Short-term and long-term glycemic variability and its relationship to microvascular complications of diabetes

Authors: Martin Prázný;  Jan Škrha;  Jan Šoupal;  Jan Škrha Jr
Authors‘ workplace: III. interní klinika 1. LF UK a VFN v Praze
Published in: Vnitř Lék 2016; 62(Suppl 4): 85-93
Category: Reviews


Vascular complications of diabetes result from long lasting unsatisfactory glycemic control. We usually assess glycemic control based on the value of glycated hemoglobin HbA1c. The glycated hemoglobin test, however, says nothing about short-term glycemic fluctuations. Recently, continuous monitoring of glycemia has enabled us an in-depth assessment of changes in glucose concentrations, called glycemic variability. In connection with the research into short-term glycemic variability, also the study of long-term fluctuations in glycemic control based on HbA1c variability has now intensified. Glycemic variability may be related to oxidation stress, endothelial dysfunction and inflammation, the factors traditionally associated with vascular damage. Several studies have described the relation of glycemic variability to macrovascular complications of diabetes, still its relation to microvascular complications remains unclear. This overview summarizes the recent findings in the field of glycemic variability and its possible association with retinopathy, nephropathy and neuropathy.

Key words:
type 1 and 2 diabetes mellitus – glycemic variability – microvascular complications – HbA1c – variability


1. Nathan DM, McGee P, Steffes MW et al. Relationship of glycated albumin to blood glucose and HbA(1c) values and to retinopathy, nephropathy and cardiovascular outcomes in the DCCT/EDIC study. Diabetes 2014; 63(1): 282–290. Dostupné z DOI: <–0782>.

2. Saisho Y. Glycemic variability and oxidative stress: a link between diabetes and cardiovascular disease? Int J Mol Sci 2014; 15(10): 18381–18406. Dostupné z DOI: <>.

3. Brownlee M. The pathobiology of diabetic complications – a unifying mechanism. Diabetes 2005; 54(6): 1615–1625.

4. El-Osta A, Brasacchio D, Yao DC et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 2008; 205(10): 2409–2417. Dostupné z DOI: <>. Erratum in J Exp Med 2008; 205(11): 2683.

5. Salisbury D, Bronas U. Reactive oxygen and nitrogen species. Impact on endothelial dysfunction. Nurs Res 2015; 64(1): 53–66. Dostupné z DOI: <>.

6. Wang L, Wang J, Fang J et al. High glucose induces and activates Toll-like receptor 4 in endothelial cells of diabetic retinopathy. Diabetol Metab Syndr 2015; 7: 89. Dostupné z DOI: <–015–0086–4>.

7. De NigrisV, Pujadas G, La Sala L et al. Short-term high glucose exposure impairs insulin signaling in endothelial cells. Cardiovasc Diabetol 2015; 14: 114. Dostupné z DOI: <–015–0278–0>.

8. Monnier L, Mas E, Ginet C et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006; 295(14): 1681–1687.

9. Zhang XG, Zhang YQ, Zhao DK et al. Relationship between blood glucose fluctuation and macrovascular endothelial dysfunction in type 2 diabetic patients with coronary heart disease. Eur Rev Med Pharmacol Sc 2014; 18(23): 3593–3600.

10. Ceriello A, Esposito K, Piconi L et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008; 57(5): 1349–1354. Dostupné z DOI: <–0063>.

11. Schisano B, Tripathi G, McGee K et al. Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia 2011; 54(5): 1219–1226. Dostupné z DOI: <–011–2049–0>.

12. Pena AS, Couper JJ, Harrington J et al. Hypoglycemia, but not glucose variability, relates to vascular function in children with type 1 diabetes. Diabetes Technol Ther 2012; 14(6): 457–462. Dostupné z DOI: <>.

13. Ceriello A, Novials A, Ortega E et al. Hyperglycemia following recovery from hypoglycemia worsens endothelial damage and thrombosis activation in type 1 diabetes and in healthy controls. Nutr Metab Cardiovasc Dis 2014; 24(2): 116–123. Dostupné z DOI: <>.

14. Kumar B, Kowluru A, Kowluru RA. Lipotoxicity augments glucotoxicity-induced mitochondrial damage in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 2015; 56(5): 2985–2992. Dostupné z DOI: <–16466>.

15. Yang HK, Kang B, Lee SH et al. Association between hemoglobin A1c variability and subclinical coronary atherosclerosis in subjects with type 2 diabetes. J Diabetes Complicat 2015; 29(6): 776–782. Dostupné z DOI: <>.

16. Chang CH, Chuang LM. Glycated hemoglobin variability and retinopathy progression in type 1 diabetes: is month-to-month instability a better predictor? J Diabetes Investig 2014; 5(2): 149–152. Dostupné z DOI: <>.

17. Cheng DS, Fei Y, Liu Y et al. HbA1c variability and the risk of renal status progression in diabetes mellitus: a meta-analysis. PLoS One 2014; 9(12): e115509. Dostupné z DOI: <>.

18. Kohnert KD, Heinke P, Vogt L et al. Utility of different glycemic control metrics for optimizing management of diabetes. World J Diabetes 2015; 6(1): 17–29. Dostupné z DOI: <>.

19. Service FJ. Glucose variability. Diabetes 2013; 62(5): 1398–1404. Dostupné z DOI: <–1396>.

20. Saisho Y, Tanaka C, Tanaka K et al. Relationships among different glycemic variability indices obtainedby continuous glucose monitoring. Primary Care Diabetes 2015; 9(4): 290–296. Dostupné z DOI: <>.

21. Fabris C, Facchinetti A, Sparacino G et al. Glucose variability indices in Type 1 diabetes: parsimonious set of indices revealed by Sparse Principal Component Analysis. Diabetes Technol Ther 2014; 16(10): 644–652. Dostupné z DOI: <>.

22. Selvin E, Rawlings AM, Grams M et al. Association of 1,5-anhydroglucitolwith diabetes and microvascular conditions. Clin Chem 2014; 60(11): 1409–1418. Dostupné z DOI: <>.

23. Ceriello A, Novials A, Ortega E et al. Vitamin C further improves the protective effect of glucagonlike peptide-1 on acute hypoglycemia-induced oxidative stress, inflammation, and endothelial dysfunction in Type 1 diabetes. Diabetes Care 2013; 36(12): 4104–4108. Dostupné z DOI: <–0750>. Erratum in Diabetes Care 2014; 37(7): 2063.

24. Yousetzade G, Nakhaee A. Insulin-induced hypoglycemia and stress oxidative state in healthy people. Acta Diabetol 2012; 49(Suppl 1): S81-S85. Dostupné z DOI: <–011–0311-z>.

25. Wang JL, Alexanian A, Ying R et al. Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochontrial oxidative stress role for AMP kinase. Arterioscler Thromb Vasc Biol 2012; 32(3): 712–720. Dostupné z DOI: <>.

26. Jaiswal M, McKeon K, Comment N et al. Association between impaired cardiovascular autonomic function and hypoglycemia in patients with Type 1 diabetes. Diabetes Care 2014; 37(9): 2616–2621. Dostupné z DOI: <–0445>.

27. Hirsch IB. Glycemic variability and diabetes complications: does it matter? Of course it does! Diabetes Care 2015; 38(8): 1610–1614. Dostupné z DOI: <–2898>.

28. Rodbard D. Evaluating quality of glycemic control: graphical displays of hypo- and hyper-glycemia, time in target range, and mean glucose. J Diabetes Sci Technol 2015; 9(1): 56–62. Dostupné z DOI: <>.

29. Ceriello A, Kilpatrick ES. Glycemic variability: both sides of the story. Diabetes Care 2013; 36(Suppl 2): S272-S275. Dostupné z DOI: <–2030>.

30. Bergenstal RM. Glycemic variability and diabetes complications: does it matter? Simply put, there are better glycemic markers! Diabetes Care 2015; 38(8): 1615–1621. Dostupné z DOI: <–0099>.

31. Cryer PE. Severe hypoglycemia predicts mortality in diabetes. Diabetes Care 2012; 35(9): 1814–1816. Dostupné z DOI: <–0749>.

32. Niskanen L, Virkamäki A, Hansen JB et al. Fasting plasma glucose variability as a marker of nocturnal hypoglycemia in diabetes: evidence from the PREDICTIVE study. Diabetes Res Clin Pract 2009; 86(2): e15-e18. Dostupné z DOI: <>.

33. Cryer PE. Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract 2008; 14(6): 750–756.

34. Smith-Palmer J, Brändle M, Trevisan R et al. Assessment of the association between glycemic variability and diabetes-related complications in type 1 and type 2 diabetes. Diabetes Res Clin Pract 2014; 105(3): 273–284. Dostupné z DOI: <>.

35. Šoupal J, Škrha J Jr, Fajmon M et al. Glycemic variability is higher in type 1 diabetes patients with microvascular complications irrespective of glycemic control. Diabetes Technol Ther 2014; 16(4): 198–203. Dostupné z DOI: <>.

36. Lachin JM, Genuth S, Nathan DM et al. Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial revisited. Diabetes 2008; 57(4): 995–1001. Dostupné z DOI: <–1618>.

37. Gorst C, Kwak CS, AslamS et al. Long-term glycemic variability and risk of adverse outcomes:a systematic review and meta-analysis. Diabetes Care 2015; 38(12): 2354–2369. Dostupné z DOI: <–1188>.

38. Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 2006; 29(7): 1486–1490.

39. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes: data from the Diabetes Control and Complications Trial. Diabetes Care 2008; 31(11): 2198–2202. Dostupné z DOI: <–0864>.

40. Hermann JM, Hammes HP, Rami-Mehar B et al. HbA1c variability as an independent risk factor for diabetic retinopathy in Type 1 diabetes: A German/Austrian multicenter analysis on 35,891 patients. PLoS One 2014; 9(3): e91137. Dostupné z DOI: <>.

41. Hietala K, Waden J, Forsblom C et al. HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes. Diabetologia 2013; 56(4): 737–745. Dostupné z DOI: <–012–2816–6>.

42. Gimeno-Orna JA, Castro-Alonso FJ, Boned-Juliani B et al. Fasting plasma glucose variability as a risk factor of retinopathy in type 2 diabetic patients. J Diabetes Complicat 2003; 17(2): 78–81.

43. Zoppini G, Verlato G, Targher G et al. Is fasting glucose variability a risk factor for retinopathy in people with type 2 diabetes? Nutr Metab Cardiovasc Dis 2009; 19(5): 334–339. Dostupné z DOI: <>.

44. Hirakawa Y, Arima H, Zoungas S et al. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care 2014; 37(8): 2359–2365. Dostupné z DOI: <–0199>.

45. Takao T, Ide T, Yanagisawa H et al. The effect of fasting plasma glucose variability on the risk of retinopathy in type 2 diabetic patients: retrospective long-term follow-up. Diabetes Res Clin Pract 2010; 89(3): 296–302. Dostupné z DOI: <>.

46. Takao T, Ide T, Yanagisawa H et al. The effects of fasting plasma glucose variability and time dependent glycemic control on the long-term risk of retinopathy in type 2 diabetic patients. Diabetes Res Clin Pract 2011; 91(2): e40-e42. Dostupné z DOI: <>.

47. Nazim J, Fendler W, Starzyk J. Metabolic control and its variability are major risk factors for microalbuminuria in children with type 1 diabetes. Endokrynol Pol 2014; 65(2): 83–89. Dostupné z DOI: <>.

48. Jin SM, Kim TH, Baek SOJ et al. Association between the extent of urinary albumin excretion and glycaemic variability indices measured by continuous glucose monitoring. Diabet Med 2015; 32(2): 274–279. Dostupné z DOI: <>.

49. Hou X, Wang C, Wang S et al. Fluctuation between fasting and 2-H postload glucose state is associated with glomerular hyperfiltration in newly diagnosed diabetes patients with HbA1c, 7%. PLoS One 2014; 9(10):e111173. Dostupné z DOI: <>.

50. Hsu CC, Chang HY, Huang MC et al. HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study. Diabetologia 2012; 55(12): 3163–3172. Dostupné z DOI: <–012–2700–4>.

51. Penno G, Solini A, Bonora E et al. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes. The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care 2013; 36(8): 2301–2310. Dostupné z DOI: <–2264>.

52. Bragd J, Adamson U, Bäcklund LB et al. Can glycaemic variability, as calculated from blood glucose selfmonitoring,predict the development of complications in type 1 diabetes over a decade? Diabetes Metab 2008; 34(6 Pt 1): 612–616. Dostupné z DOI: <>.

53. Sharma D, Morrison G, Joseph F et al. The role of continuous subcutaneous insulin infusion therapy in patients with diabetic gastroparesis. Diabetologia 2011; 54(11): 2768–2770. Dostupné z DOI: <–011–2282–6>.

54. Samsom M, Akkermans LM, Jebbink RJ et al. Gastrointestinal motor mechanisms in hyperglycaemia induced delayed gastric emptying in type I diabetes mellitus. Gut 1997; 40(5): 641–646.

55. Bellastella G, Maiorino MI, Olita L et al. Premature ejaculation is associated with glycemic control in Type 1 diabetes. J Sex Med 2015; 12(1): 93–99. Dostupné z DOI: <>.

56. Iwasaki S, Kozawa J, Fukui K et al. Coefficient of variation of R-R interval closely correlates with glycemic variability assessed by continuous glucose monitoring in insulin-depleted patients with type 1 diabetes. Diab Res Clin Pract 2015; 109(2): 397–403. Dostupné z DOI: <>.

57. Xu F, Zhao L, Su J et al. The relationship between glycemic variability and diabetic peripheral neuropathy in type 2 diabetes with well-controlled HbA1c. Diabet Metab Syndr 2014; 6(1): 139. Dostupné z DOI: <–5996–6-139>.

58. Jun JE, Jin SM, Baek J et al. The association between glycemic variability and diabetic cardiovascular autonomic neuropathy in patients with type 2 diabetes. Cardiovasc Diabetol 2015; 14: 70. Dostupné z DOI: <–015–0233–0>.

59. Martín-Cora FJ, Fornal CA, Metzler CW et al. Insulin induced hypoglycemia decreases single-unit activity of serotonergic medullary raphe neurons in freely moving cats: relationship to sympathetic and motor output. Eur J Neurosci 2002; 16(4): 722–734.

60. Hsu CR, Chen YT, Sheu WH. Glycemic variability and diabetes retinopathy: a missing link. J Diabetes Complicat 2015; 29(2): 302–306. Dostupné z DOI: <>.

61. Probstfield JL, Hirsch I, O’Brien K et al. [The FLAT-SUGAR Trial investigators]. Design of FLAT-SUGAR: Randomized trial of prandial insulin versus prandial GLP-1 receptor agonist together with basal insulin and metformin for high-risk Type 2 diabetes. Diabetes Care 2015; 38(8): 1558–1566. Dostupné z DOI: <–2689>.

62. Kuricová K, Pácal L, Šoupal J et al. Effect of glucose variability on pathways associated with glucotoxicity in diabetes: Evaluation of a novel in vitro experimental approach. Diabetes Res Clin Pract 2016; 114: 1–8. Dostupné z DOI: <>.

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