Added Fructose: A Principal Driver of Type 2 Diabetes Mellitus and Its Consequences

doi:10.1016/j.mayocp.2014.12.019

Mayo Clinic Proceedings

Volume 90, Issue 3, March 2015, Pages 372-381

https://doi.org/10.1016/j.mayocp.2014.12.019 Get rights and content

Abstract

Data from animal experiments and human studies implicate added sugars (eg, sucrose and high-fructose corn syrup) in the development of diabetes mellitus and related metabolic derangements that raise cardiovascular (CV) risk. Added fructose in particular (eg, as a constituent of added sucrose or as the main component of high-fructose sweeteners) may pose the greatest problem for incident diabetes, diabetes-related metabolic abnormalities, and CV risk. Conversely, whole foods that contain fructose (eg, fruits and vegetables) pose no problem for health and are likely protective against diabetes and adverse CV outcomes. Several dietary guidelines appropriately recommend consuming whole foods over foods with added sugars, but some (eg, recommendations from the American Diabetes Association) do not recommend restricting fructose-containing added sugars to any specific level. Other guidelines (such as from the Institute of Medicine) allow up to 25% of calories as fructose-containing added sugars. Intake of added fructose at such high levels would undoubtedly worsen rates of diabetes and its complications. There is no need for added fructose or any added sugars in the diet; reducing intake to 5% of total calories (the level now suggested by the World Health Organization) has been shown to improve glucose tolerance in humans and decrease the prevalence of diabetes and the metabolic derangements that often precede and accompany it. Reducing the intake of added sugars could translate to reduced diabetes-related morbidity and premature mortality for populations.

Section snippets

Basic Science Data

From an evolutionary standpoint, the body’s response to fructose may have conferred a survival advantage.¹³ Fructose stimulates epigenetic changes¹⁴ and metabolic alterations that shunt calories into storage depots in abdominal fat cells.⁴ Such effects were desirable for early humans who may have needed to endure long periods of food scarcity. Whereas fructose in Paleolithic times was likely encountered only rarely and seasonally (at least in populations living in nontropical climates) in low

Observational Data

Although fructose is found naturally in some whole foods, such as fruits and vegetables, consumption of these foods poses no problem for human health and indeed may be protective against diabetes and broader cardiometabolic dysfunction.77, 78 Moreover, consumption of whole fruits and vegetables is associated with reduced premature mortality.⁷⁹ The difference may be a matter of dose and context; fructose in natural foods exists in lower concentrations (eg, the peach example from earlier) and is

Clinical Trials

One human trial investigated the isocaloric exchange of sucrose for starch among individuals with normal glucose tolerance. When sucrose was provided in a “nibbling pattern” (small doses at frequent intervals throughout the day), no statistically significant increase in insulin levels was found,¹⁰⁴ suggesting (as with the difference between processed foods and natural fruit) that dose and context are important. However, even lower doses buffered by other dietary constituents resulted in

Discussion

From 1776 to 1994, the estimated consumption of added sugar by Americans increased from 4 lb per person per year to 120 lb per person per year.⁸⁰ Approximately 75% of all packaged foods and beverages in the United States today have sugars added to them,¹¹⁷ and 13% of the US population consumes at least 25% of their total calories as added sugars.¹¹⁸ Estimated consumption of sugar-sweetened beverages has increased from 10.8 gallons per person per year in 1950 to 49.3 gallons in 2000.⁸⁰ The

Conclusion

There is no biological need for any added sugars in the diet, particularly those containing fructose (eg, sucrose and HFCS). Although biological response to fructose consumption may have been adaptive for early human ancestors, this response evolved from fructose encountered rarely (at least in populations not living in tropical regions) and in low concentrations in nature. The same biological response is maladaptive when the fructose is encountered frequently and in high concentrations in

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The metabolic syndrome's hepatic form, Non-Alcoholic Fatty Liver Disease (NAFLD), is becoming more common at the same time that obesity and diabetes are rising. A fatty liver and the buildup of 5% fat are characteristics of NAFLD with the absence of any secondary cause. Fatty acid intake increases into the liver, very low-density lipoprotein lowers the transport of TGs through the liver, free fatty acid oxidation decreases, and de novo lipogenesis increases in the liver – these are the four processes by which fatty liver develops. Factors that cause the pathogenesis of NAFLD include a modern, unhealthy lifestyle. Honey, fruit, commercially produced high-fructose corn syrup and many vegetables contains fructose as a monosaccharide. Sorbitol common in many vegetables and fruits is converted to fructose through reaction of sorbitol dehydrogenase in liver. Although end products of fructose catabolism are like those of glucose, after digestion, fructose does not cause the hormonal reaction that glucose does, and metabolism regulation is different. In this review, fructose is highlighted because it has been shown to have an impact on the pathogenesis of NAFLD by causing the buildup of visceral fatty tissue, the emergence of insulin resistance, endoplasmic reticulum stress, inflammation, and oxidative stress.
La forme hépatique du syndrome métabolique, la stéatose hépatique non-alcoolique (NAFLD), est de plus en plus fréquente en même temps que l’obésité et le diabète augmentent. Un foie gras et l’accumulation de 5 % de graisse sont des caractéristiques de la NAFLD en l’absence de toute cause secondaire. L’apport d’acides gras augmente dans le foie, les lipoprotéines de très faible densité (VLDL) réduisent le transport des TG à travers le foie, l’oxydation des acides gras libres diminue et la lipogenèse de novo (DNL) augmente dans le foie : ce sont les quatre processus par lesquels la stéatose hépatique se développe. Les facteurs de la pathogenèse de la NAFLD comprennent un mode de vie moderne et malsain. Le miel, les fruits, le sirop de maïs à haute teneur en fructose produit commercialement et de nombreux légumes contiennent du fructose en tant que monosaccharide. Le sorbitol, commun à de nombreux légumes et fruits, est converti en fructose par la réaction de la sorbitol déshydrogénase dans le foie. Bien que les produits finaux du catabolisme du fructose soient semblables à ceux du glucose, après la digestion, le fructose ne provoque pas la réaction hormonale du glucose, et la régulation du métabolisme est différente. Dans cette revue, le fructose est mis en avant, car il a été démontré qu’il avait un impact sur la pathogenèse de la NAFLD en provoquant l’accumulation de tissu adipeux viscéral, l’émergence d’une résistance à l’insuline (IR), le stress du réticulum endoplasmique, l’inflammation et le stress oxydatif.
The potential therapeutic roles of quercetin and luteolin in hereditary fructose intolerance
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Hereditary fructose intolerance (HFI) is a genetic condition caused by a deficiency in the aldolase B enzyme. Patients with HFI are sensitive to fructose, and exposure to fructose can cause symptoms ranging from nausea to death. Treatment of HFI is currently limited to dietary restriction of fructose intake. However, emerging evidence indicates that dietary restriction is insufficient to fully protect patients from the adverse consequences of HFI. Despite strict dietary adherence, patients with HFI are more likely than the general population to develop non-alcoholic fatty liver disease and insulin resistance. This review proposes and examines evidence supporting the hypothesis that quercetin and luteolin, two inexpensive and widely available supplements, may mitigate the sequelae of HFI by inhibiting gastrointestinal fructose uptake and inhibiting endogenous fructose production. It further explores the additional hypothesis that quercetin and luteolin may mitigate the harms associated with a high-fructose diet in the general, fructose-tolerant populace.
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Early-life environmental factors, such as maternal diet or early-life nutrition, have been described as significant risk factors for anxiety and depression later in life. With the rising intake of fructose since the 1960 s, several adverse effects have been described, but little is known about the impact of early-life high fructose exposure on the risk of developing depression and anxiety later in life. Since animal models provide ways to test this hypothesis longitudinally in an experimental and controlled environment, we performed a systematic review to investigate whether high fructose exposure during early life influences the risk of developing depression or anxiety-like behaviours in animals. We adopted a high-sensitivity strategy to find potential studies. We included 1805 papers for screening, but only found nine eligible studies that tested only high fructose exposure during development, all conducted in rats. Data extraction and analysis revealed that 6 studies found evidence indicating that fructose exposure in early life increases the risk of anxiety or depression. The remaining 3 studies found no altered behavior after fructose exposure. The discrepancies may be caused by multiple factors, such as time of diet exposure, animal strain, behavioural testing differences, and fructose's metabolic influence. Due to weak and contradictory evidence, we could not conclude if early-life fructose exposure influences the risk of anxiety or depression-like behaviors. We propose future directions and suggestions for future studies to strengthen their findings.
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GLUT5, a key protein encoded by the SLC2A5 gene, is involved in the uptake of fructose from the intestine. Currently, with the increased consumption of this sugar and the associated increased incidence of obesity, diabetes and cancer, GLUT5 may represent an important molecular target in the prevention and treatment of these diseases. Here, we demonstrate that overexpression of the SNAI1 and SNAI2 transcription factors in cells expressing high levels of SLC2A5 mRNA reduced SLC2A5 gene expression. Furthermore, a histone deacetylase inhibitor, trichostatin A, which induces SNAI1 and SNAI2 expression, inhibits SLC2A5/GLUT5 expression and sensitizes colon cancer cells to cisplatin and oxaliplatin. This finding might have potential relevance for the development of therapeutic treatments aimed at modulating fructose transport or genes involved in this process for use with certain cancers.
Sugar reduction and sweeteners to improve foods
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Sugar is one of the most controversial additives these days. Apart from its functional properties, it has been generally used to provide foods with a sweet taste. However, health claims associated with the high intake of this component, some of them still elucidating, moved the market to the use of artificial sweeteners to sweeten foods. However, the use of artificial sweeteners is not exempt from several health and environmental risks although the evidence is scarce. The current tendency is focused on the search and employment of natural sweeteners such as stevia, monk fruit, or sweet proteins, which will involve new research to be considered a feasible and profitable alternative. In light of the evidence, reducing sugar concentration in foods should be the priority strategy that public policies should focus on. In this chapter, these aspects are considered including the Mexican efforts to reduce sugar consumption.
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Special articleAdded Fructose: A Principal Driver of Type 2 Diabetes Mellitus and Its Consequences

Abstract

Section snippets

Basic Science Data

Observational Data

Clinical Trials

Discussion

Conclusion

Lancet

Lancet Diabetes Endocrinol

Am J Clin Nutr

J Am Diet Assoc

Am J Clin Nutr

J Biol Chem

Am J Clin Nutr

Biochem Biophys Res Commun

J Am Diet Assoc

Am J Clin Nutr

Am J Clin Nutr

Metabolism

Metabolism

Am J Clin Nutr

Am J Clin Nutr

Am J Clin Nutr

J Pharmacol Toxicol Methods

Atherosclerosis

J Nutr

Am J Clin Nutr

Metabolism

J Nutr

Am J Clin Nutr

Metabolism

Am J Hypertens

Am J Clin Nutr

Metabolism

Metabolism

Metabolism

Metabolism

Lancet

Am J Clin Nutr

Nutrition

J Food Composit Anal

Lancet

Appetite

Am J Clin Nutr

CDC News Room Press Release

Good Calories, Bad Calories

Role of insulin resistance in human disease (syndrome X): an expanded definition

Annu Rev Med

New measure of insulin sensitivity predicts cardiovascular disease better than HOMA estimated insulin resistance

PLoS One

Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis

PLoS One

Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland

Diabetes Care

Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations

Diabetes Care

High fructose corn syrup and diabetes prevalence: a global perspective

Glob Public Health

Woodward Award: the evolution of obesity: insights from the mid-Miocene

Trans Am Clin Climatol Assoc

Diet-induced epigenetic regulation in vivo of the intestinal fructose transporter Glut5 during development of rat small intestine

Biochem J

Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content

Obesity (Silver Spring)

Special article
Added Fructose: A Principal Driver of Type 2 Diabetes Mellitus and Its Consequences