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fructose metabolism and metabolic disease
Cui XL, Soteropoulos P, Tolias P, Ferraris RP. Federal government websites often end in .gov or .mil. In the Putative mechanisms linking excess fructose consumption to the metabolic syndrome. Complexity, cost, compliance, and potential ethical issues likely prohibit the conducting of such studies. We recently demonstrated that while hepatic ChREBP is essential for fructose-mediated upregulation of fructolytic, glycolytic, and lipogenic enzymes, ChREBP also mediated upregulation of G6PC, the terminal enzyme in glucose production (133). PMC However, high-fructose feeding readily induces hyperinsulinemia in animal models. While the relationships between some measures of dietary sugar exposure and cardiometabolic risk factors are inconsistent, greater SSB consumption consistently associates with indices of higher cardiometabolic risk (5). A fatty liver will be picked up on ultrasound if the livers fat content is 10-15% or more. 2021 Nov 18;8:760120. doi: 10.3389/fcvm.2021.760120. Other major contributors to added sugar intake include candy and desserts, contributing approximately 4% to 9% of daily energy intake depending on age (2, 4). The role of the carbohydrate response element-binding protein in male fructose-fed rats. Long-Acting ART: Navigating Uncharted Territory in HIV Treatment Recent approval of the first complete long-acting injectable antiretroviral therapy (ART) regimen has set the stage for a new wave of long-acting options that stand to transform HIV treatment. As people get older, their metabolic rate slows down. [38,46,47] in both rats and mice, high Thus, fructose contributes to hepatic triglyceride production both by providing substrate for fatty acid and triglyceride synthesis and by activating signaling systems to enhance lipid production (Figure 2). eCollection 2021. Enzymatic conversion of D-glucose to D-fructose. Stanhope KL. Asipu A, Hayward BE, OReilly J, Bonthron DT. since 2008 and hes spent the last 19 years being a division chief across three very prestigious medical schools. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. />
    • One concern with such studies is that the amount of fructose consumed often exceeds that commonly found in ad libitum diets. If expression of a trait requires only one copy of a gene (one allele) read more ; incidence is unknown. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. Kim M-S, Krawczyk SA, Doridot L, et al. Topping DL, Mayes PA. Thus, it is possible that high-fructose feeding may increase circulating VLDL both by enhancing VLDL production and secretion and by reducing VLDL clearance, but the precise mechanisms remain to be determined. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. ChREBP stimulates glucose-6 phosphatase expression to drive glucose production, and this action is dominant over insulins ability to suppress glucose.6. Fructose metabolism in key metabolic tissues including the small, MeSH Inheritance is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. Karim S, Adams DH, Lalor PF. Intravenous hydration and glucose must be given in a timely fashion, otherwise the disease can be fatal. During periods of metabolic stress, affected individuals may develop hypoglycemia, lethargy, vomiting, seizures, and liver dysfunction. Consequences of fructose overconsumption. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Since removing sugar, artificial sweeteners and fructose including caffeine to reduce (BS highs + lows + sugar cravings). o [ abdominal pain pediatric ] Steinitz H, Mizrahy O. Baraille F, Planchais J, Dentin R, Guilmeau S, Postic C. Integration of ChREBP-mediated glucose sensing into whole body metabolism. Fructose effects on appetite and adiposity, Next-Generation Sequencing in Medicine (Jun 2022), New Therapeutic Targets in Cardiovascular Diseases (Mar 2022), http://health.gov/dietaryguidelines/2015/guidelines/, https://escholarship.org/uc/item/7vv7z7zw, http://www.who.int/nutrition/publications/guidelines/sugars_intake/en/, American Society for Clinical Investigation. #232 Shoulder, elbow, wrist, and hand: diagnosis, treatment, and surgery of the upper extremities | Alton Barron, M.D. Hereditary fructose intolerance. Thus, PGC1 is uniquely positioned to coordinately regulate both ChREBP and SREBP1c activities in the context of high-fructose feeding. Feeding animals large amounts of fructose can rapidly produce multiple features of the metabolic syndrome, including obesity, dyslipidemia, fatty liver, hypertension, insulin resistance, and diabetes (18, 19). Ali M, Rellos P, Cox TM. They hardly age, its incredible, and they seem to be thriving, whilst eating ridiculous amounts of fruit everyday! Bethesda, MD 20894, Web Policies Look how many Pfizer drugs are used to treat the symptoms of metabolic disease. The precise mechanisms by which ALDOB deficiency causes symptoms are not entirely clear. Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. 2022 Oct 13;23(20):12215. doi: 10.3390/ijms232012215. | Bile acids in the plasma act as signaling molecules and are altered in many liver diseases. in: Specifically, dietary fructose is a major promoter of hepatic de novo lipogenesis, in which carbon precursors of acetyl-CoA are converted into fatty acids, contributing to fatty liver, said Kathryn E. Wellen, PhD, associate professor of cancer biology, University of Pennsylvania, Philadelphia. Enzymes are made of amino acids, and glyphosate is an analogue of glycine, the smallest amino acid, how could that affect enzyme function? Before Increased sugar consumption results in increased uptake of fructose, resulting in ATP depletion that may cause increased uric acid production and hyperuricemia leading to arterial hypertension. Banting Lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Google Scholar, Find articles by As fructose is robustly metabolized in the kidney, fructose-mediated changes in renal salt handling may also be important. Otherwise, high fasting glucose or Type 2 diabetes plus two or more of the additional signs and symptoms of metabolic syndrome is a strong indication. Consistent with this, we recently showed that carbohydrate-responsive elementbinding protein (ChREBP), a transcription factor that responds to intracellular carbohydrate nutrients and a known transcriptional regulator of TXNIP (37), also regulates intestinal GLUT5 expression and is required for systemic fructose tolerance (38). The conversation over salt helping to create fructose was a little concerning. Moreover, elevated serum uric acid levels and gout are associated with other cardiometabolic risk factors in diverse populations (7678). Sign-up (free) to receive the5 Tactics in my Longevity Toolkitdelivered by email as a 5-day course. 2022 Sep 29;23(1):75. doi: 10.1186/s40360-022-00613-2. The trusted provider of medical information since 1899, Introduction to Inherited Disorders of Metabolism, Approach to the Patient With a Suspected Inherited Disorder of Metabolism, Mitochondrial Oxidative Phosphorylation Disorders, Overview of Amino Acid and Organic Acid Metabolism Disorders, Branched-Chain Amino Acid Metabolism Disorders, Overview of Carbohydrate Metabolism Disorders, Overview of Fatty Acid and Glycerol Metabolism Disorders, Cholesteryl Ester Storage Disease and Wolman Disease, Overview of Purine and Pyrimidine Metabolism Disorders, Medically Reviewed Oct 2021 | Modified Sep 2022. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Criticism and skepticism can be far more useful than praise and unflinching belief. -, Douard V., Ferraris R.P. Metabolic and endocrine profiles in response to systemic infusion of fructose and glucose in rhesus macaques. Lin J, Handschin C, Spiegelman BM. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. and transmitted securely. In this episode, Rick explains how the body can generate fructose from glucose and how circulating glucose and salt levels can activate this conversion. Metabolic Pathways Involving Fructose Fructose is passively absorbed in the enterocytes by facilitative glucose transporter 5 (GLUT5) and to a lesser extent by facilitative glucose transporter 2 (GLUT2), which plays a major role in the liver. Great episode! Novel treatment strategies without undesirable effects are urgently needed. The small intestine clears most low-dose fructose before fructose reaches the liver, but high-dose fructose overwhelms intestinal catabolism and spills over to the liver where it is converted to fat.2 Intestinal fructose catabolism shields the liver from steatosis.3 Slow fructose intake can suppress fructose-induced hepatic lipogenesis. This site complies with the HONcode standard for trustworthy health information: verify here. GCKR sequesters GCK in an inactive state in the nucleus (6365). Laeger T, et al. Such compensatory mechanisms may contribute to difficulties in accurately assessing dietary sugar consumption in both observational and interventional studies. Conflict of interest: M.A. Cheng HM, Gonzlez RG. the relationship between the glucose-centric model of insulin resistance and fructose/uric acid metabolism. I love Richard Johnson as a guest! Metabolic Effects of Fructose with Rick Johnson, M.D. Science. A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Address correspondence to: Mark A. Herman, 300 N. Duke Street, Carmichael Building, Duke University, Durham, North Carolina 27705, USA. Uyeda K, Repa JJ. Pezel T, Unterseeh T, Hovasse T, Asselin A, Lefvre T, Chevalier B, Neylon A, Benamer H, Champagne S, Sanguineti F, Toupin S, Garot P, Garot J. For instance, decreases in intracellular free phosphate due to rapid hepatic fructose phosphorylation can increase uric acid production through activation of AMP deaminase, which leads to catabolism of AMP to uric acid (72, 73). For some, dangerous. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. Fructose may also activate SREBP1c independently of insulin, since SREBP1c responds to high-fructose feeding in liver-specific insulin receptorknockout (LIRKO) mice (125). Nutrients. Bookshelf Mooradian A.D., Smith M., Tokuda M. The role of artificial and natural sweeteners in reducing the consumption of table sugar: A narrative review. Consequences of fructose ingestion are not limited to the intestine or liver, but also affect multiple organs including adipose tissue, the vasculature, heart, and kidney, as well as the satiety regulation regions in the brain. Regulation of hepatic de novo lipogenesis in humans. 2011 Jan;201(1):55-62. doi: 10.1111/j.1748-1716.2010.02167.x. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar Comments that harass other posters will be deleted. Acta Physiol (Oxf). Then have lunch at the destination. 2022. A causal association is supported by evidence that intake of 1 liter of SSB daily for 6 months increased visceral and liver fat, but increases were not observed in those consuming isocaloric semiskim milk, noncaloric diet soda, or water (10). These facts will cause the increase in AMPK activity, which will lead to the repression of POMC/CART neurons and the activation of NPY/AgRP, leading to reduced satiety suppression, as well as higher hedonic reward to food and increasing food intake, in addition to playing a possible role in cognitive functions. Glucose (G) binds and activates the taste receptor type 1 member (STR) comprised of a heterodimer T1R2+T1R3 and G-protein gustducin, leading to its dissociation into G and G subunits and activation of phospholipase C . I also wouldve like to see some commentary about how this pertains to non-concentrated sources of fructose. Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Deletion of Glut5 in mice reduces fructose absorption by 75% and causes cecum and colon dilatation as well as gas accumulation (29). Hannou SA, Haslam DE, McKeown NM, Herman MA. An Aldob-deficient mouse model mimics the human HFI condition (98). Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. | doi: 10.1126/science.125.3249.648. Bjrkman O, Felig P. Role of the kidney in the metabolism of fructose in 60-hour fasted humans. FGF21 regulates sweet and alcohol preference. Cell Metab. Additionally, dietary fructose decreases leptin excursions compared with isocaloric dietary glucose, and fructose is less potent than glucose in suppressing the orexigenic hormone ghrelin (171). American Society for Clinical Investigation. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Sobrecases H, et al. All rights reserved. Separate circuitries encode the hedonic and nutritional values of sugar. Recent data showed that high-fructose feeding induces intestinal thioredoxin-interacting protein (TXNIP), which binds and regulates GLUT5-mediated intestinal fructose transport (36). Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. Martini AC, et al. Fructose biochemistry. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. I have the same question and not the answer. Metabolic intermediates in liver of rats given large amounts of fructose or dihydroxyacetone. Lanaspa MA, et al. Emerging data suggest that this tissue restriction of fructose metabolism can be rescinded in oxygen-deprived environments. ASOs targeting PGC1 prevented SREBP1c expression and lipogenesis, which in turn decreased lipid accumulation in fructose-fed rat livers. J Physiol. Jang C, Wada S, Yang S, et al. Jin J, Liu J, Luo Y, He H, Zheng X, Zheng C, Huang Y, Chen Y. Nutr Metab (Lond). J Muscle Res Cell Motil. Unabsorbed fructose can impose an osmotic load on the distal small intestine and the colon, which may contribute to gastrointestinal symptoms (32). Hepatic lipid accumulation results from a combination of increased hepatic de novo lipogenesis (DNL), esterification of preformed fatty acids derived from the diet or adipose stores, decreased VLDL secretion, and decreased hepatic fatty acid oxidation. Eur Heart J. Erion DM, et al. His primary focus in research has been on the mechanisms causing kidney disease, but it was in doing this that he became really interested in the connection between fructose (and fructose metabolism) and obesity, diabetes, heart disease, hypertension, and metabolic disease. F1P is cleaved to DHAP and glyceraldehyde by ALDOB. fructose absorption by 75% and causes cecum and colon dilatation as well as gas accumulation (29). Regards, Rob (Vancouver). Accessibility eCollection 2022. Would you like email updates of new search results? However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease (84). Comments requesting medical advice will not be responded to, as I am not legally permitted to practice medicine over the internet. Fructose is replaced in The average consumption of fructose in US populations accounts for approximately 9% of total energy intake, while consumers in the 95th percentile average approximately 15% of total energy from fructose (22). WHO Website. This deficiency can be fatal in neonates. The liver is at a metabolic crossroads and is crucial for gauging nutrient consumption and integrating peripheral nutrient status to regulate systemic fuel storage versus provisioning. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. metabolic syndrome, and diabetes. The mechanisms by which fructose contributes to the development of hypertension are less well characterized than its effects on glucose and lipid homeostasis. Sugar-sweetened beverage consumption is associated with change of visceral adipose tissue over 6 years of follow-up. Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity. However, these results are confounded by the fact that GLUT5-knockout mice suffer generalized malabsorption and become ill when challenged with fructose. Lanaspa MA, Tapia E, Soto V, Sautin Y, Snchez-Lozada LG. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Acute treatment of fructose-1,6-biphosphatase deficiency is oral or IV glucose. Nevertheless, some short-term interventional studies, even those within the range of normal fructose consumption, show that fructose can rapidly impair intermediate physiological endpoints like circulating lipids and insulin sensitivity in humans (25). Inheritance is autosomal recessive Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. sharing sensitive information, make sure youre on a federal Due to the differences in hepatic glucose and fructose metabolism, a larger fraction of diet-derived fructose than glucose metabolites are available for conversion to fat in the liver via DNL in animals and humans (20, 118120). | Part I, How Fructose Drives Metabolic Disease with Rick Johnson, M.D. Measurement of glucose and fructose in clinical samples using gas chromatography/mass spectrometry. Avena NM. Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. Despite strong indications that increased consumption of added sugars correlates with greater risks of developing cardiometabolic syndrome (CMS) and cardiovascular disease (CVD), independent of the caloric intake, the worldwide sugar consumption remains high. Comparison with sucrose and its constituent monosaccharides. These results are consistent with dietary intervention studies in humans indicating that either eucaloric substitution or hypercaloric addition of fructose may have more significant effects on hepatic insulin resistance than peripheral insulin resistance (157). PGC1 can also bind SREBP1 and ChREBP and enhance their transcriptional activity (147, 148). Herman MA, Samuel VT. in: Review article: Fructose malabsorption and the bigger picture. Both fructose-derived DHAP and GA3P enter the glycolytic/gluconeogenic metabolite pool at the triose-phosphate level, and these metabolites have numerous metabolic fates. Burch HB, Max P, Ghyu K, Lowry OH. Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. F-1-P is then cleaved by aldolase B into dihydroxyacetone phosphate and glyceraldehyde. An unbelievably prolific author, Rick has well over 700 publications in JAMA, New England Journal of Medicine, Science, et Cetera. The .gov means its official. Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF. But I think we all know why they would not want to move forward. Yes! Clinical features include various combinations of hypoglycemia (low blood sugar), liver enlargement, 2013;591:401414. Johnson RJ, et al. Parks EJ, Skokan LE, Timlin MT, Dingfelder CS. Crescenzo R, Bianco F, Falcone I, Coppola P, Liverini G, Iossa S. Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Raivio KO, Becker MA, Meyer LJ, Greene ML, Nuki G, Seegmiller JE. [ 7] The canonical pathway of fructose metabolism is fructolysis, that is initiated by KHK to produce fructose-1-phosphate (F-1-P). Enhanced palatability may increase feeding behavior and thus encourage overeating (164). On the basis of short-term overfeeding studies conducted predominantly in animals, the fructose component of SSBs and added sugar appears to be particularly harmful. These features are suggestive of fructose malabsorption, frequently cited as a cause of Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. Office of Disease Prevention and Health Promotion. Timely diagnosis leads to early treatment and read more .).