Glycemic Variability: Clinical and Prognostic Significance
DOI:
https://doi.org/10.17140/DROJ-1-108Keywords:
Type 1 diabetes, Type 2 diabetes, Glycemic variability, Diabetic complicationsAbstract
Minimizing development or progression of chronic diabetic micro and macro-vascular complications has been always the goal of glycemic control. In recent years, much attention has been focused on the possibility that glycemic variability confers an additional risk factor for diabetic complications independent of glycated hemoglobin (HbA1c). Evidence suggests that fluctuating glucose levels produce endothelial dysfunction as well as an increase in free radicals, the key link between hyperglycemia and diabetic complications and that these changes are greater than those produced by sustained hyperglycemia in in vitro and in animal studies. In humans studies, experimental setting also support the hypothesis that plasma glucose fluctuations produce a higher increase in oxidative stress as well as endothelial dysfunction than those produced by sustained hyperglycemia in type 2 diabetes. Moreover, glycemic variability may have a role in the prediction of severe hypoglycemia, which may act as a precipitating factor of diabetic complications. Based on review of available evidence, we advocate decreasing hyperglycemia and diminishing glycemic variability as well as avoiding hypoglycemia in diabetic patients as targets of diabetic therapy. Future trials targeting the influence of the control of plasma glucose fluctuations on the development of diabetic micro-and macro-vascular complications are needed to further strengthen the evidence base.
References
American Diabetes Association. Standard of medical care in diabetes - 2015. Diabetes Care. 2015; 38: S4-S69.
The American Heart Association and American Stoke Asso-ciation. Guidelines for the primary prevention of stoke: A guide-line for healthcare professional. Stoke. 2011; 42: 517-584.
Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c independent risk factor for diabetic complications. JAMA. 2006; 295: 1707-1782.
Hirsch IB, Brownlee M. Should minimal blood glucose vari-ability become the gold standard of glycemic control? J Diabe-tes Complications. 2005; 19: 178-181.
The effect of intensive treatment of diabetes on the develop-ment and progression of long-term complication in insulin-de-pendent diabetes mellitus. The Diabetes Control and Complica-tion Trial Research Group. N Engl J Med. 1993; 329: 977-986. doi: 10.1056/NEJM199309303291401
The relationship of glycemic exposure (hba1c) to the risk of development and progression of retinopathy in the diabetes con-trol and complication trail. The Diabetes Control and Complica-tions Trial Research Group. Diabetes. 1995; 44: 968-983.
The diabetes control and complication trail/epidemiology of diabetes interventions and complication research group. Effect of intensive therapy on the microvascular complication of type 1 diabetes mellitus. JAMA. 2002; 287: 2563-2569.
Gerstein HC, Miller ME, Byington RP, et al. Effects of inten-sive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358: 2545-2559. doi: 10.1056/NEJMoa0802743
Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358: 2560-2572. doi: 10.1056/ NEJMoa0802987
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360: 129-139. doi: 10.1056/NEJMoa0808431
Cavalot F. Do data in the literature indicate that glycaemic variability is a clinical problem? Glycaemic variability and vas-cular complications of diabetes. Diabetes Obes Metab. 2013: 15: 3-8. doi: 10.1111/dom.12140
Muggeo M, Verlato G, Bonora E, et al. Long-term instability of fasting plasma glucose predicts mortality in elderly NIDDM patients: the Verona Diabetes Study. Diabetologia. 1995; 38:
Muggeo M, Verlato G, Bonora E, Zoppini G, Corbellini M, de Marco R. Long-term instability of fasting plasma glucose, a novel predictor of cardiovascular mortality in elderly patients with non-insulin-dependent- diabetes mellitus: the Verona Dia-betes Study. Circulation. 1997; 96: 1750-1754.
MuggeoM, Zoppini G, Bonora E, et al. Fasting plasma glu-cose variability predicts 10-year survival of type 2 diabetes patients: the Verona Diabetes Study. Diabetes Care. 2000; 23:
Zoppini G, Verlato G, Targher G, et al. Variability of body weight, plus pressure and glycaemia strongly predict total mortality in elderly type 2 diabetic patients. The Verona Dia-betes Study. Diabetes Metab Res Rev. 2008; 24: 624-628. doi: 10.1002/dmrr.897
MuggeoM, Verlato G, Bonora E, et al. The Verona Diabetes Study: a population-based survey on known diabetes mellitus prevalence and 5-year all-cause mortality. Diabetologia. 1995; 38: 318-325.
Lin CC, Li CI, Yang SY, et al. Variation of fasting plas-ma glucose: a predictor of mortality in patients with type 2 diabetes. Am J Med. 2012; 125: 416. e9-e18. doi: 10.1016/j. amjmed.2011.07.027
Lin CC, Li CI, Liu CS, et al. Annual fasting plasma glu-cose variation increases risk of cancer incidence and mortality in patients with type 2 diabetes: The Taichung Diabetes Study. Endocr Relat Cancer. 2012; 19: 473-483. doi: 10.1530/ERC-12- 0038
Lin CC, Yang CP, Li CI, et al. Visit-to-visit variability of fasting plasma glucose as predictor of ischemic stroke: compet-ing risk analysis in a national cohort of Taiwan Diabetes Study. BMC Med. 2014; 12: 165. doi: 10.1186/s12916-014-0165-7
Siegelaar S, Holleman F, Hoekstra J, DeVries JH. Glucose variability; Does it matter? Endocrine Rev. 2010; 31: 171-182. doi: 10.1210/er.2009-0021
Service FJ, O’Brien PC. The relation of glycaemia to the risk of development and progression of retinopathy in the Dia-betic Control and Complications Trial. Diabetologia. 2001; 44:
Molnar GD, Taylor WF, Ho MM. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability. Diabetologia. 1972; 8: 342-348.
Eslami S1, Taherzadeh Z, Schultz MJ, Abu-Hanna A. Glu-cose variability measures and their effect on mortality: a sys-tematic review. Intensive Care Med. 2011; 37: 583-593. doi: 10.1007/s00134-010-2129-5
Ceriello A, Ihnat MA. Glycemic variability: a new therapeu-tic challenge in diabetes and the critical care setting. Diabet Med. 2010; 27: 862-867. doi: 10.1111/j.1464-5491.2010.02967.x
Risso A, Mercuri F, Quagliaro L, DamanteG, Ceriello A. In-termittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Me-tab. 2001; 281: E924-E930.
Del Guerra S, Grupillo M, Masini M, et al. Gliclazide pro-tects human islet beta-cells from apoptosis induced by intermit-tent high glucose. Diabetes Metab Res Rev. 2007; 23: 234-238.
Quagliaro L, Piconi L, Assaloni R, Martinelli L, MotzE, Ce-riello A. 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. Dia-betes. 2003; 52: 2795-2804.
Piconi L, Quagliaro L, Da Ros R, et al. Intermittent high glu-cose enhances ICAM-1, VCAM-1, Eselectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost. 2004; 2: 1453-1459.
Quagliaro L, Piconi L, Assaloni R, et al. Intermittent high glucose enhances ICAM-1, VCAM-1 and Eselectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide produc-tion. Atherosclerosis. 2005; 183: 259-267.
Piconi L, Quagliaro L, Assaloni R, et al. Constant and inter-mittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev. 2006; 22: 198-203.
Azuma K, Kawamori R, Toyofuku Y, et al. Repetitive fluc-tuations in blood glucose enhance monocyte adhesion to the en-dothelium of rat thoracic aorta. Arterioscler ThrombVasc Biol. 2006; 26: 2275-2280.
Mita T, Otsuka A, Azuma K, et al. Swings in blood glucose levels accelerate atherogenesis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun. 2007; 358: 679-685.
Azuma K, Toyofuku Y, Iesaki T, et al. Acarbose, an a-glu-cosidase inhibitor, improves endothelial dysfunction in Goto-Kakizaki rats exhibiting repetitive blood glucose fluctuation. Biochem Biophys Res Commun. 2006; 345: 688-693.
Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Gly-caemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes Metab. 2010; 12: 288-298. doi: 10.1111/j.1463- 1326.2009.01160.x.
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: 1681-1687.
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. Diabe-tes. 2008; 57: 1349-1354. doi: 10.2337/db08-0063
Hu Y, Liu W, Huang R, Zhang X. Post challenge plasma glucose excursions, carotid intima-media thickness, and risk factors for atherosclerosis in Chinese population with type 2 diabetes. Atherosclerosis. 2010; 210: 302-306. doi: 10.1016/j. atherosclerosis.2009.11.015
Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leon-hardt W, Fuecker K, HanefeldM. Post challenge plasma glucose and glycemic spikes are more strongly associated with athero-sclerosis than fasting glucose or HbA1c level. Diabetes Care. 2000; 23: 1830-1834.
Barbieri M, Rizzo MR, Marfella R, et al. Decreased ca-rotid atherosclerotic process by control of daily acute glu-cose fluctuations in diabetic patients treated by DPP-IV in-hibitors. Atherosclerosis. 2013; 227: 349-354. doi: 10.1016/j. atherosclerosis.2012.12.018
Wentholt IM, Kulik W, Michels RP, Hoekstra JB, DeVries JH. Glucose fluctuations and activation of oxidative stress in pa-tients with type 1 diabetes. Diabetologia. 2008; 51: 183-190.
Bragd J, Adamson U, Bäcklund LB, Lins PE, Moberg E, Oskarsson P. Can glycemic variability, as calculated from blood glucose self-monitoring, predict the development of complica-tion in type 1 diabetes, over a decade? Diabetes Metab. 2008; 34: 612-616. doi: 10.1016/j.diabet.2008.04.005
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: 1486-1490.
Kilpatrick ES, Rigby AS, Atkin SL. Mean blood glucose compared with HbA1c in the prediction of cardiovascular dis-ease in patients with type 1 diabetes. Diabetologia. 2008; 51:
Moberg EA, Lins PE, Adamson UK. Variability of blood glucose levels in patients with type 1 diabetes mellitus on inten-sified insulin regimens. Diabetes Metab. 1994; 20: 546-552.
Gordin D, Ronnback M, Forsblom C, Mäkinen V, Saraheimo M, Groop PH. Glucose variability, blood pressure and arterial stiffness in type 1 diabetes. Diabetes Res Clin Pract. 2008; 80: e4-e7. doi: 10.1016/j.diabres.2008.01.010
Gimeno-Orna JA, Castro-Alonso FJ, Boned-Juliani B, Lou-Arnal LM. Fasting plasma glucose variability as a risk factor of retinopathy in type 2 diabetic patients. J Diabetes Complica-tions. 2003; 17: 78-81.
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: 334-339. doi: 10.1016/j.numecd.2008.02.007
Cox DJ, Kovatchev BP, Julian DM, et al. Frequency of se-vere hypoglycemia in insulin-dependent diabetes mellitus can be predicted from self-monitoring blood glucose data. J Clin Endo-crinol Metab. 1994; 79: 1659-1662.
Murata GH, Hoffman RM, Shah JH, Wendel CS, Duckworth WC. A probabilistic model for predicting hypoglycemia in type 2 diabetes mellitus: the Diabetes Outcomes in Veterans Study (DOVES). Arch Intern Med. 2004; 164: 1445-1450.
Zoungas S, Patel A, Chalmers J, et al. ADVANCE Collabor-ative Group: Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010; 363: 1410-1418. doi: 10.1056/ NEJMoa1003795
Yakubovich N, Gerstein HC. Serious cardiovascular out-comes in diabetes: the role of hypoglycemia. Circulation. 2011; 123: 342-348. doi: 10.1161/CIRCULATIONAHA.110.948489
Ceriello A, Novials A, Ortega E, et al. Evidence that hyper-glycemia after recovery from hypoglycemia worsens endothe-lial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes. Dia-betes. 2012; 61: 2993-2997. doi: 10.2337/db12-0224
Standards of medical care in diabetes 2015: summary of re-visions. Diabetes Care. 2015; 8: S4. doi: 10.2337/dc15-S003
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