Tissue-Specific Fructose Metabolism in Obesity and Diabetes

Helsley, Robert N; Marchand, François; Gupta, Manoj Kumar; Radulescu, Aurelia; DeBosch, Brian J.; Softic, Samir

doi:10.1007/s11892-020-01342-8

Cited by 48 publications

(32 citation statements)

References 222 publications

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“…Gck also plays an important role in regulating insulin secretion [ 23 , 24 , 25 ]. Khk is expressed in pancreatic islets and contributes to fructose metabolism [ 26 , 27 ]. Their expression in the HFCS group was significantly decreased compared with that in the control group ( Figure 5 A,B).…”

Section: Resultsmentioning

confidence: 99%

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

et al. 2021

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The number of patients with diabetes was approximately 463 million worldwide in 2019, with almost 57.6% of this population concentrated in Asia. Asians often develop type 2 diabetes (T2D), even if they are underweight and consume a smaller amount of food. Soft drinks contain large amounts of sweeteners, such as high-fructose corn syrup (HFCS). Excessive intake of HFCS drinks is considered to be one of the causes of T2D. In the present study, we investigated the effect of excessive consumption of HFCS–water on glucose tolerance and obesity under conditions of controlled caloric intake using a mouse model. Three-week-old male ICR mice were divided into two groups and given free access to 10% HFCS–water or deionized water. The caloric intake was adjusted to be the same in both groups using a standard rodent diet. The excess HFCS–water intake did not lead to obesity, but led to impaired glucose tolerance (IGT) due to insulin-secretion defect. It affected glucose and fructose metabolism; for example, it decreased the expression of glucokinases, ketohexokinase, and glucose transporter 2 in the pancreas. These results suggest that excessive consumption of HFCS drinks, such as soft drinks, without a proper diet, induces nonobese IGT due to insulin-secretion defect.

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Section: Resultsmentioning

confidence: 99%

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

et al. 2021

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“…Furthermore, the expression of HK (Km for fructose 1-4 mM) is greater than KHK-a in these cells, which may explain the preference for this route of metabolism [38,50]. Our data suggests that this route is most relevant in tissues such as the liver, kidney, seminal vesicles, and prostate, where fructose levels achieve concentrations higher than 5 mM [17,51,52].…”

Section: Discussionmentioning

confidence: 81%

GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

et al. 2021

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Background Fructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation. Methods Live cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to “train” non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK-/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose. Results We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK). Conclusions We show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

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“… 28 In summary, the difference in unique enzymes of early fructose metabolism as compared to glucose metabolism causes a much faster and unregulated catabolism, leading to metabolic complications such as ATP depletion, excess uric acid production, and other whole-body metabolic consequences. 29 …”

Section: Dietary Hexose and Pentose Sugarsmentioning

confidence: 99%

Metabolism and Health Impacts of Dietary Sugars

Alam

Kim

Jang

2022

J Lipid Atheroscler

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Consumption of excessive amounts of added sugars and their effects on human health has been a major concern in the last several decades. Epidemiological data suggest that the incidence of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, cardiovascular disease and diabetes, has increased due to chronic surplus consumption of these sugars. While many of these sugars have been isolated and studied for centuries, their health impacts and exact underlying mechanisms are still unclear. In this review, we discuss the pathophysiological role of 6 major simple sugars present in the human diet and the biochemical and molecular pathways related to their metabolism by different organs and gut microbiota, with a focus on the most recent investigations.

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Tissue-Specific Fructose Metabolism in Obesity and Diabetes

Cited by 48 publications

References 222 publications

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of ketohexokinase

Metabolism and Health Impacts of Dietary Sugars

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