Skip to main content
SpringerLink
Log in

Two-hour postload plasma glucose and pigment epithelium-derived factor levels are markers of coronary artery inflammation in type 2 diabetic patients

  • Original Article
  • Published:
Journal of Nuclear Cardiology Aims and scope

Abstract

Background

We have previously found that pioglitazone attenuates inflammation in the left main trunk of coronary artery (LMT), evaluated as target-to-background ratio (TBR) by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with impaired glucose tolerance or type 2 diabetes.

Objectives

We assessed which clinical variables could predict the change in TBR in the LMT after 4-month add-on therapy with oral hypoglycemic agents (OHAs).

Methods

A total of 38 type 2 diabetic patients with carotid atherosclerosis who had already received OHAs except for pioglitazone was enrolled. At baseline and 4 months after add-on therapy with pioglitazone or glimepiride, all patients underwent 75 g oral glucose tolerance test, blood chemistry analysis, and FDG-PET/CT.

Results

Fasting plasma glucose, 30-, 60-, 90-, 120-minutes postload plasma glucose, HbA1c, and LMT-TBR values were significantly decreased by add-on therapy, whereas high-density lipoprotein-cholesterol and adiponectin levels were increased. Increased serum levels of pigment epithelium-derived factor (PEDF), a marker of insulin resistance and non-use of aspirin at baseline could predict the favorable response of LMT-TBR to add-on therapy. Moreover, Δ120-minutes postload plasma glucose and ΔPEDF were independent correlates of ΔLMT-TBR.

Conclusions

Our present study suggests that 120-minutes postload plasma glucose and PEDF values may be markers and potential therapeutic targets of coronary artery inflammation in type 2 diabetic patients.

Clinical Trial Registration

URL: http://clinicaltrials.gov. Unique identifier: NCT00722631.

Graphic Abstract

New markers for diabetes and CAD is on the horizon! Two-hour postload plasma glucose and pigment epithelium derived factor are markers of coronary artery inflammation in type 2 diabetic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

CVD:

Cardiovascular disease

CT:

Computed tomography

FDG:

18F-fluorodeoxyglucose

PET:

Positron emission tomography

TBR:

Target-to-background ratio

75 g OGTT:

75 g oral glucose tolerance test

OHAs:

Oral hypoglycemic agents

PEDF:

Pigment epithelium-derived factor

LMT:

Left main trunk of coronary artery

LMT-TBR:

TBR in the LMT

References

  1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.

    CAS  PubMed  Google Scholar 

  2. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Emerging Risk Factors Collaboration, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829-41.

    PubMed  PubMed Central  Google Scholar 

  3. Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999;48:937-42.

    CAS  PubMed  Google Scholar 

  4. Prospective Studies Collaboration and Asia Pacific Cohort Studies Collaboration. Sex-specific relevance of diabetes to occlusive vascular and other mortality: A collaborative meta-analysis of individual data from 980793 adults from 68 prospective studies. Lancet Diabetes Endocrinol 2018;6:538-46.

    Google Scholar 

  5. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis of diagnostic criteria in Europe. Lancet 1999;354:617-21.

  6. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999;22:920-4.

    CAS  PubMed  Google Scholar 

  7. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: The Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996;39:1577-83.

    CAS  PubMed  Google Scholar 

  8. Abdul-Ghani MA, Jayyousi A, DeFronzo RA, Asaad N, Al-Suwaidi J. Insulin resistance the link between T2DM and CVD: Basic mechanisms and clinical implications. Curr Vasc Pharmacol 2017. https://doi.org/10.2174/1570161115666171010115119.

    Article  Google Scholar 

  9. Di Filippo C, Verza M, Coppola L, Rossi F, D’Amico M, Marfella R. Insulin resistance and postprandial hyperglycemia the bad companions in natural history of diabetes: Effects on health of vascular tree. Curr Diabetes Rev 2007;3:268-73.

    PubMed  Google Scholar 

  10. Osborn EA, Jaffer FA. Imaging atherosclerosis and risk of plaque rupture. Curr Atheroscler Rep 2013;15:359.

    PubMed  Google Scholar 

  11. Burke AP, Kolodgie FD, Zieske A, Fowler DR, Weber DK, Varghese PJ, et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: A postmortem study. Arterioscler Thromb Vasc Biol 2004;24:1266-71.

    CAS  PubMed  Google Scholar 

  12. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36-44.

    PubMed  Google Scholar 

  13. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005;111:3481-8.

    PubMed  Google Scholar 

  14. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, CANTOS Trial Group, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.

    CAS  PubMed  Google Scholar 

  15. Celeng C, Takx RA, Ferencik M, Maurovich-Horvat P. Non-invasive and invasive imaging of vulnerable coronary plaque. Trends Cardiovasc Med 2016;26:538-47.

    PubMed  Google Scholar 

  16. Fujino Y, Attizzani GF, Tahara S, Wang W, Takagi K, Naganuma T, et al. Association of skin autofluorescence with plaque vulnerability evaluated by optical coherence tomography in patients with cardiovascular disease. Atherosclerosis 2018;274:47-53.

    CAS  PubMed  Google Scholar 

  17. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708-11.

    CAS  PubMed  Google Scholar 

  18. Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol 2006;48:1818-24.

    PubMed  Google Scholar 

  19. Tahara N, Kai H, Ishibashi M, Nakaura H, Kaida H, Baba K, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825-31.

    CAS  PubMed  Google Scholar 

  20. Rudd JH, Myers KS, Bansilal S, Machac J, Rafique A, Farkouh M, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: Implications for atherosclerosis therapy trials. J Am Coll Cardiol 2007;50:892-6.

    PubMed  Google Scholar 

  21. Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging 2011;4:1110-8.

    PubMed  Google Scholar 

  22. Rogers IS, Nasir K, Figueroa AL, Cury RC, Hoffmann U, Vermylen DA, et al. Feasibility of FDG imaging of the coronary arteries: Comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging 2010;3:388-97.

    PubMed  Google Scholar 

  23. Nitta Y, Tahara N, Tahara A, Honda A, Kodama N, Mizoguchi M, et al. Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: Evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging 2013;6:1172-82.

    PubMed  Google Scholar 

  24. Singh P, Emami H, Subramanian S, Maurovich-Horvat P, Marincheva-Savcheva G, Medina HM, et al. Coronary plaque morphology and the anti-inflammatory impact of atorvastatin: A multicenter 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic study. Circ Cardiovasc Imaging 2016;9:e004195.

    PubMed  PubMed Central  Google Scholar 

  25. Honda A, Tahara N, Nitta Y, Tahara A, Igata S, Bekki M, et al. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography is associated with endothelial dysfunction. Arterioscler Thromb Vasc Biol 2016;36:1980-8.

    CAS  PubMed  Google Scholar 

  26. Rominger A, Saam T, Wolpers S, Cyran CC, Schmidt M, Foerster S, et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med 2009;50:1611-20.

    PubMed  Google Scholar 

  27. Figueroa AL, Abdelbaky A, Truong QA, Corsini E, MacNabb MH, Lavender ZR, et al. Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging 2013;6:1250-9.

    PubMed  Google Scholar 

  28. Moon SH, Cho YS, Noh TS, Choi JY, Kim BT, Lee KH. Carotid FDG uptake improves prediction of future cardiovascular events in asymptomatic individuals. JACC Cardiovasc Imaging 2015;8:949-56.

    PubMed  Google Scholar 

  29. Yamagishi S, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K, et al. Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab 2006;91:2447-50.

    CAS  PubMed  Google Scholar 

  30. Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Inoue H. Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with visceral adiposity in Japanese patients with type 2 diabetes. Diabetes Metab Res Rev 2009;25:52-6.

    CAS  PubMed  Google Scholar 

  31. Nakamura K, Yamagishi S, Adachi H, Matsui T, Kurita Y, Imaizumi T. Serum levels of pigment epithelium-derived factor (PEDF) are an independent determinant of insulin resistance in patients with essential hypertension. Int J Cardiol 2010;143:96-8.

    PubMed  Google Scholar 

  32. Chen C, Tso AW, Law LS, Cheung BM, Ong KL, Wat NM, et al. Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: A 10-year prospective study. J Clin Endocrinol Metab 2010;95:5074-81.

    CAS  PubMed  Google Scholar 

  33. Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, et al. Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. J Clin Endocrinol Metab 2011;96:831-6.

    CAS  PubMed  Google Scholar 

  34. Yamagishi SI, Matsui T. Pigment epithelium-derived factor: A novel therapeutic target for cardiometabolic diseases and related complications. Curr Med Chem 2018;25:1480-500.

    CAS  PubMed  Google Scholar 

  35. Tahara N, Yamagishi S, Tahara A, Nitta Y, Kodama N, Mizoguchi M, et al. Serum level of pigment epithelium-derived factor is a marker of atherosclerosis in humans. Atherosclerosis 2011;219:311-5.

    CAS  PubMed  Google Scholar 

  36. Tahara N, Yamagishi S, Tahara A, Ishibashi M, Hayabuchi N, Takeuchi M, et al. Adiponectin is inversely associated with ratio of serum levels of AGEs to sRAGE and vascular inflammation. Int J Cardiol 2012;158:461-2.

    PubMed  Google Scholar 

  37. Bucerius J, Hyafil F, Verberne HJ, Slart RH, Lindner O, Sciagra R, Cardiovascular Committee of the European Association of Nuclear Medicine (EANM), et al. Position paper of the Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis. Eur J Nucl Med Mol Imaging 2016;43:780-92.

    PubMed  Google Scholar 

  38. Tahara N, Yamagishi S, Kodama N, Tahara A, Honda A, Nitta Y, et al. Clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues by FDG-PET/CT. J Clin Endocrinol Metab 2015;100:E739-47.

    PubMed  Google Scholar 

  39. Rask-Madsen C, King GL. Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 2007;3:46-56.

    CAS  PubMed  Google Scholar 

  40. McCoy RG, Irving BA, Soop M, Srinivasan M, Tatpati L, Chow L, et al. Effect of insulin sensitizer therapy on atherothrombotic and inflammatory profiles associated with insulin resistance. Mayo Clin Proc 2012;87:561-70.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, PROactive Investigators, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005;366:1279-89.

    CAS  PubMed  Google Scholar 

  42. Seo SM, Kim TH, Kim CJ, Hwang BH, Kang MK, Koh YS, Korean Acute Myocardial Infarction Registry Investigators, et al. Prognostic impact of significant non-infarct-related left main coronary artery disease in patients with acute myocardial infarction who receive a culprit-lesion percutaneous coronary intervention. Coron Artery Dis 2012;23:307-14.

    PubMed  Google Scholar 

  43. Tombran-Tink J, Chader GG, Johnson LV. PEDF: Pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res 1991;53:411-4.

    CAS  PubMed  Google Scholar 

  44. Tombran-Tink J, Barnstable CJ. PEDF: A multifaceted neurotrophic factor. Nat Rev Neurosci 2003;4:628-36.

    CAS  PubMed  Google Scholar 

  45. Famulla S, Lamers D, Hartwig S, Passlack W, Horrighs A, Cramer A, et al. Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells. Int J Obes (Lond) 2011;35:762-72.

    CAS  Google Scholar 

  46. Sabater M, Moreno-Navarrete JM, Ortega FJ, Pardo G, Salvador J, Ricart W, et al. Circulating pigment epithelium-derived factor levels are associated with insulin resistance and decrease after weight loss. J Clin Endocrinol Metab 2010;95:4720-8.

    CAS  PubMed  Google Scholar 

  47. Gattu AK, Birkenfeld AL, Jornayvaz F, Dziura J, Li F, Crawford SE, et al. Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients. Acta Diabetol 2012;49(Suppl 1):S161-9.

    PubMed  Google Scholar 

  48. Sunderland KL, Tryggestad JB, Wang JJ, Teague AM, Pratt LV, Zhang SX, et al. Pigment epithelium-derived factor (PEDF) varies with body composition and insulin resistance in healthy young people. J Clin Endocrinol Metab 2012;97:E2114-8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bucerius J, Mani V, Moncrieff C, Machac J, Fuster V, Farkouh ME, et al. Optimizing 18F-FDG PET/CT imaging of vessel wall inflammation: The impact of 18F-FDG circulation time, injected dose, uptake parameters, and fasting blood glucose levels. Eur J Nucl Med Mol Imaging 2014;41:369-83.

    CAS  PubMed  Google Scholar 

  50. Zhuang HM, Cortés-Blanco A, Pourdehnad M, Adam LE, Yamamoto AJ, Martínez-Lázaro R, et al. Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? Nucl Med Commun 2001;22:1123-8.

    CAS  PubMed  Google Scholar 

  51. Rabkin Z, Israel O, Keidar Z. Do hyperglycemia and diabetes affect the incidence of false-negative 18F-FDG PET/CT studies in patients evaluated for infection or inflammation and cancer? A Comparative analysis. J Nucl Med 2010;51:1015-20.

    PubMed  Google Scholar 

  52. Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, et al. 2-Deoxy-2-[18F]fluoro-d-mannose positron emission tomography imaging in atherosclerosis. Nat Med 2014;20:215-9.

    CAS  PubMed  Google Scholar 

  53. Tarkin JM, Joshi FR, Evans NR, Chowdhury MM, Figg NL, Shah AV, et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to [18F]FDG PET imaging. J Am Coll Cardiol 2017;69:1774-91.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Holman RR, Coleman RL, Chan JCN, Chiasson JL, Feng H, Ge J, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:877-86.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Mami Nakayama, Miho Nakao-Kogure, Katsue Shiramizu, Miyuki Nishikata, Yuri Nishino, Makiko Kiyohiro (Kurume University), and Kouichi Nitta (Hitachi Ltd., Tokyo, Japan) for their technical assistance.

Disclosure

This study was supported in part by research grants from the Kimura Memorial Foundation (to YN, MB, AT, SM, AH and TN), the Grant-in-Aid for Scientific Research C (17K09564 and 17K08968) from the Japan Society for the Promotion of Science (JSPS KAKENHI), Tokyo, Japan (to NT and SY). Yoichi Sugiyama, Sachiyo Igata, Jiahui Sun, Seiji Kurata, Kiminori Fujimoto, Toshi Abe, Takanori Matsui, and Yoshihiro Fukumoto have nothing to disclose.

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan

    Nobuhiro Tahara MD, PhD, Yoshikazu Nitta MD, PhD, Munehisa Bekki MD, Atsuko Tahara MD, Shoko Maeda-Ogata MD, Yoichi Sugiyama MD, Akihiro Honda MD, PhD, Sachiyo Igata PhD, Tomohisa Nakamura MD, Jiahui Sun MD & Yoshihiro Fukumoto MD, PhD

  2. Department of Radiology, Kurume University School of Medicine, Kurume, Japan

    Seiji Kurata MD, PhD, Kiminori Fujimoto MD, PhD & Toshi Abe MD, PhD

  3. Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan

    Takanori Matsui PhD

  4. Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo, 142-8666, Japan

    Sho-ichi Yamagishi MD, PhD

Authors
  1. Nobuhiro Tahara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshikazu Nitta MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Munehisa Bekki MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atsuko Tahara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shoko Maeda-Ogata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoichi Sugiyama MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akihiro Honda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sachiyo Igata PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tomohisa Nakamura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiahui Sun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Seiji Kurata MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kiminori Fujimoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Toshi Abe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Takanori Matsui PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sho-ichi Yamagishi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yoshihiro Fukumoto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nobuhiro Tahara MD, PhD.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarises the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPT 664 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tahara, N., Nitta, Y., Bekki, M. et al. Two-hour postload plasma glucose and pigment epithelium-derived factor levels are markers of coronary artery inflammation in type 2 diabetic patients. J. Nucl. Cardiol. 27, 1352–1364 (2020). https://doi.org/10.1007/s12350-019-01842-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12350-019-01842-5

Keywords

Search

Navigation