Is There Glucose Production Outside of the Liver and Kidney?

Previs, Stephen F.; Brunengraber, Daniel Z.; Brunengraber, Henri

doi:10.1146/annurev-nutr-080508-141134

Cited by 37 publications

(26 citation statements)

References 73 publications

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“…Gluconeogenic activity is not normally presented in cells that are not originated from liver, kidney, intestine or muscle (53). The glycogenic feature of brain metastatic cells enables another pro-survival ability to these cells, glucose storage, which helps cancer cells to resist external metabolic stresses.…”

Section: Discussionmentioning

confidence: 99%

Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain

et al. 2015

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Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the non-oxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBPs) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis, and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain

et al. 2015

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“…The resulting intestinal glucose release, detected by a hepatoportal sensor, activates hypothalamic nuclei involved in the regulation of food intake. Whereas some authors claim for no credible evidence to support the concept that glucose can be produced by intestine (43), it has been recently demonstrated that protein-induced satiety was abolished in the absence of intestinal gluconeogenesis in mice with intestine-specific deletion of the glucose-6-phosphatase (42). This points to the importance of protein absorption mediated by PEPT1 in the control of body energy homeostasis and is also in line with the improved glucose homeostasis reported in obese diabetic patients fed on a protein-enriched diet (53).…”

Section: Discussionmentioning

confidence: 99%

Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance

Huong

Hindlet

Waligora‐Dupriet

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Previous studies demonstrated that PEPT1 expression and function in jejunum are reduced in diabetes and obesity, suggesting a nitrogen malabsorption from the diet. Surprisingly, we reported here a decrease in gut nitrogen excretion in high-fat diet (HFD)-fed mice and further investigated the mechanisms that could explain this apparent contradiction. Upon HFD, mice exhibited an increased concentration of free amino acids (AAs) in the portal vein (60%) along with a selective increase in the expression of two AA transporters (Slc6a20a, Slc36a1), pointing to a specific and adaptive absorption of some AAs. A delayed transit time (ϩ40%) and an increased intestinal permeability (ϩ80%) also contribute to the increase in nitrogen absorption. Besides, HFD mice exhibited a 2.2-fold decrease in fecal DNA resulting from a reduction in nitrogen catabolism from cell desquamation and/or in the intestinal microbiota. Indeed, major quantitative (2.5-fold reduction) and qualitative alterations of intestinal microbiota were observed in feces of HFD mice. Collectively, our results strongly suggest that both increased AA transporters, intestinal permeability and transit time, and changes in gut microbiota are involved in the increased circulating AA levels. Modifications in nitrogen homeostasis provide a new insight in HFD-induced obesity and glucose intolerance; however, whether these modifications are beneficial or detrimental for the HFD-associated metabolic complications remains an open issue.

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“…Although the small intestine in adult mammals is thought to have a low capacity for gluconeogenic activity (41), recent studies (reviewed in Ref. 35) suggest that intestinal gluconeogenesis may contribute up to 25% of total endogenous glucose production during fasting, thereby, via the periportal neural system, modulating hunger sensations and whole body glucose homeostasis, especially between meals.…”

Section: R505 Fructose Regulates Fructolytic and Gluconeogenic Genesmentioning

confidence: 99%

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK

Patel

Douard

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Patel C, Douard V, Yu S, Tharabenjasin P, Gao N, Ferraris RP. Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Am J Physiol Regul Integr Comp Physiol 309: R499 -R509, 2015. First published June 17, 2015; doi:10.1152/ajpregu.00128.2015.-Marked increases in fructose consumption have been tightly linked to metabolic diseases. One-third of ingested fructose is metabolized in the small intestine, but the underlying mechanisms regulating expression of fructose-metabolizing enzymes are not known. We used genetic mouse models to test the hypothesis that fructose absorption via glucose transporter protein, member 5 (GLUT5), metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein in brain 11a (Rab11a)-dependent endosomes are required for the regulation of intestinal fructolytic and gluconeogenic enzymes. Fructose feeding increased the intestinal mRNA and protein expression of these enzymes in the small intestine of adult wild-type (WT) mice compared with those gavage fed with lysine or glucose. Fructose did not increase expression of these enzymes in the GLUT5 knockout (KO) mice. Blocking intracellular fructose metabolism by KHK ablation also prevented fructose-induced upregulation. Glycolytic hexokinase I expression was similar between WT and GLUT5-or KHK-KO mice and did not vary with feeding solution. Gavage feeding with the fructose-specific metabolite glyceraldehyde did not increase enzyme expression, suggesting that signaling occurs before the hydrolysis of fructose to three-carbon compounds. Impeding GLUT5 trafficking to the apical membrane using intestinal epithelial cell-specific Rab11a-KO mice impaired fructose-induced upregulation. KHK expression was uniformly distributed along the villus but was localized mainly in the basal region of the cytosol of enterocytes. The feedforward upregulation of fructolytic and gluconeogenic enzymes specifically requires GLUT5 and KHK and may proactively enhance the intestine's ability to process anticipated increases in dietary fructose concentrations. fructolysis; glyceraldehyde; gluconeogenesis; glucose transporter protein, member 5; ketohexokinase; Ras-related protein in brain 11a; mice; small intestine

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Is There Glucose Production Outside of the Liver and Kidney?

Cited by 37 publications

References 73 publications

Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain

Gain of Glucose-Independent Growth upon Metastasis of Breast Cancer Cells to the Brain

Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK

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