THE ROLE OF GLYCEMIA VARIABILITY IN THE PROCESSES OF CELLULAR AND VASCULAR AGEING IN PATIENTS WITH TYPE 2 DIABETES

Aim. To investigate  on  the  presence and  relation characteristics of glycemia  variability (GV) and   vascular   wall  parameters,  chronic inflammation, oxidation status,   telomere  biology in type  2  diabetes patients (DM2).

Material and methods. Into the single-movement study, 50 DM2 patients included, with no signs of cardiovascular diseases. All participants  were evaluated on the carbohydrate  metabolism, glycemia variablity, underwent duplex  scan   of  carotid   arteries   with  intima-media  complex  (IMC) measurement, and  assessment for atherosclerotic  plaques;  underwent carotid-femoral pulse wave velocity measurement, endothelium dependent vasodialtion, telomere length measurement and telomerase activity (TA).

Results. The parameters of vessel wall, together with the classical CVD risk  factors,   independently   related   with the  various  carbohydrate metabolism parameters: glycated hemoglobin, fasting glucose plasma, HOMA-IR index, C-peptide, immune reactive insulin. The GV of moderate amplitude  of glycemia (MAGE) was related  to IMC increase  in DM2 patients.  There was significant relation of telomere length (TL) not just with a chronic hyperglycemia, but with glucose level fluctuations as well, e.g. with GV standard deviation (SD), MAGE, CONGA (continuous overall net glycemic action), and such relation is higher in the analysis of “the longest”  telomeres.  Relation of TL  and  GV  is not dependent on the cardiovascular risk factors,  chronic inflammation and TA, but depends on fasting plasma glucose.  There was no significant relation of TA with GV in DM2. There was direct correlation of GV CONGA  and oxidative stress marker malonic dialdehyde, and independent negative correlation of GV (MAGE, SD, CONGA) with TL.

Conclusion. GV is related  with subclinical atherosclerosis (IMC) and shorter  TL in DM2 patients,  which is mediated  by activated oxidation stress under glycemia fluctuations.

glycemia variability, telomere length, vascular ageing, diabetes mellitus, telomerase activity

1. Chen L.Z. Wang B, Zhang H, Yang JM. Analyses of carotid intima-media thickness and quantitative arterial stiffness in type 2 diabetes mellitus patients with follow-ups Zhonghua Yi Xue Za Zhi. 2013 Mar 26;93(12):927-9.

2. Mukai N, Ninomiya T, Hata J. Association of hemoglobin A1C and glycated albumin with carotid atherosclerosis in community-dwelling Japanese subjects: the Hisayama Study., No. Cardiovasc Diabetol. 2015 Jun; 14:84

3. Temelkova-KurktschievTS, KoehlerC, HenkelE, LeonhardtW, FueckerK, HanefeldM: Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1 clevel. Diabetes Care 2000, 23(12):1830-1834

4. Monnier L., Colette C., Owens D.R. Glycemic variability: the third component of the dysglycemia in diabetes. Is it important? How to measure it? // J Diabetes Sci Technol. 2008; 2(6): 1094-1100.

5. KohnertKD, AugsteinP, ZanderE, HeinkeP, PetersonK. Glycemic variability correlates strongly with postprandial beta-cell dysfunction in asegment of type 2 diabetic patients using oral hypoglycemic agents. DiabetesCare 2009, 32:1058-1062.

6. Tylee, TracyS.; Trence, DaceL. GlycemicVariability: LookingBeyondtheA1C. Diabetes Spectrum; 2012, Vol. 25, Number 3, p149-153.

7. RodbardD. Interpretation of continuous glucose monitoring data: glycemic variability and quality of glycemic control. // DiabetesTechnolTher. 2009; 11 Suppl 1:55-67.

8. Su G, MiSHTH, LiZ, YangHX, ZhengH, ZhouY,etal. Impact of Admission Glycemic Variability, Glucose, and Glycosylated Hemoglobin on Major Adverse Cardiac Events After Acute Myocardial Infarction. Diabetes Care. 2013; 36(4):1026-1032.

9. Su G., MiS., TaoH. etal. Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes. // CardiovascDiabetol. 2011; 10:19.

10. Standl E., Shnell O., Seriello A. Postprandial Hyperglycemia and Glycemic Variability Should we care? Diabetes Care 34(Suppl. 2):S120-S127, 2011.

11. Stehouwer, C. D, Henry, R. M, Ferreira, I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia 2008, 51, 527-39.

12. Lipska KJ, Venkitachalam L, Gosch K, Kovatchev B, Van den Berghe G, Meyfroidt G. Glucose variability and mortality in patients hospitalized with acute myocardial infarction. CircCardiovascQual Outcomes 2012, 5:550-557.

13. Borg, R.; Kuenen, J.C.; Carstensen, B.; Zheng, H.; HbA(1)(c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes:, No. TheA1C-DerivedAverageGlucose (ADAG) study. Diabetologia2011, 54,69-72.

14. HirschIB. Glycemic Variability: It’s Not Just About A1C Anymore! DiabetesTechnolTher, 2005; 7(5):780-83.

15. Sutton-Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, Lakatta E, Spurgeon H, Vaitkevicius P. Aortic stiffness is associated with visceral adiposity in older adults enrolled in the study of health, aging, and body composition., No. Hypertension. 2001;38:429-433.

16. Watanabe et al. Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease BMC Cardiovascular Disorders 2013, 13:11.

17. Mihm MJ, Jing L, Bauer JA: Nitrotyrosine causes selective vascular endothelial dysfunction and DNA damage. J Cardiovasc Pharmacol2000, 36:182-187.

18. Ceriello A, Cavarape A, Martinelli L, et al. The post-prandial state in type 2 diabetes and endothelial dysfunction: effects of insulin aspart. Diabet Med 2004;21:171-175

19. Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004. 110:214-219.

20. Esposito, K.; Ciotola, M.; Carleo, D.; Schisano, B.; Sardelli, L.; di Tommaso, D.; Misso, L.; Saccomanno, F.; Ceriello, A.; Giugliano, D. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes., No. J. Clin. Endocrinol. Metab. 2008, 93 1345-1350.

21. Chen XM, Zhang Y, Shen XP, Huang Q, Ma H, Huang YL, Zhang WQ, Wu HJ: Correlation between glucose fluctuations and carotid intima-media thickness in type 2 diabetes. Diabetes Res ClinPract 2010, 90:95-99.

22. BarbieriM, RizzoMR, MarfellaR. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic atientstreatedbyDPP-IVinhibitorsAtherosclerosis.2013 Apr;227(2):349-54.

23. Watanabe et al. Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease BMC Cardiovascular Disorders 2013, 13:11.

24. Zhong Guo Tang Niao Bing Za Zhi. Chinese Diabetes Society: China glucose monitoring clinical application guide (2011 edition). 2011 Mar. 15; 91(10): 656 664.

25. Di Flaviani A, PicconiF, DiStefanoP, GiordaniI, MalandruccoI, MaggioP, PalazzoP. Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. Diabetes Care. 2011 Jul;34(7):1605-9

26. Cesana F, Giannattasio C, Nava S. Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus. BloodPress. 2013 Dec;22(6):355-61.

27. Mo Y, JianZhou, MeiLi, YuweiWang. Glycemic variability is associated with subclinical atherosclerosis in Chinese type 2 diabetic patients. Cardiovascular Diabetology 2013, 12:15.

28. Maeda M, Hayashi T, Mizuno N. Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase PLoSOne.2015 Apr 16; 10(4):e0123169.

29. Makino N., Sasaki M., Maeda T., Mimori K. Telomere biology in cardiovascular disease - role of insulin sensitivity in diabetic hearts. Experimental and clinical cardiology 2010; 15(4):128-33.

30. Choi ES, Rhee EJ, Choi JH, Bae JC. The association of brachial-ankle pulse wave velocity with 30-minute post-challenge plasma glucose levels in korean adults with no history of type 2 diabetes. Korean Diabetes J. 2010 Oct; 34(5):287-93.

31. Watanabe K, Oba K, Suzuki T, Ouchi M, Suzuki K, Futami-Suda S, Sekimizu K, Yamamoto N, Nakano H. Oral glucose loading attenuates endothelial function in normal individual. Eur J Clin Invest 2011, 41:465-473.

32. GordinD, RönnbackM, ForsblomC, MäkinenV, SaraheimoM, GroopPH. Glucose variability, blood pressure and arterial stiffness in type 1 diabetes. DiabetesResClinPract 2008;80:e4-7.

33. Oliver, J. J. Webb DJ: Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol, 2003, 23, 554-566.

34. Piconi L, Quagliaro L, Da Ros R. Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly (ADP-ribose) polymerase. J Thromb Haemost. 2004;2(8):1453-1459.