There is now unequivocal evidence that improving glycemic control in both type 1 and type 2 diabetes reduces the likelihood of developing the micro- and macrovascular complications of the disease. However, it is still unclear whether a patient with very variable glucose is at any different a risk of these problems than someone who has the same mean glucose but much more stable glycemia. This article reviews the evidence that exists to both support and refute the claim that increased glucose variability should be regarded as an independent risk factor for the development of diabetic vascular disease.
The Diabetes Control and Complications Trial Research Group. Diabetes Control and Complications Trial (DCCT): results of feasibility study. Diabetes Care.1987;10 (1): 1–19.
2.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med.1993;329 (14): 977–86.
3.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet.1998;352 (9131): 837–53.
4.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med.2005;353 (25): 2643–53.
5.
HolmanRPaulSBethelMMatthewsDNeilH. 10–year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.2008;359 (15): 1577.
6.
LachinJMGenuthSNathanDMZinmanBRutledgeBN; DCCT/EDIC Research Group. The effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial—revisited. Diabetes.2008;57 (4): 995–1001.
7.
HirschIBBrownleeM. Should minimal blood glucose variability become the gold standard of glycemic control?J Diabetes Complications.2005;19 (3): 178–81.
8.
McCallALKovatchevBP. The median is not the only message: a clinician's perspective on mathematical analysis of glycemic variability and modeling in diabetes mellitus. J Diabetes Sci Technol.2009;3 (1): 3–11.
9.
ServiceFJMolnarGDRosevearJWAckermanEGatewoodLCTaylorWF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes.1970;19 (9): 644–55.
10.
KovatchevBClarkeWBretonMBraymanKMcCallA. Quantifying temporal glucose variability in diabetes via continuous glucose monitoring: mathematical methods and clinical application. Diabetes Technol Ther.2005;7 (6): 849–62.
11.
KovatchevBOttoECoxDGonder-FrederickLClarkeW. Evaluation of a new measure of blood glucose variability in diabetes. Diabetes Care.2006;29 (11): 2433–8.
12.
HillNRHindmarshPCStevensRJStrattonIMLevyJCMatthewsDR. A method for assessing quality of control from glucose profiles. Diabet Med.2007;24 (7): 753–8.
13.
KovatchevB. Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the low blood glucose index. Diabetes Care.1998;21 (11): 1870–5.
14.
KovatchevBPCoxDJGonder-FrederickLClarkeWL. Methods for quantifying self-monitoring blood glucose profiles exemplified by an examination of blood glucose patterns in patients with type 1 and type 2 diabetes. Diabetes Technol Ther.2002;4 (3): 295–303.
15.
BrownleeM. The pathobiology of diabetic complications: a unifying mechanism. Diabetes.2005;54 (6): 1615–25.
16.
MonnierLMasEGinetCMichelFVillonLCristolJPColetteC. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA.2006;295 (14): 1681–7.
17.
EspositoKNappoFMarfellaRGiuglianoGGiuglianoFCiotolaMQuagliaroLCerielloAGiuglianoD. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation.2002;106 (16): 2067–72.
18.
QuagliaroLPiconiLAssaloniRMartinelliLMotzECerielloA. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes.2003;52: 2795–804.
19.
CerielloAQuagliaroLPiconiLAssaloniRDa RosRMaierAEspositoKGiuglianoD. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes.2004;53 (3): 701–10.
20.
QuagliaroLPiconiLAssaloniRDa RosRMaierAZuodarGCerielloA. Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. Atherosclerosis.2005;183 (2): 259–67.
21.
IhnatMThorpeJCerielloA. Hypothesis: the ‘metabolic memory’, the new challenge of diabetes. Diabet Med.2007;24 (6): 582–6.
22.
MonnierLLapinskiHColetteC. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care.2003;26 (3): 881–5.
23.
MonnierLColetteCDunseathGOwensD. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care.2007;30 (2): 263–9.
24.
The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes.1995;44 (8): 968–83.
25.
MohsinFCraigMECusumanoJChanAKHingSLeeJWSilinkMHowardNJDonaghueKC. Discordant trends in microvascular complications in adolescents with type 1 diabetes from 1990 to 2002. Diabetes Care.2005;28 (8): 1974–80.
26.
Gimeno-OrnaJCastro-AlonsoFBoned-JulianiBLou-ArnalL. Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients. J Diabetes Complications.2003;17 (2): 78–81.
27.
BragdJAdamsonUBäcklundLLinsPMobergEOskarssonP. Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade?Diabetes Metab.2008;34 (6): 612–6.
28.
KilpatrickESRigbyASAtkinSL. 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): 2198–202.
29.
DonahueRAbbottRReedDYanoK. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes.1987;36 (6): 689–92.
30.
LoweLLiuKGreenlandPMetzgerBDyerAStamlerJ. Diabetes, asymptomatic hyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care.1997;20 (2): 163–9.
31.
BalkauBShipleyMJarrettRPyöräläKPyöräläMForhanAEschwègeE. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care.1998;21 (3): 360–7.
32.
De VegtFDekkerJMRuhèHGStehouwerCDNijpelsGBouterLMHeineRJ. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia.1999;42 (8): 926–31.
33.
EspositoKCiotolaMCarleoDSchisanoBSardelliLDi TommasoDMissoLSaccomannoFCerielloAGiuglianoD. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab.2008;93 (4): 1345–50.
34.
HanefeldMFischerSJuliusUSchulzeJSchwanebeckUSchmechelHZiegelaschHJLindnerJ. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia.1996;39 (12): 1577–83.
35.
CavalotFPetrelliATraversaMBonomoKFioraEContiMAnfossiGCostaGTrovatiM. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab.2006;91 (3): 813–9.
36.
EspositoKGiuglianoDNappoFMarfellaR. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation.2004;110 (2): 214–9.
37.
ChiassonJJosseRGomisRHanefeldMKarasikALaaksoM. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM Trial. JAMA.2003;290 (4): 486–94.
38.
WentholtIKulikWMichelsRHoekstraJDeVriesJ. Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes. Diabetologia.2008;51 (1): 183–90.
39.
DerrRGarrettEStacyGASaudekCD. Is HbA(1c) affected by glycemic instability?Diabetes Care.2003;26 (10): 2728–33.
40.
McCarterRJHempeJMChalewSA. Mean blood glucose and biological variation have greater influence on HbA1c levels than glucose instability: an analysis of data from the Diabetes Control and Complications Trial. Diabetes Care.2006;29 (2): 352–5.
41.
KohnertKDAugsteinPHeinkePZanderEPetersonKFreyseEJSalzsiederE. Chronic hyperglycemia but not glucose variability determines HbA1c levels in well-controlled patients with type 2 diabetes. Diabetes Res Clin Pract.2007;77 (3): 420–6.
42.
KilpatrickESRigbyASAtkinSL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care.2006;29 (7): 1486–1490.
43.
KilpatrickESRigbyASAtkinSL. Variability in the relationship between mean plasma glucose and HbA1c: implications for the assessment of glycemic control. Clin Chem.2007;53 (5): 897–901.
44.
PankowJKwanDDuncanBSchmidtMCouperDGoldenSBallantyneCM. Cardiometabolic risk in impaired fasting glucose and impaired glucose tolerance: the Atherosclerosis Risk in Communities Study. Diabetes Care.2007;30 (2): 325–31.
45.
BarrEZimmetPWelbornTJolleyDMaglianoDDunstanDCameronAJDwyerTTaylorHRTonkinAMWongTYMcNeilJShawJE. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation.2007;116 (2): 151–7.
46.
The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med.2008;358 (24): 2545–59.
47.
The ADVANCE Collaborative GroupPatelAMacMahonSChalmersJNealBBillotLWoodwardMMarreMCooperMGlasziouPGrobbeeDHametPHarrapSHellerSLiuLManciaGMogensenCEPanCPoulterNRodgersAWilliamsBBompointSde GalanBEJoshiRTravertF. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med.2008;358 (24): 2560–72.
48.
DuckworthWAbrairaCMoritzTRedaDEmanueleNReavenPDZieveFJMarksJDavisSNHaywardRWarrenSRGoldmanSMcCarrenMVitekMEHendersonWGHuangGD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med.2009;360 (2): 129–39.
49.
KilpatrickESRigbyASAtkinSL. Mean blood glucose compared with HbA1c in the prediction of cardiovascular disease in patients with type 1 diabetes. Diabetologia.2008;51 (2): 365–71.
50.
AmoriRELauJPittasAG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA.2007;298 (2): 194–206.
