The Interconnection Between Immuno-Metabolism, Diabetes, and CKD

  • Fabrizia Bonacina
  • Andrea Baragetti
  • Alberico Luigi Catapano
  • Giuseppe Danilo NorataEmail author
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

Metabolic reprogramming is increasingly recognized as an essential trait of functional activation of immune cells. Here, we describe the link between immuno-metabolism, diabetes, and diabetic nephropathy.

Recent Findings

Crosstalk between cellular metabolic functions and immune activation occurs when plasma levels of glucose, triglycerides, and free fatty acids increase, thus promoting systemic low-grade inflammation that further boosts the development of metabolic complications. In the long run, this settles an “apparent paradox,” where, despite excessive inflammation, the immune system is suppressed, further promoting progression to end-stage renal disease (ESRD) and predisposing to premature deaths from infections and cardiovascular diseases. Reviewing the effects of diabetes treatments on immuno-inflammatory responses suggests that the benefit of these drugs might extend beyond the simple control of glucose homeostasis.


Hyperglycemia and dyslipidemia correlate with enhancement of the immuno-inflammatory response that can promote and worsen metabolic diseases and support the progression toward ESRD. The identification of cellular checkpoints that modulate the immuno-metabolic machinery of immune cells opens new venues for metabolic drugs.


Immune response Metabolism Diabetes Kidney disease 


Compliance with Ethical Standards

Conflict of Interest

Fabrizia Bonacina and Andrea Baragetti declare that they have no conflict of interest.

Alberico Luigi Catapano reports grants from Sanofi, Amgen. He reports speaker fees from AstraZeneca, Genzyme, Bayer, SigmaTau, Menarini, Kowa, Eli Lilly, Recordati, Pfizer, Sanofi, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, and Amgen.

Giuseppe Danilo Norata reports grants from Pfizer and Amgen, and speaker fees from Sanofi, Aegerion, Amgen, Alnylam, and Novartis.

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.
    •• Norata GD, Caligiuri G, Chavakis T, Matarese G, Netea MG, Nicoletti A, et al. The cellular and molecular basis of translational immuno-metabolism. Immunity. 2015;43(3):421–34. This review discusses from a translational perspective the connection between cellular metabolism and immune cell activations. CrossRefGoogle Scholar
  2. 2.
    Tomas E, Lin YS, Dagher Z, Saha A, Luo Z, Ido Y, et al. Hyperglycemia and insulin resistance: possible mechanisms. Ann N Y Acad Sci. 2002;967:43–51.CrossRefGoogle Scholar
  3. 3.
    Zmora N, Bashiardes S, Levy M, Elinav E. The role of the immune system in metabolic health and disease. Cell Metab. 2017;25(3):506–21. Scholar
  4. 4.
    Ellulu MS, Patimah I, Khaza'ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci. 2017;13(4):851–63. Scholar
  5. 5.
    Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Haring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol. 2016;12(12):721–37. Scholar
  6. 6.
    Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, et al. Differential modulation of toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res. 2003;44(3):479–86. Scholar
  7. 7.
    Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity. 2008;16(6):1248–55. Scholar
  8. 8.
    Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, et al. SREBP1 contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism. Cell Metab. 2017;25(2):412–27. Scholar
  9. 9.
    Souza CO, Teixeira AA, Biondo LA, Silveira LS, Calder PC, Rosa Neto JC. Palmitoleic acid reduces the inflammation in LPS-stimulated macrophages by inhibition of NFkappaB, independently of PPARs. Clin Exp Pharmacol Physiol. 2017;44(5):566–75. Scholar
  10. 10.
    Carrillo C, Cavia Mdel M, Alonso-Torre S. Role of oleic acid in immune system; mechanism of action; a review. Nutr Hosp. 2012;27(4):978–90. Scholar
  11. 11.
    Talbot NA, Wheeler-Jones CP, Cleasby ME. Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance. Mol Cell Endocrinol. 2014;393(1–2):129–42. Scholar
  12. 12.
    Tardif N, Salles J, Landrier JF, Mothe-Satney I, Guillet C, Boue-Vaysse C, et al. Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats. Clin Nutr. 2011;30(6):799–806. Scholar
  13. 13.
    Bernstein AM, Roizen MF, Martinez L. Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double-blinded, randomized, placebo controlled study. J Clin Lipidol. 2014;8(6):612–7. Scholar
  14. 14.
    • Singer K, DelProposto J, Morris DL, Zamarron B, Mergian T, Maley N, et al. Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells. Mol Metab. 2014;3(6):664–75. This paper highlights how obesity triggers activation and proliferation of progenitors cells contributing to adipose tissue inflammation.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19(5):821–35. Scholar
  16. 16.
    Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328(5986):1689–93. Scholar
  17. 17.
    Yvan-Charvet L, Welch C, Pagler TA, Ranalletta M, Lamkanfi M, Han S, et al. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation. 2008;118(18):1837–47. Scholar
  18. 18.
    Westerterp M, Murphy AJ, Wang M, Pagler TA, Vengrenyuk Y, Kappus MS, et al. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res. 2013;112(11):1456–65. Scholar
  19. 19.
    Bonacina F, Coe D, Wang G, Longhi MP, Baragetti A, Moregola A, et al. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation. Nat Commun. 2018;9(1):3083. Scholar
  20. 20.
    Ito A, Hong C, Oka K, Salazar JV, Diehl C, Witztum JL, et al. Cholesterol accumulation in CD11c(+) immune cells is a causal and targetable factor in autoimmune disease. Immunity. 2016;45(6):1311–26. Scholar
  21. 21.
    Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol. 2013;14(5):489–99. Scholar
  22. 22.
    • Mauro C, Smith J, Cucchi D, Coe D, Fu H, Bonacina F, et al. Obesity-induced metabolic stress leads to biased effector memory CD4(+) T cell differentiation via PI3K p110delta-Akt-mediated signals. Cell Metab. 2017;25(3):593–609. This work identifies how fatty acids primed CD4+T cells activation resulting in increased circulating levels of T effector memory cells in obese individuals. CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    O’Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41(1):75–88. Scholar
  24. 24.
    • Sestan M, Marinovic S, Kavazovic I, Cekinovic D, Wueest S, Turk Wensveen T, et al. Virus-induced interferon-gamma causes insulin resistance in skeletal muscle and derails glycemic control in obesity. Immunity. 2018;49(1):164–77 e6. This paper describes how immune response derails glucose homeostasis in pre-diabetic conditions. CrossRefGoogle Scholar
  25. 25.
    Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P. Metabolism of stromal and immune cells in health and disease. Nature. 2014;511(7508):167–76. Scholar
  26. 26.
    Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419–30. Scholar
  27. 27.
    Soehnlein O, Swirski FK. Hypercholesterolemia links hematopoiesis with atherosclerosis. Trends Endocrinol Metab. 2013;24(3):129–36. Scholar
  28. 28.
    Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17(5):695–708. Scholar
  29. 29.
    Marino E, Richards JL, McLeod KH, Stanley D, Yap YA, Knight J, et al. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol. 2017;18(5):552–62. Scholar
  30. 30.
    Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, et al. D-mannose induces regulatory T cells and suppresses immunopathology. Nat Med. 2017;23(9):1036–45. Scholar
  31. 31.
    •• Zoccali C, Vanholder R, Massy ZA, Ortiz A, Sarafidis P, Dekker FW, et al. The systemic nature of CKD. Nat Rev Nephrol. 2017;13(6):344–58. A comprehensive review of the circuits linking renal disease to energy balance, immune response and neuroendocrine signalling. CrossRefGoogle Scholar
  32. 32.
    Aroor AR, McKarns S, Demarco VG, Jia G, Sowers JR. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metab Clin Exp. 2013;62(11):1543–52. Scholar
  33. 33.
    Vaziri ND, Pahl MV, Crum A, Norris K. Effect of uremia on structure and function of immune system. J Ren Nutr. 2012;22(1):149–56. Scholar
  34. 34.
    • Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008;3(5):1526–33. This review provides an integrate review about the alteration in immune response during kidney disease.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    • Obi Y, Qader H, Kovesdy CP, Kalantar-Zadeh K. Latest consensus and update on protein-energy wasting in chronic kidney disease. Curr Opin Clin Nutr Metab Care. 2015;18(3):254–62. This is a consensus paper about the relevance of cachexia, malnutrition, and their pathological consequences in advanced renal disease. CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Donath MY. When metabolism met immunology. Nat Immunol. 2013;14(5):421–2. Scholar
  37. 37.
    Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(23):2237–8. Scholar
  38. 38.
    Malin SK, Finnegan S, Fealy CE, Filion J, Rocco MB, Kirwan JP. Beta-cell dysfunction is associated with metabolic syndrome severity in adults. Metab Syndr Relat Disord. 2014;12(2):79–85. Scholar
  39. 39.
    Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol. 2013;4:37. Scholar
  40. 40.
    Guiteras R, Flaquer M, Cruzado JM. Macrophage in chronic kidney disease. Clin Kidney J. 2016;9(6):765–71. Scholar
  41. 41.
    Wentworth JM, Fourlanos S, Harrison LC. Reappraising the stereotypes of diabetes in the modern diabetogenic environment. Nat Rev Endocrinol. 2009;5(9):483–9. Scholar
  42. 42.
    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107. Scholar
  43. 43.
    Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care. 2015;38(7):1356–64. Scholar
  44. 44.
    Moreno-Manzano V, Ishikawa Y, Lucio-Cazana J, Kitamura M. Selective involvement of superoxide anion, but not downstream compounds hydrogen peroxide and peroxynitrite, in tumor necrosis factor-alpha-induced apoptosis of rat mesangial cells. J Biol Chem. 2000;275(17):12684–91.CrossRefGoogle Scholar
  45. 45.
    Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol. 2012;3:179. Scholar
  46. 46.
    Di Marco E, Gray SP, Jandeleit-Dahm K. Diabetes alters activation and repression of pro- and anti-inflammatory signaling pathways in the vasculature. Front Endocrinol. 2013;4:68. Scholar
  47. 47.
    Woltman AM, de Fijter JW, Zuidwijk K, Vlug AG, Bajema IM, van der Kooij SW, et al. Quantification of dendritic cell subsets in human renal tissue under normal and pathological conditions. Kidney Int. 2007;71(10):1001–8. Scholar
  48. 48.
    Kurts C, Panzer U, Anders HJ, Rees AJ. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol. 2013;13(10):738–53. Scholar
  49. 49.
    Lukacs-Kornek V, Burgdorf S, Diehl L, Specht S, Kornek M, Kurts C. The kidney-renal lymph node-system contributes to cross-tolerance against innocuous circulating antigen. J Immunol. 2008;180(2):706–15.CrossRefGoogle Scholar
  50. 50.
    Zewinger S, Schumann T, Fliser D, Speer T. Innate immunity in CKD-associated vascular diseases. Nephrol Dial Transplant. 2016;31(11):1813–21. Scholar
  51. 51.
    Xi Y, Shao F, Bai XY, Cai G, Lv Y, Chen X. Changes in the expression of the toll-like receptor system in the aging rat kidneys. PLoS One. 2014;9(5):e96351. Scholar
  52. 52.
    Gill PS, Wilcox CS. NADPH oxidases in the kidney. Antioxid Redox Signal. 2006;8(9–10):1597–607. Scholar
  53. 53.
    Chang A, Ko K, Clark MR. The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens. 2014;23(3):204–10. Scholar
  54. 54.
    Liu J, Kennedy DJ, Yan Y, Shapiro JI. Reactive oxygen species modulation of Na/K-ATPase regulates fibrosis and renal proximal tubular sodium handling. Int J Nephrol. 2012;2012:381320. Scholar
  55. 55.
    Srikanthan K, Shapiro JI, Sodhi K. The role of Na/K-ATPase signaling in oxidative stress related to obesity and cardiovascular disease. Molecules 2016;21(9). doi: Scholar
  56. 56.
    Xiao J, Zhang X, Fu C, Yang Q, Xie Y, Zhang Z, et al. Impaired Na(+)-K(+)-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury. Exp Mol Med. 2018;50(3):e452. Scholar
  57. 57.
    • 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(11):1901–12. This work presents a metabolomic analysis showing alteration in cellular energetic metabolism during CKD. CrossRefPubMedCentralPubMedGoogle Scholar
  58. 58.
    Yu B, Zheng Y, Nettleton JA, Alexander D, Coresh J, Boerwinkle E. Serum metabolomic profiling and incident CKD among African Americans. Clin J Am Soc Nephrol. 2014;9(8):1410–7. Scholar
  59. 59.
    Darshi M, Van Espen B, Sharma K. Metabolomics in diabetic kidney disease: unraveling the biochemistry of a silent killer. Am J Nephrol. 2016;44(2):92–103. Scholar
  60. 60.
    Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity. 2014;40(6):833–42. Scholar
  61. 61.
    Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM, et al. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One. 2011;6(6):e21205. Scholar
  62. 62.
    Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016;90(6):1191–8. Scholar
  63. 63.
    Xiang FF, Zhu JM, Cao XS, Shen B, Zou JZ, Liu ZH, et al. Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients. Ren Fail. 2016;38(1):7–14. Scholar
  64. 64.
    Fadini GP, Rigato M, Cappellari R, Bonora BM, Avogaro A. Long-term prediction of cardiovascular outcomes by circulating CD34+ and CD34+CD133+ stem cells in patients with type 2 diabetes. Diabetes Care. 2017;40(1):125–31. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Fabrizia Bonacina
    • 1
  • Andrea Baragetti
    • 1
    • 2
  • Alberico Luigi Catapano
    • 1
    • 3
  • Giuseppe Danilo Norata
    • 1
    • 2
    Email author
  1. 1.Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB)Università Degli Studi di MilanoMilanItaly
  2. 2.SISA CentreBassini HospitalCinisello BalsamoItaly
  3. 3.IRCSS MultimedicaMilanItaly

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