, respectively, are now associated with numerous diseases and syndromes. The role of the fructose transporters GLUT5 and GLUT2 in causing, contributing to or exacerbating these diseases is not well known. GLUT5 expression seems extremely low in neonatal intestines, and limited absorptive capacities for fructose may explain the high incidence of malabsorption in infants and cause problems in adults unable to upregulate GLUT5 levels to match fructose concentrations in the diet. GLUT5- and GLUT2-mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose-induced hypertension. Likewise, GLUT2 may contribute to the development of non-alcoholic fatty liver disease by facilitating the uptake of fructose. Finally, GLUT5 may play a role in the atypical growth of certain cancers and fat tissues. We also highlight research areas that should yield information needed to better understand the role of these GLUTs in fructose-induced diseases.

Figure 1. Fructose intake by male Americans

The average total (naturally occurring plus supplementary) fructose intake by male Americans in 1978 (light blue) and 2004 (dark blue) in various age groups. The higher fructose intake of the population belonging to the 90th percentile of fructose consumers (in red) is shown for comparison. Data were obtained from Park & Yetley (1993) and Marriott et al. (2009). Between 1978 and 2004, there has been a significant ∼10 to 20% increase in mean total fructose intake in children, and a marked ∼20 to 60% increase in teenagers and adults. Primarily because of lower body weights, the rate of total fructose intake is less in females, but otherwise the pattern of increases is generally similar to that of adult males. Fructose intake by adults in the 90th percentile is almost twice that of the general population, rendering tens of millions of Americans vulnerable to the risk factors associated with excessive consumption of this sugar.

Figure 2. Low or modest expression of the fructose transporter GLUT5 may cause intestinal fructose malabsorption in humans

A, fructose malabsorption in humans measured by breath hydrogen (data from Jones et al. 2011a). Subjects received either 0.5 g (kg body weight)⁻¹ of fructose (maximum of 10 g) or 2 g kg⁻¹ of lactose (maximum of 20 g), and were tested for 2.5 h. Patient age had a remarkable effect on the proportion of subjects that tested positive, so that the odds of testing positive for fructose malabsorption in patients 15 years or younger decreased by a factor of 0.82 for each year of increasing age. B, relative GLUT5 (left red bars) and GLUT2 (right blue bars) mRNA expression in the small intestine of rats as a function of age, from suckling to adults (V. Douard and R. P. Ferraris, reanalysis of archived materials from Douard et al. 2010, 2012). Bars are means ± SEM. Weaning and adult rats were fed a high-glucose or high-fructose diet; the ‘diets’ of suckling (<14 days old) rats reflected those of their mothers. All mRNA levels were normalized to GLUT5 expression (arbitrarily set as 1.0) in rats fed high glucose. Intestines of rats 1–2 days of age represented those of humans in the last trimester of gestation, 10–13 days of neonatal humans, 19–22 days of weaning, 45–50 days of teenagers, and >90 days of adult humans. GLUT5 expression increases dramatically while that of GLUT2 increases modestly with age. GLUT5 expression is enhanced specifically by a high-fructose diet when compared with a high glucose or any fructose-free diet. GLUT2 expression increases modestly with both glucose and fructose when compared with protein diets (not shown). Since GLUT5 expression levels determine rates of rat fructose transport rates (Jiang & Ferraris, 2001), fructose malabsorption in young children may be caused by lack of GLUT5.

Figure 3. Model showing the interactive effects of chronically excessive fructose intake among multiple organ systems

In rodent models, consumption of high-fructose diets may lead to >20 mm free fructose in the intestinal lumen and, after transport by GLUTs 5 and 2 and metabolism by KHK, yields >1 mm fructose concentration in the portal vein (step 1). The liver catabolizes most of the fructose, but under chronic conditions, may increase lipogenesis in this organ by the unregulated production of two carbon precursors, eventually leading to NAFLD. Step 2, high luminal fructose may also increase transepithelial permeability, allowing the passage of bacterial endotoxins that induce inflammatory reactions in hepatocytes, contributing to NAFLD. Step3, GLUT5 may interact with intestinal chloride transporters as to perturb electrolyte homeostasis and contribute to hypertension. Step 4, the chronic delivery of high fructose in the portal blood lowers ATP levels in hepatocytes and increases uric acid production which may contribute to the etiology not only of NAFLD but also of hypertension and renal disease. Step 5, as the liver removes most of the fructose, peripheral blood level is only ∼0.2 mm. Thus, with the exception of the liver and intestine, organ systems thought to be negatively impacted by a high fructose intake actually are bathed in modest fructose concentrations < 1 mM during postprandial periods, and < 0.2 mM between meals. Step 6: however, a chronic, ∼10-fold increase in these modest (relative to glucose) peripheral fructose concentrations seems sufficient to cause marked increases in proximal tubular cells, GLUT5 and GLUT2 expression, and renal hypertrophy, negatively impacting the synthesis of 1,25 (OH)₂D₃, contributing potentially to hypertension.