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Serum complement C3 and islet β-cell function in patients with type 2 diabetes: A 4.6-year prospective follow-up study

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Abstract

Purpose

Serum complement C3 has been shown to contribute to the incidence of type 2 diabetes (T2D), but how serum complement C3 affects islet β-cell function throughout the course of T2D is unclear. This study explored whether serum complement C3 is independently associated with changes in islet β-cell function over time in patients with T2D.

Methods

Serum complement C3 was measured, and endogenous β-cell function was evaluated by area under the C-peptide curve (AUCcp) during an oral glucose tolerance test (OGTT) in 411 patients with T2D at baseline from 2011 to 2015. Next, 347 of those patients with available data were pooled for a final follow-up analysis from 2014 to 2018. Changes in islet β-cell function at follow-up were evaluated by AUCcp percentage changes (ΔAUCcp%). In addition, other possible clinical risks for diabetes were also examined.

Results

The 347 patients included in the analysis had a diabetes duration of 4.84 ± 3.63 years at baseline. Baseline serum complement C3 (baseline C3) levels were positively correlated with baseline natural logarithm of AUCcp (lnAUCcp) (n = 347, r = 0.288, p < 0.001), and baseline C3 was independently associated with baseline lnAUCcp (β = 0.17, t = 3.52, p < 0.001) after adjustment for baseline glycemic status and other clinical confounders by multivariate liner regression analysis. Compared with the baseline values, complement C3 changes (ΔC3) and ΔAUCcp% was –0.15 ± 0.28 mg/ml and –17.2 ± 18.4%, respectively, at a follow-up visit 4.57 ± 0.78 years later. Moreover, ΔC3 was positively correlated with ΔAUCcp% (n = 347, r = 0.302, p < 0.001). Furthermore, each 0.1 mg/ml increase in ΔC3 was associated with a higher ΔAUCcp% (1.41% [95% CI, 0.82–2.00%]) after adjusting for changes in glycemic status and other clinical confounders at follow-up.

Conclusions

In addition to serum complement C3 being independently associated with islet β-cell function at baseline, its changes were also independently associated with changes in islet β-cell function over time in patients with T2D.

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Abbreviations

T2D:

type 2 diabetes

AUCcp :

area under the C-peptide curve

lnAUCcp :

natural logarithm of AUCcp

ΔAUCcp%:

percentage AUCcp change

AUCglu :

area under the glucose curve

baseline C3:

complement C3 at baseline

ΔC3:

changes in complement C3

OGTT:

oral glucose tolerance test

BMI:

body mass index

SBP/DBP:

systolic/diastolic blood pressure

serum UA:

serum uric acid

TG:

triglyceride

TC:

total cholesterol

LDLC:

low-density lipoprotein cholesterol

HDLC:

high-density lipoprotein cholesterol

eGFR:

estimated glomerular filtration rate

IScp :

insulin sensitivity from C-peptide

HbA1c:

glycosylated hemoglobin A1c

References

  1. B.L. Wajchenberg, beta-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev. 28(2), 187–218 (2007). https://doi.org/10.1210/10.1210/er.2006-0038

    Article  CAS  PubMed  Google Scholar 

  2. R.C. Tubner, C.A. Cull, R.R. Holman, U.K. prospective diabetes study. Diabetes Care 19(2), 182–183 (1996)

    Article  CAS  Google Scholar 

  3. M.Y. Donath, S.E. Shoelson, Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11(2), 98–107 (2011). https://doi.org/10.1038/nri2925

    Article  CAS  PubMed  Google Scholar 

  4. J. Rojas, V. Bermudez, J. Palmar, M.S. Martinez, L.C. Olivar, M. Nava, D. Tomey, M. Rojas, J. Salazar, C. Garicano, M. Velasco, Pancreatic beta cell death: novel potential mechanisms in diabetes therapy. J. Diabetes Res. 2018, 9601801 (2018). https://doi.org/10.1155/2018/9601801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. N.S. Merle, S.E. Church, V. Fremeaux-Bacchi, L.T. Roumenina, Complement system part I—molecular mechanisms of activation and regulation. Front. Immunol. 6, 262 (2015). https://doi.org/10.3389/fimmu.2015.00262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. D. Ricklin, G. Hajishengallis, K. Yang, J.D. Lambris, Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11(9), 785–797 (2010). https://doi.org/10.1038/ni.1923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. J.M. Moreno-Navarrete, J.M. Fernandez-Real, The complement system is dysfunctional in metabolic disease: Evidences in plasma and adipose tissue from obese and insulin resistant subjects. Semin. Cell Dev. Biol. 85, 164–172 (2019). https://doi.org/10.1016/j.semcdb.2017.10.025

    Article  CAS  PubMed  Google Scholar 

  8. G. Bajic, S.E. Degn, S. Thiel, G.R. Andersen, Complement activation, regulation, and molecular basis for complement-related diseases. Embo. J. 34(22), 2735–2757 (2015). https://doi.org/10.15252/embj.201591881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. E. Hertle, M.M. van Greevenbroek, C.D. Stehouwer, Complement C3: an emerging risk factor in cardiometabolic disease. Diabetologia 55(4), 881–884 (2012). https://doi.org/10.1007/s00125-012-2462-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. X. Bao, Y. Xia, Q. Zhang, H.M. Wu, H.M. Du, L. Liu, C.J. Wang, H.B. Shi, X.Y. Guo, X. Liu, C.L. Li, Q. Su, G. Meng, B. Yu, S.M. Sun, X. Wang, M. Zhou, Q.Y. Jia, K. Song, K.J. Niu, Elevated serum complement C3 levels are related to the development of prediabetes in an adult population: the Tianjin Chronic Low-Grade Systematic Inflammation and Health Cohort Study. Diabet. Med. 33(4), 446–453 (2016). https://doi.org/10.1111/dme.12827

    Article  CAS  PubMed  Google Scholar 

  11. G. Engstrom, B. Hedblad, K.F. Eriksson, L. Janzon, F. Lindgarde, Complement C3 is a risk factor for the development of diabetes: a population-based cohort study. Diabetes 54(2), 570–575 (2005)

    Article  Google Scholar 

  12. J. Phieler, R. Garcia-Martin, J.D. Lambris, T. Chavakis, The role of the complement system in metabolic organs and metabolic diseases. Semin. Immunol. 25(1), 47–53 (2013). https://doi.org/10.1016/j.smim.2013.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. J. Sjolander, G.T. Westermark, E. Renstrom, A.M. Blom, Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation. J. Biol. Chem. 287(14), 10824–10833 (2012). https://doi.org/10.1074/jbc.M111.244285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. S. He, C. Atkinson, F. Qiao, K. Cianflone, X. Chen, S. Tomlinson, A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice. J. Clin. Investig. 119(8), 2304–2316 (2009). https://doi.org/10.1172/jci38289

    Article  CAS  PubMed  Google Scholar 

  15. American Diabetes Association, Diagnosis and classification of diabetes mellitus. Diabetes Care 34(Suppl 1), S62–S69 (2011). https://doi.org/10.2337/dc11-S062

    Article  CAS  PubMed Central  Google Scholar 

  16. T. Radaelli, K.A. Farrell, L. Huston-Presley, S.B. Amini, J.P. Kirwan, H.D. McIntyre, P.M. Catalano, Estimates of insulin sensitivity using glucose and C-Peptide from the hyperglycemia and adverse pregnancy outcome glucose tolerance test. Diabetes Care 33(3), 490–494 (2010). https://doi.org/10.2337/dc09-1463

    Article  CAS  PubMed  Google Scholar 

  17. L. Zhao, J. Ma, S. Wang, Y. Xie, Relationship between beta-cell function, metabolic control, and microvascular complications in type 2 diabetes mellitus. Diabetes Technol. Ther. 17(1), 29–34 (2015). https://doi.org/10.1089/dia.2014.0214

    Article  CAS  PubMed  Google Scholar 

  18. L.A. Inker, C.H. Schmid, H. Tighiouart, J.H. Eckfeldt, H.I. Feldman, T. Greene, J.W. Kusek, J. Manzi, F. Van Lente, Y.L. Zhang, J. Coresh, A.S. Levey, Estimating glomerular filtration rate from serum creatinine and cystatin C. N. Engl. J. Med. 367(1), 20–29 (2012). https://doi.org/10.1056/NEJMoa1114248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. J.J. Meier, B.A. Menge, T.G. Breuer, C.A. Muller, A. Tannapfel, W. Uhl, W.E. Schmidt, H. Schrader, Functional assessment of pancreatic beta-cell area in humans. Diabetes 58(7), 1595–1603 (2009). https://doi.org/10.2337/db08-1611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. J.M. Fernandez-Real, G. Penarroja, A. Castro, F. Garcia-Bragado, I. Hernandez-Aguado, W. Ricart, Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 51(4), 1000–1004 (2002)

    Article  CAS  Google Scholar 

  21. A. Mallipedhi, T. Min, S.L. Prior, C. MacIver, S.D. Luzio, G. Dunseath, R.M. Bracken, S. Islam, J.D. Barry, S. Caplin, J.W. Stephens, Association between the preoperative fasting and postprandial C-peptide AUC with resolution of type 2 diabetes 6 months following bariatric surgery. Metabolism 64(11), 1556–1563 (2015). https://doi.org/10.1016/j.metabol.2015.08.009

    Article  CAS  PubMed  Google Scholar 

  22. H. Tfayli, F. Bacha, N. Gungor, S. Arslanian, Islet cell antibody-positive versus -negative phenotypic type 2 diabetes in youth: does the oral glucose tolerance test distinguish between the two? Diabetes Care 33(3), 632–638 (2010). https://doi.org/10.2337/dc09-0305

    Article  CAS  PubMed  Google Scholar 

  23. P. Rowe, C. Wasserfall, B. Croker, M. Campbell-Thompson, A. Pugliese, M. Atkinson, D. Schatz, Increased complement activation in human type 1 diabetes pancreata. Diabetes Care 36(11), 3815–3817 (2013). https://doi.org/10.2337/dc13-0203

    Article  PubMed  PubMed Central  Google Scholar 

  24. A. Klegeris, P.L. McGeer, Complement activation by islet amyloid polypeptide (IAPP) and alpha-synuclein 112. Biochem. Biophys. Res. Commun. 357(4), 1096–1099 (2007). https://doi.org/10.1016/j.bbrc.2007.04.055

    Article  CAS  PubMed  Google Scholar 

  25. Y. Mamane, C. Chung Chan, G. Lavallee, N. Morin, L.J. Xu, J. Huang, R. Gordon, W. Thomas, J. Lamb, E.E. Schadt, B.P. Kennedy, J.A. Mancini, The C3a anaphylatoxin receptor is a key mediator of insulin resistance and functions by modulating adipose tissue macrophage infiltration and activation. Diabetes 58(9), 2006–2017 (2009). https://doi.org/10.2337/db09-0323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. J.C. McNelis, J.M. Olefsky, Macrophages, immunity, and metabolic disease. Immunity 41(1), 36–48 (2014). https://doi.org/10.1016/j.immuni.2014.05.010

    Article  CAS  PubMed  Google Scholar 

  27. W. Quan, E.K. Jo, M.S. Lee, Role of pancreatic beta-cell death and inflammation in diabetes. Diabetes Obes. Metab. 15(Suppl 3), 141–151 (2013). https://doi.org/10.1111/dom.12153

    Article  CAS  PubMed  Google Scholar 

  28. S.S. Rensen, Y. Slaats, A. Driessen, C.J. Peutz-Kootstra, J. Nijhuis, R. Steffensen, J.W. Greve, W.A. Buurman, Activation of the complement system in human nonalcoholic fatty liver disease. Hepatology 50(6), 1809–1817 (2009). https://doi.org/10.1002/hep.23228

    Article  CAS  PubMed  Google Scholar 

  29. H. Esterbauer, F. Krempler, H. Oberkofler, W. Patsch, The complement system: a pathway linking host defence and adipocyte biology. Eur. J. Clin. Investig. 29(8), 653–656 (1999)

    Article  CAS  Google Scholar 

  30. Z. Liu, Q. Tang, J. Wen, Y. Tang, D. Huang, Y. Huang, J. Xie, Y. Luo, M. Liang, C. Wu, Z. Lu, A. Tan, Y. Gao, Q. Wang, Y. Jiang, Z. Yao, X. Lin, H. Zhang, Z. Mo, X. Yang, Elevated serum complement factors 3 and 4 are strong inflammatory markers of the metabolic syndrome development: a longitudinal cohort study. Sci. Rep. 6, 18713 (2016). https://doi.org/10.1038/srep18713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. N. Wlazlo, M.M. van Greevenbroek, I. Ferreira, E.J. Feskens, C.J. van der Kallen, C.G. Schalkwijk, B. Bravenboer, C.D. Stehouwer, Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM Study. Diabetes Care 37(7), 1900–1909 (2014). https://doi.org/10.2337/dc13-2804

    Article  CAS  PubMed  Google Scholar 

  32. K.L. Rasmussen, B.G. Nordestgaard, S.F. Nielsen, Complement C3 and risk of diabetic microvascular disease: a cohort study of 95,202 individuals from the general population. Clin. Chem. 64(7), 1113–1124 (2018). https://doi.org/10.1373/clinchem.2018.287581

    Article  CAS  PubMed  Google Scholar 

  33. G. Engstrom, B. Hedblad, L. Janzon, F. Lindgarde, Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: a population-based cohort study. Eur. J. Cardiovasc. Prev. Rehabil. 14(3), 392–397 (2007). https://doi.org/10.1097/01.hjr.0000244582.30421.b2

    Article  PubMed  Google Scholar 

  34. I.U. Schraufstatter, R.G. Discipio, M. Zhao, S.K. Khaldoyanidi, C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. J. Immunol. 182(6), 3827–3836 (2009). https://doi.org/10.4049/jimmunol.0803055

    Article  CAS  PubMed  Google Scholar 

  35. N. Matsumoto, A. Satyam, M. Geha, P.H. Lapchak, J.J. Dalle Lucca, M.G. Tsokos, G.C. Tsokos, C3a enhances the formation of intestinal organoids through C3aR1. Front. Immunol. 8, 1046 (2017). https://doi.org/10.3389/fimmu.2017.01046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. T. Haynes, A. Luz-Madrigal, E.S. Reis, N.P. Echeverri Ruiz, E. Grajales-Esquivel, A. Tzekou, P.A. Tsonis, J.D. Lambris, K. Del Rio-Tsonis, Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration. Nat. Commun. 4, 2312 (2013). https://doi.org/10.1038/ncomms3312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. C.W. Strey, M. Markiewski, D. Mastellos, R. Tudoran, L.A. Spruce, L.E. Greenbaum, J.D. Lambris, The proinflammatory mediators C3a and C5a are essential for liver regeneration. J. Exp. Med. 198(6), 913–923 (2003). https://doi.org/10.1084/jem.20030374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. M.M. Markiewski, D. Mastellos, R. Tudoran, R.A. DeAngelis, C.W. Strey, S. Franchini, R.A. Wetsel, A. Erdei, J.D. Lambris, C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J. Immunol. 173(2), 747–754 (2004). https://doi.org/10.4049/jimmunol.173.2.747

    Article  CAS  PubMed  Google Scholar 

  39. T.V. Fiorentino, M.L. Hribal, F. Andreozzi, M. Perticone, A. Sciacqua, F. Perticone, G. Sesti, Plasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals. Nutr. Metab. Cardiovasc. Dis. 25(5), 510–517 (2015). https://doi.org/10.1016/j.numecd.2015.02.007

    Article  CAS  PubMed  Google Scholar 

  40. R.S. Dos Santos, L. Marroqui, F.A. Grieco, L. Marselli, M. Suleiman, S.R. Henz, P. Marchetti, R. Wernersson, D.L. Eizirik, Protective role of complement C3 against cytokine-mediated beta-cell apoptosis. Endocrinology 158(8), 2503–2521 (2017). https://doi.org/10.1210/en.2017-00104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. B.C. King, K. Kulak, U. Krus, R. Rosberg, E. Golec, K. Wozniak, M.F. Gomez, E. Zhang, D.J. O’Connell, E. Renstrom, A.M. Blom, Complement component C3 is highly expressed in human pancreatic islets and prevents beta cell death via ATG16L1 interaction and autophagy regulation. Cell Metab. 29(1), 202–210.e206 (2019). https://doi.org/10.1016/j.cmet.2018.09.009

    Article  CAS  PubMed  Google Scholar 

  42. B. Ahren, P.J. Havel, G. Pacini, K. Cianflone, Acylation stimulating protein stimulates insulin secretion. Int. J. Obes. Relat. Metab. Disord. 27(9), 1037–1043 (2003). https://doi.org/10.1038/sj.ijo.0802369

    Article  CAS  PubMed  Google Scholar 

  43. J.C. Lo, S. Ljubicic, B. Leibiger, M. Kern, I.B. Leibiger, T. Moede, M.E. Kelly, D. Chatterjee Bhowmick, I. Murano, P. Cohen, A.S. Banks, M.J. Khandekar, A. Dietrich, J.S. Flier, S. Cinti, M. Bluher, N.N. Danial, P.O. Berggren, B.M. Spiegelman, Adipsin is an adipokine that improves beta cell function in diabetes. Cell 158(1), 41–53 (2014). https://doi.org/10.1016/j.cell.2014.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. M. Kolev, G. Le Friec, C. Kemper, Complement–tapping into new sites and effector systems. Nat. Rev. Immunol. 14(12), 811–820 (2014). https://doi.org/10.1038/nri3761

    Article  CAS  PubMed  Google Scholar 

  45. M. Wysoczynski, M. Solanki, S. Borkowska, P. van Hoose, K.R. Brittian, S.D. Prabhu, M.Z. Ratajczak, G. Rokosh, Complement component 3 is necessary to preserve myocardium and myocardial function in chronic myocardial infarction. Stem Cells 32(9), 2502–2515 (2014). https://doi.org/10.1002/stem.1743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Y. Rahpeymai, M.A. Hietala, U. Wilhelmsson, A. Fotheringham, I. Davies, A.K. Nilsson, J. Zwirner, R.A. Wetsel, C. Gerard, M. Pekny, M. Pekna, Complement: a novel factor in basal and ischemia-induced neurogenesis. Embo. J. 25(6), 1364–1374 (2006). https://doi.org/10.1038/sj.emboj.7601004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Y. Ma, Y. Liu, Z. Zhang, G.Y. Yang, Significance of complement system in ischemic stroke: a comprehensive review. Aging Dis. 10(2), 429–462 (2019). https://doi.org/10.14336/ad.2019.0119

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by the Social Development Projects of Nantong (HS2012028, MS22015065) and the Medical Research Project of Jiangsu Health Commission (QNRC2016408).

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Author notes

  1. These authors contributed equally: Jian-bin Su and Yun-Yu Wu

Authors and Affiliations

  1. Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China

    Jian-bin Su, Feng Xu, Xing Wang, Li-hua Zhao, Hai-yan Huang & Xue-qin Wang

  2. Medical School of Nantong University, No. 19, Qixiu Road, Nantong, 226001, China

    Yun-Yu Wu

  3. Department of Geriatrics, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No. 6 North Haierxiang Road, Nantong, 226001, China

    Hong-li Cai

  4. Department of Clinical Laboratory, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No. 6, Haierxiang North Road, Nantong, 226001, China

    Xiu-lin Zhang & Tong Chen

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  1. Jian-bin Su
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Su, Jb., Wu, YY., Xu, F. et al. Serum complement C3 and islet β-cell function in patients with type 2 diabetes: A 4.6-year prospective follow-up study. Endocrine 67, 321–330 (2020). https://doi.org/10.1007/s12020-019-02144-z

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