Current Diabetes Reports

, 18:97 | Cite as

Metabolic Abnormalities in Diabetes and Kidney Disease: Role of Uremic Toxins

  • Laetitia KoppeEmail author
  • Denis Fouque
  • Christophe O. Soulage
Microvascular Complications—Nephropathy (M Afkarian and B Roshanravan, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Nephropathy


Purpose of Review

Chronic kidney disease (CKD) is characterized by the accumulation of uremic retention solutes (URS) and is associated with perturbations of glucose homeostasis even in absence of diabetes. The underlying mechanisms of insulin resistance, β cell failure, and increase risk of diabetes in CKD, however, remain unclear. Metabolomic studies reported that some metabolites are similar in CKD and diabetic kidney disease (DKD) and contribute to the progression to end-stage renal disease. We attempted to discuss the mechanisms involved in the disruption of carbohydrate metabolism in CKD by focusing on the specific role of URS.

Recent Findings

Recent clinical data have demonstrated a defect of insulin secretion in CKD. Several studies highlighted the direct role of some URS (urea, trimethylamine N-oxide (TMAO), p-cresyl sulfate, 3-carboxylic acid 4-methyl-5-propyl-2-furan propionic (CMPF)) in glucose homeostasis abnormalities and diabetes incidence.


Gut dysbiosis has been identified as a potential contributor to diabetes and to the production of URS. The complex interplay between the gut microbiota, kidney, pancreas β cell, and peripheral insulin target tissues has brought out new hypotheses for the pathogenesis of CKD and DKD. The characterization of intestinal microbiota and its associated metabolites are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials, and new treatments for CKD and DKD.


Glucose homeostasis Insulin resistance Pancreas β cells Chronic kidney disease Uremic toxins Dysbiosis 


Compliance with Ethical Standards

Conflict of Interest

L. Koppe and C.O. Soulage declare that they have no conflict of interest.

D. Fouque received honoraria and travel support from Fresenius Kabi, which markets a ketoanalogue supplement.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Menon V, Greene T, Pereira AA, Wang X, Beck GJ, Kusek JW, et al. Glycosylated hemoglobin and mortality in patients with nondiabetic chronic kidney disease. J Am Soc Nephrol. 2005;16:3411–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Koppe L, Pelletier CC, Alix PM, Kalbacher E, Fouque D, Soulage CO, et al. Insulin resistance in chronic kidney disease: new lessons from experimental models. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2014;29:1666–74.Google Scholar
  4. 4.
    • Sharma K, Karl B, Mathew AV, Gangoiti JA, Wassel CL, Saito R, et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013;24:1901–12. This study present a large urine metabolomics study in diabetic kidney disease and identify potential biomarkers of diabetic complications. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012;23:1258–70.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Eloot S, Schepers E, Barreto DV, Barreto FC, Liabeuf S, Van Biesen W, et al. Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol. 2011;6:1266–73.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. Vidal-Puig AJ, editor. PLoS Biol. 2011;9:e1001212.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cox AJ, West NP, Cripps AW. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol. 2015;3:207–15.CrossRefPubMedGoogle Scholar
  10. 10.
    de Goffau MC, Fuentes S, van den Bogert B, Honkanen H, de Vos WM, Welling GW, et al. Aberrant gut microbiota composition at the onset of type 1 diabetes in young children. Diabetologia. 2014;57:1569–77.CrossRefPubMedGoogle Scholar
  11. 11.
    Koppe L, Mafra D, Fouque D. Probiotics and chronic kidney disease. Kidney Int. 2015;88:958–66.CrossRefPubMedGoogle Scholar
  12. 12.
    DeFronzo RA, Tobin JD, Rowe JW, Andres R. Glucose intolerance in uremia. Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin. J Clin Invest. 1978;62:425–35.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J. Insulin resistance in uremia. J Clin Invest. 1981;67:563–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Friedman JE, Dohm GL, Elton CW, Rovira A, Chen JJ, Leggett-Frazier N, et al. Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors. Am J Phys. 1991;26:E87–94.Google Scholar
  15. 15.
    Chapagain A, Caton PW, Kieswich J, Andrikopoulos P, Nayuni N, Long JH, et al. Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia. Proc Natl Acad Sci U S A. 2014;111:3817–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fadda GZ, Hajjar SM, Perna AF, Zhou XJ, Lipson LG, Massry SG. On the mechanism of impaired insulin secretion in chronic renal failure. J Clin Invest. 1991;87:255–61.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    •• Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai X-Q, Nguyen BN, et al. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest. 2016;126:3598–612. This study demonstrates the role of kidney disease and particular of urea in perturbation of insulin secretion associated with renal failure in mice and human islets. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Sui Y, Zhao H-L, Ma RCW, Ho CS, Kong APS, Lai FMM, et al. Pancreatic islet beta-cell deficit and glucose intolerance in rats with uninephrectomy. Cell Mol Life Sci CMLS. 2007;64:3119–28.CrossRefPubMedGoogle Scholar
  19. 19.
    Nakamura Y, Yoshida T, Kajiyama S, Kitagawa Y, Kanatsuna T, Kondo M. Insulin release from column-perifused isolated islets of uremic rats. Nephron. 1985;40:467–9.CrossRefPubMedGoogle Scholar
  20. 20.
    •• de Boer IH, Zelnick L, Afkarian M, Ayers E, Curtin L, Himmelfarb J, et al. Impaired glucose and insulin homeostasis in moderate-severe CKD. J Am Soc Nephrol. 2016;27:2861–71. This study shows a combination of insulin resistance and inadequate augmentation of insulin secretion led to an impaired of glucose tolerance in nondiabetic patients with CKD. PubMedPubMedCentralGoogle Scholar
  21. 21.
    Idorn T, Knop FK, Jørgensen M, Holst JJ, Hornum M, Feldt-Rasmussen B. Gastrointestinal factors contribute to glucometabolic disturbances in nondiabetic patients with end-stage renal disease. Kidney Int. 2013;83:915–23.CrossRefPubMedGoogle Scholar
  22. 22.
    Alvestrand A, Mujagic M, Wajngot A, Efendic S. Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance. Clin Nephrol. 1989;3:175–83.Google Scholar
  23. 23.
    Kanauchi M, Akai Y, Hashimoto T. Validation of simple indices to assess insulin sensitivity and pancreatic Beta-cell function in patients with renal dysfunction. Nephron. 2002;92:713–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Meier JJ, Nauck MA, Kranz D, Holst JJ, Deacon CF, Gaeckler D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Sechi LA, Catena C, Zingaro L, Melis A, Marchi SD. Abnormalities of glucose metabolism in patients with early renal failure. Diabetes. 2002;51:1226–32.CrossRefPubMedGoogle Scholar
  26. 26.
    • Jia T, Risérus U, Xu H, Lindholm B, Arnlöv J, Sjögren P, et al. Kidney function, β-cell function and glucose tolerance in older men. J Clin Endocrinol Metab. 2014;100:587–93. This study shows in a large cohort of patients with CKD by euglycaemic hyperinsulinaemic clamp that β-cell function appropriately compensated the loss in insulin sensitivity. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    • Pham H, Robinson-Cohen C, Biggs ML, Ix JH, Mukamal KJ, Fried LF, et al. Chronic kidney disease, insulin resistance, and incident diabetes in older adults. Clin J Am Soc Nephrol. 2012;7:588–94. This study observes that renal failure was associated with insulin resistance and β cell function was appropriately augmented and incident diabetes were not increased. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Allegra V, Mengozzi G, Martimbianco L, Vasile A. Glucose-induced insulin secretion in uremia: effects of aminophylline infusion and glucose loads. Kidney Int. 1990;38:1146–50.CrossRefPubMedGoogle Scholar
  29. 29.
    Mak RH. Effect of metabolic acidosis on insulin action and secretion in uremia. Kidney Int. 1998;54:603–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Hampers CL, Soeldner JS, Doak PB, Merrill JP. Effect of chronic renal failure and hemodialysis on carbohydrate metabolism. J Clin Invest. 1966;45:1719–31.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mak RH. 1,25-Dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney Int. 1998;53:1353–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Mak RH, Bettinelli A, Turner C, Haycock GB, Chantler C. The influence of hyperparathyroidism on glucose metabolism in uremia. J Clin Endocrinol Metab. 1985;60:229–33.CrossRefPubMedGoogle Scholar
  33. 33.
    Nerpin E, Risérus U, Ingelsson E, Sundström J, Jobs M, et al. Insulin sensitivity measured with euglycemic clamp is independently associated with glomerular filtration rate in a community-based cohort. Diabetes Care. 2008;31:1550–5.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Flier JS, Minaker KL, Landsberg L, Young JB, Pallotta J, Rowe JW. Impaired in vivo insulin clearance in patients with severe target-cell resistance to insulin. Diabetes. 1982;31:132–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Fliser D, Pacini G, Engelleiter R, Kautzky-Willer A, Prager R, Franek E, et al. Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int. 1998;53:1343–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Trirogoff ML, Shintani A, Himmelfarb J, Ikizler TA. Body mass index and fat mass are the primary correlates of insulin resistance in nondiabetic stage 3-4 chronic kidney disease patients. Am J Clin Nutr. 2007;86:1642–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Gnudi L, Coward RJM, Long DA. Diabetic nephropathy: perspective on novel molecular mechanisms. Trends Endocrinol Metab. 2016;27:820–30.CrossRefPubMedGoogle Scholar
  38. 38.
    Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Häring H-U. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol. 2016;12:721–37.CrossRefPubMedGoogle Scholar
  39. 39.
    Lorenzo C, Nath SD, Hanley AJG, Abboud HE, Gelfond JAL, Haffner SM. Risk of type 2 diabetes among individuals with high and low glomerular filtration rates. Diabetologia. 2009;52:1290–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Sahakyan K, Lee KE, Shankar A, Klein R. Serum cystatin C and the incidence of type 2 diabetes mellitus. Diabetologia. 2011;54:1335–40.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    •• Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus. Kidney Int. 2018;93:741–52. This study shows in more than 1 million on USA veterans that higher levels of urea and lower glomerular filtration rate are associated with increased risk of incident diabetes. CrossRefPubMedGoogle Scholar
  42. 42.
    Werder AA, Amos MA, Nielsen AH, Wolfe GH. Comparative effects of germfree and ambient environments on the development of cystic kidney disease in CFWwd mice. J Lab Clin Med. 1984;103:399–407.PubMedGoogle Scholar
  43. 43.
    Aronov PA, Luo FJ-G, Plummer NS, Quan Z, Holmes S, Hostetter TH, et al. Colonic contribution to uremic solutes. J Am Soc Nephrol. 2011;22:1769–76.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    • Mishima E, Fukuda S, Mukawa C, Yuri A, Kanemitsu Y, Matsumoto Y, et al. Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. Kidney Int. 2017;92:634–45. Using germ-free mice models, this study has determined the role of intestinal microbiota on uremic toxins production. CrossRefPubMedGoogle Scholar
  45. 45.
    Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.CrossRefGoogle Scholar
  46. 46.
    Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104:979–84.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Caesar R, Reigstad CS, Bäckhed HK, Reinhardt C, Ketonen M, Lundén GÖ, et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut. 2012;61:1701–7.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and clinical impact of organic uremic retention solutes: a comprehensive update. Toxins. 2018;8:10.Google Scholar
  49. 49.
    Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–84.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kim RB, Morse BL, Djurdjev O, Tang M, Muirhead N, Barrett B, et al. Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events. Kidney Int. 2016;89:1144–52.CrossRefPubMedGoogle Scholar
  51. 51.
    Xu K-Y, Xia G-H, Lu J-Q, Chen M-X, Zhen X, Wang S, et al. Impaired renal function and dysbiosis of gut microbiota contribute to increased trimethylamine-N-oxide in chronic kidney disease patients. Sci Rep. 2017;7:1445.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kikuchi M, Ueno M, Itoh Y, Suda W, Hattori M. Uremic toxin-producing gut microbiota in rats with chronic kidney disease. Nephron. 2017;135:51–60.CrossRefPubMedGoogle Scholar
  53. 53.
    • van der Kloet FM, Tempels FWA, Ismail N, van der Heijden R, Kasper PT, Rojas-Cherto M, et al. Discovery of early-stage biomarkers for diabetic kidney disease using ms-based metabolomics (FinnDiane study). Metabolomics. 2012;8:109–19. This study shows that changes in some uremic toxins in urine measured by metabolomics analyze are predictive of significant rise in albumin excretion rate in type 1 diabetes patients. CrossRefPubMedGoogle Scholar
  54. 54.
    • Niewczas MA, Sirich TL, Mathew AV, Skupien J, Mohney RP, Warram JH, et al. Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study. Kidney Int. 2014;85:1214–24. This study is a large metabolomic study that has described abnormal plasma concentrations of uremic solutes either contribute to progression to end stage renal disease in type 2 diabetes. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wong J, Piceno YM, Desantis TZ, Pahl M, Andersen GL, Vaziri ND. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am J Nephrol. 2014;39:230–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Vaziri ND, Yuan J, Norris K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am J Nephrol. 2013;37:1–6.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang F, Zhang P, Jiang H, Cheng S. Gut bacterial translocation contributes to microinflammation in experimental uremia. Dig Dis Sci. 2012;57:2856–62.CrossRefPubMedGoogle Scholar
  58. 58.
    Wang F, Jiang H, Shi K, Ren Y, Zhang P, Cheng S. Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. Nephrol Carlton Vic. 2012;17:733–8.CrossRefGoogle Scholar
  59. 59.
    Vaziri ND, Dure-Smith B, Miller R, Mirahmadi MK. Pathology of gastrointestinal tract in chronic hemodialysis patients: an autopsy study of 78 cases. Am J Gastroenterol. 1985;80:608–11.PubMedGoogle Scholar
  60. 60.
    Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol. 2014;25:1897–907.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhao T, Zhang H, Zhao T, Zhang X, Lu J, Yin T, et al. Intrarenal metabolomics reveals the association of local organic toxins with the progression of diabetic kidney disease. J Pharm Biomed Anal. 2012;60:32–43.CrossRefPubMedGoogle Scholar
  62. 62.
    Andrade-Oliveira V, Amano MT, Correa-Costa M, Castoldi A, Felizardo RJF, de Almeida DC, et al. Gut Bacteria products prevent AKI induced by ischemia-reperfusion. J Am Soc Nephrol. 2015;26:1877–88.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Nigam SK, Wu W, Bush KT, Hoenig MP, Blantz RC, Bhatnagar V. Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin J Am Soc Nephrol. 2015;10:2039–49.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Koppe L, Fouque D. Microbiota and prebiotics modulation of uremic toxin generation. Panminerva Med. 2017;59:173–87.PubMedGoogle Scholar
  65. 65.
    McCaleb ML, Izzo MS, Lockwood DH. Characterization and partial purification of a factor from uremic human serum that induces insulin resistance. J Clin Invest. 1985;75:391–6.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Raubenheimer PJ, Nyirenda MJ, Walker BR. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes. 2006;55:2015–20.CrossRefPubMedGoogle Scholar
  67. 67.
    Schugar RC, Shih DM, Warrier M, Helsley RN, Burrows A, Ferguson D, et al. The TMAO-producing enzyme Flavin-containing monooxygenase 3 regulates obesity and the Beiging of white adipose tissue. Cell Rep. 2017;19:2451–61.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol. 2013;24:88–99.CrossRefPubMedGoogle Scholar
  69. 69.
    Koppe L, Alix PM, Croze ML, Chambert S, Vanholder R, Glorieux G, et al. P-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance. Nephrol Dial Transplant. 2017;32:2000–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Minakuchi H, Wakino S, Hosoya K, Sueyasu K, Hasegawa K, Shinozuka K, et al. The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats. Nephrol Dial Transplant. 2016;31:413–23.CrossRefPubMedGoogle Scholar
  71. 71.
    Pelantová H, Bugáňová M, Holubová M, Šedivá B, Zemenová J, Sýkora D, et al. Urinary metabolomic profiling in mice with diet-induced obesity and type 2 diabetes mellitus after treatment with metformin, vildagliptin and their combination. Mol Cell Endocrinol. 2016;431:88–100.CrossRefPubMedGoogle Scholar
  72. 72.
    Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23:850–8.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56:1761–72.CrossRefGoogle Scholar
  74. 74.
    Gomes JMG, Costa JA, Alfenas RCG. Metabolic endotoxemia and diabetes mellitus: a systematic review. Metabolism. 2017;68:133–44.CrossRefPubMedGoogle Scholar
  75. 75.
    Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, Reyes-Gavilán DL, et al. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Zhao L, Zhang F, Ding X, Wu G, Lam YY, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science. 2018;359:1151–6.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    • D’Apolito M, Du X, Zong H, Catucci A, Maiuri L, Trivisano T, et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest. 2010;120:203–13. This study demonstrates the role of urea in insulin resistance in rodent and cell models. CrossRefPubMedGoogle Scholar
  78. 78.
    • Prentice KJ, Luu L, Allister EM, Liu Y, Jun LS, Sloop KW, et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell Metab. 2014;19:653–66. This study shows that CMPF a metabolite increase in diabete and renal desease is involved in β-Ccell dysfunction. CrossRefPubMedGoogle Scholar
  79. 79.
    Gruppen EG, Garcia E, Connelly MA, Jeyarajah EJ, Otvos JD, Bakker SJL, et al. TMAO is associated with mortality: impact of modestly impaired renal function. Sci Rep. 2017;7:13781.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Heianza Y, Sun D, Li X, DiDonato JA, Bray GA, Sacks FM, et al. Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS lost trial. Gut. 2018;
  81. 81.
    Poesen R, Evenepoel P, de Loor H, Delcour JA, Courtin CM, Kuypers D, et al. The influence of prebiotic Arabinoxylan oligosaccharides on microbiota derived uremic retention solutes in patients with chronic kidney disease: a randomized controlled trial. PLoS One. 2016;11:e0153893.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Chiu C-A, Lu L-F, Yu T-H, Hung W-C, Chung F-M, Tsai I-T, et al. Increased levels of total P-Cresylsulphate and indoxyl sulphate are associated with coronary artery disease in patients with diabetic nephropathy. Rev Diabet Stud. 2010;7:275–84.CrossRefPubMedGoogle Scholar
  83. 83.
    Roh E, Kwak SH, Jung HS, Cho YM, Pak YK, Park KS, et al. Serum aryl hydrocarbon receptor ligand activity is associated with insulin resistance and resulting type 2 diabetes. Acta Diabetol. 2015;52:489–95.CrossRefPubMedGoogle Scholar
  84. 84.
    Zhang A, Sun H, Yan G, Yuan Y, Han Y, Wang X. Metabolomics study of type 2 diabetes using ultra-performance LC-ESI/quadrupole-TOF high-definition MS coupled with pattern recognition methods. J Physiol Biochem. 2014;70:117–28.CrossRefPubMedGoogle Scholar
  85. 85.
    Atoh K, Itoh H, Haneda M. Serum indoxyl sulfate levels in patients with diabetic nephropathy: relation to renal function. Diabetes Res Clin Pract. 2009;83:220–6.CrossRefPubMedGoogle Scholar
  86. 86.
    Creely SJ, McTernan PG, Kusminski CM, Fisher fM, Da Silva NF, Khanolkar M, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E740–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Koppe L, Poitout V. CMPF: a biomarker for type 2 diabetes mellitus progression? Trends Endocrinol Metab. 2016;27:439–40.CrossRefPubMedGoogle Scholar
  88. 88.
    Lankinen MA, Hanhineva K, Kolehmainen M, Lehtonen M, Auriola S, Mykkänen H, et al. CMPF does not associate with impaired glucose metabolism in individuals with features of metabolic syndrome. PLoS One. 2015;10:e0124379.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Luce M, Bouchara A, Pastural M, Granjon S, Szelag JC, Laville M, et al. Is 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) a clinically relevant uremic toxin in haemodialysis patients? Toxins. 2018;10. Scholar
  90. 90.
    Retnakaran R, Ye C, Kramer CK, Connelly PW, Hanley AJ, Sermer M, et al. Evaluation of circulating determinants of Beta-cell function in women with and without gestational diabetes. J Clin Endocrinol Metab. 2016;101:2683–91.CrossRefPubMedGoogle Scholar
  91. 91.
    Liu Y, Prentice KJ, Eversley JA, Hu C, Batchuluun B, Leavey K, et al. Rapid elevation in CMPF may act as a tipping point in diabetes development. Cell Rep. 2016;14:2889–900.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Laetitia Koppe
    • 1
    • 2
    Email author
  • Denis Fouque
    • 1
    • 2
  • Christophe O. Soulage
    • 2
  1. 1.Department NephrologyCentre Hospitalier Lyon SudPierre-BeniteFrance
  2. 2.Univ. Lyon, CarMeN lab, INSA-Lyon, INSERM U1060, INRAUniversité Claude Bernard Lyon 1VilleurbanneFrance

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