Top

Current Diabetes Reports

Published in:

01-05-2019 | Hyperglycemia | Microvascular Complications—Nephropathy (M Afkarian and B Roshanravan, Section Editors)

The Interconnection Between Immuno-Metabolism, Diabetes, and CKD

Authors: Fabrizia Bonacina, Andrea Baragetti, Alberico Luigi Catapano, Giuseppe Danilo Norata

Published in: Current Diabetes Reports | Issue 5/2019

Abstract

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.

Summary

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.

•• 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. https://doi.org/10.1016/j.immuni.2015.08.023. This review discusses from a translational perspective the connection between cellular metabolism and immune cell activations. CrossRefPubMed

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.CrossRefPubMed

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. https://doi.org/10.1016/j.cmet.2017.02.006.CrossRefPubMed

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. https://doi.org/10.5114/aoms.2016.58928.CrossRefPubMed

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. https://doi.org/10.1038/nrneph.2016.145.CrossRefPubMed

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. https://doi.org/10.1194/jlr.M200361-JLR200.CrossRefPubMed

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. https://doi.org/10.1038/oby.2008.210.CrossRefPubMed

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. https://doi.org/10.1016/j.cmet.2016.11.009.CrossRefPubMed

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. https://doi.org/10.1111/1440-1681.12736.CrossRefPubMed

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. https://doi.org/10.3305/nh.2012.27.4.5783.CrossRefPubMed

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. https://doi.org/10.1016/j.mce.2014.06.010.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.clnu.2011.05.009.CrossRefPubMed

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. https://doi.org/10.1016/j.jacl.2014.08.001.CrossRefPubMed

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. https://doi.org/10.1016/j.molmet.2014.06.005. This paper highlights how obesity triggers activation and proliferation of progenitors cells contributing to adipose tissue inflammation.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.cmet.2014.03.029.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1126/science.1189731.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1161/CIRCULATIONAHA.108.793869.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1161/CIRCRESAHA.113.301086.CrossRefPubMed

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. https://doi.org/10.1038/s41467-018-05322-1.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.immuni.2016.11.008.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1038/ni.2570.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.cmet.2017.01.008. This work identifies how fatty acids primed CD4+T cells activation resulting in increased circulating levels of T effector memory cells in obese individuals. CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.immuni.2014.06.005.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1016/j.immuni.2018.05.005. This paper describes how immune response derails glucose homeostasis in pre-diabetic conditions. CrossRefPubMed

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. https://doi.org/10.1038/nature13312.CrossRefPubMed

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. https://doi.org/10.1016/j.immuni.2015.02.005.CrossRefPubMed

27.

Soehnlein O, Swirski FK. Hypercholesterolemia links hematopoiesis with atherosclerosis. Trends Endocrinol Metab. 2013;24(3):129–36. https://doi.org/10.1016/j.tem.2012.10.008.CrossRefPubMed

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. https://doi.org/10.1016/j.cmet.2013.04.001.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1038/ni.3713.CrossRefPubMed

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. https://doi.org/10.1038/nm.4375.CrossRefPubMed

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. https://doi.org/10.1038/nrneph.2017.52. A comprehensive review of the circuits linking renal disease to energy balance, immune response and neuroendocrine signalling. CrossRefPubMed

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. https://doi.org/10.1016/j.metabol.2013.07.001.CrossRefPubMed

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. https://doi.org/10.1053/j.jrn.2011.10.020.CrossRefPubMedCentralPubMed

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. https://doi.org/10.2215/CJN.00950208. This review provides an integrate review about the alteration in immune response during kidney disease.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1097/MCO.0000000000000171. This is a consensus paper about the relevance of cachexia, malnutrition, and their pathological consequences in advanced renal disease. CrossRefPubMedCentralPubMed

36.

Donath MY. When metabolism met immunology. Nat Immunol. 2013;14(5):421–2. https://doi.org/10.1038/ni.2591.CrossRefPubMed

37.

Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(23):2237–8. https://doi.org/10.1056/NEJMc1412427.CrossRefPubMed

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. https://doi.org/10.1089/met.2013.0083.CrossRefPubMedCentralPubMed

39.

Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol. 2013;4:37. https://doi.org/10.3389/fendo.2013.00037.CrossRef

40.

Guiteras R, Flaquer M, Cruzado JM. Macrophage in chronic kidney disease. Clin Kidney J. 2016;9(6):765–71. https://doi.org/10.1093/ckj/sfw096.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1038/nrendo.2009.149.CrossRefPubMed

42.

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107. https://doi.org/10.1038/nri2925.CrossRefPubMed

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. https://doi.org/10.2337/dc14-3008.CrossRefPubMed

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.CrossRefPubMed

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. https://doi.org/10.3389/fendo.2012.00179.CrossRef

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. https://doi.org/10.3389/fendo.2013.00068.CrossRef

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. https://doi.org/10.1038/sj.ki.5002187.CrossRefPubMed

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. https://doi.org/10.1038/nri3523.CrossRefPubMed

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.CrossRefPubMed

50.

Zewinger S, Schumann T, Fliser D, Speer T. Innate immunity in CKD-associated vascular diseases. Nephrol Dial Transplant. 2016;31(11):1813–21. https://doi.org/10.1093/ndt/gfv358.CrossRefPubMed

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. https://doi.org/10.1371/journal.pone.0096351.CrossRefPubMedCentralPubMed

52.

Gill PS, Wilcox CS. NADPH oxidases in the kidney. Antioxid Redox Signal. 2006;8(9–10):1597–607. https://doi.org/10.1089/ars.2006.8.1597.CrossRefPubMed

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. https://doi.org/10.1097/01.mnh.0000444814.49755.90.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1155/2012/381320.CrossRefPubMedCentralPubMed

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:https://doi.org/10.3390/molecules21091172.CrossRefPubMedCentral

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. https://doi.org/10.1038/emm.2017.287.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1681/ASN.2013020126. This work presents a metabolomic analysis showing alteration in cellular energetic metabolism during CKD. CrossRefPubMedCentralPubMed

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. https://doi.org/10.2215/CJN.11971113.CrossRefPubMedCentralPubMed

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. https://doi.org/10.1159/000447954.CrossRefPubMed

60.

Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity. 2014;40(6):833–42. https://doi.org/10.1016/j.immuni.2014.05.014.CrossRefPubMed

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. https://doi.org/10.1371/journal.pone.0021205.CrossRefPubMedCentralPubMed

62.

Pluznick JL. Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int. 2016;90(6):1191–8. https://doi.org/10.1016/j.kint.2016.06.033.CrossRefPubMedCentralPubMed

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. https://doi.org/10.3109/0886022X.2015.1106871.CrossRefPubMed

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. https://doi.org/10.2337/dc16-1755.CrossRefPubMed

Title: The Interconnection Between Immuno-Metabolism, Diabetes, and CKD
Authors: Fabrizia Bonacina
Andrea Baragetti
Alberico Luigi Catapano
Giuseppe Danilo Norata
Publication date: 01-05-2019
Publisher: Springer US
Keyword: Hyperglycemia
Published in: Current Diabetes Reports / Issue 5/2019
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI: https://doi.org/10.1007/s11892-019-1143-4

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The Interconnection Between Immuno-Metabolism, Diabetes, and CKD

Abstract

Purpose of Review

Recent Findings

Summary

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 5/2019

Islet Transplantation Alone Versus Solitary Pancreas Transplantation: an Outcome-Driven Choice?

Current Status on Immunological Therapies for Type 1 Diabetes Mellitus

Diabetes Prevention and Care Programs in the US-Affiliated Pacific Islands: Challenges, Innovation, and Recommendations for Effective Scale-Up

Economics of Genetic Testing for Diabetes

Genetic Mechanisms Highlight Shared Pathways for the Pathogenesis of Polygenic Type 1 Diabetes and Monogenic Autoimmune Diabetes

The Contribution of Low-Frequency and Rare Coding Variation to Susceptibility to Type 2 Diabetes

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page