Diabetic Kidney Disease: Is There a Role for Glycemic Variability?
Purpose of Review
Diabetes is the leading cause of kidney disease globally. Diabetic kidney disease (DKD) is a heterogeneous disorder manifested as albuminuria and/or decreasing GFR. Hyperglycemic burden is the major contributor to the development of DKD. In this article, we review the evidence for the contribution of glycemic variability and the pitfalls associated with use of hemoglobin A1c (A1C), the gold standard for assessment of glucose control, in the setting of DKD.
Glycemic variability, characterized by swings in blood glucose levels, can result in generation of mitochondrial reactive oxygen species, a putative inciting factor for hyperglycemia-induced alterations in intracellular metabolic pathways. While there is indirect evidence supporting the role of glycemic variability in the pathogenesis of DKD, definitive data are lacking. A1C has many limitations and is a particularly suboptimal measure in patients with kidney disease, because its accuracy is compromised by variables affecting RBC survival and other factors. Continuous glucose monitoring (CGM) technology has the potential to enable us to use glucose as a more important clinical tool, for a more definitive understanding of glucose variability and its role in DKD.
Glycemic variability may be a factor in the development of DKD, but definitive evidence is lacking. Currently, all available glycemic biomarkers, including A1C, have limitations and in the setting of DKD and should be used cautiously. Emerging data suggest that personal and professional CGM will play an important role in managing diabetes in patients with DKD, where risk of hypoglycemia is high.
KeywordsDiabetes Diabetic kidney disease A1C Glycemic variability Continuous glucose monitoring Flash glucose monitoring
Compliance with Ethical Standards
Conflict of Interest
Savitha Subramanian reports personal fees from Intarcia Pharmaceuticals and Akcea Therapeutics and grants from Ionis Pharmaceuticals.
Irl B. Hirsch reports grants from Medtronic Diabetes and Novo Nordisk and personal fees from Abbott Diabetes Care, Adocia, Intarcia, Roche, and Valeritas.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 7.Pirart J. Glycaemic control and development of diabetic nephropathy. Acta Endocrinol Suppl (Copenh). 1981;242:41–2.Google Scholar
- 8.Diabetes C, Complications Trial Research G, Nathan DM, Genuth S, Lachin J, Cleary P, et al. 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. https://doi.org/10.1056/NEJM199309303291401.CrossRefGoogle Scholar
- 11.Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK, et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009;58(5):1229–36. https://doi.org/10.2337/db08-1666.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49(11):1939–45. https://doi.org/10.2337/diabetes.49.11.1939.CrossRefPubMedGoogle Scholar
- 15.Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–33. https://doi.org/10.2337/diabetes.55.01.06.db05-0894.CrossRefPubMedGoogle Scholar
- 16.Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, 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):1349–54. https://doi.org/10.2337/db08-0063.CrossRefPubMedGoogle Scholar
- 17.Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, 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):1681–7. https://doi.org/10.1001/jama.295.14.1681.CrossRefPubMedGoogle Scholar
- 19.Waden J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH, et al. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009;58(11):2649–55. https://doi.org/10.2337/db09-0693.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, 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):2301–10. https://doi.org/10.2337/dc12-2264.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Downie E, Craig ME, Hing S, Cusumano J, Chan AK, Donaghue KC. Continued reduction in the prevalence of retinopathy in adolescents with type 1 diabetes: role of insulin therapy and glycemic control. Diabetes Care. 2011;34(11):2368–73. https://doi.org/10.2337/dc11-0102.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Lachin JM, Bebu I, Bergenstal RM, Pop-Busui R, Service FJ, Zinman B, et al. Association of glycemic variability in type 1 diabetes with progression of microvascular outcomes in the diabetes control and complications trial. Diabetes Care. 2017;40(6):777–83. https://doi.org/10.2337/dc16-2426.CrossRefPubMedGoogle Scholar
- 28.Mirani M, Berra C, Finazzi S, Calvetta A, Radaelli MG, Favareto F, et al. Inter-day glycemic variability assessed by continuous glucose monitoring in insulin-treated type 2 diabetes patients on hemodialysis. Diabetes Technol Ther. 2010;12(10):749–53. https://doi.org/10.1089/dia.2010.0052.CrossRefPubMedGoogle Scholar
- 33.Ceriello A, Novials A, Ortega E, La Sala L, Pujadas G, Testa R, et al. Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes. Diabetes. 2012;61(11):2993–7. https://doi.org/10.2337/db12-0224.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Raimann JG, Kruse A, Thijssen S, Kuntsevich V, Dabel P, Bachar M, et al. Metabolic effects of dialyzate glucose in chronic hemodialysis: results from a prospective, randomized crossover trial. Nephrol Dial Transplant. 2012;27(4):1559–68. https://doi.org/10.1093/ndt/gfr520.CrossRefPubMedGoogle Scholar
- 49.Uzu T, Hatta T, Deji N, Izumiya T, Ueda H, Miyazawa I, et al. Target for glycemic control in type 2 diabetic patients on hemodialysis: effects of anemia and erythropoietin injection on hemoglobin A(1c). Ther Apher Dial. 2009;13(2):89–94. https://doi.org/10.1111/j.1744-9987.2009.00661.x.CrossRefPubMedGoogle Scholar
- 51.Inaba M, Okuno S, Kumeda Y, Yamada S, Imanishi Y, Tabata T, et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol. 2007;18(3):896–903. https://doi.org/10.1681/ASN.2006070772.CrossRefPubMedGoogle Scholar
- 52.Batacchi ZAI, Zelnick L, Robinson-Cohen C, Healy J, Henry C, Robinson N, et al. Accuracy of glycosylated hemoglobin in chronic kidney disease. Diabetes. 2017;67(Suppl 1):LB7.Google Scholar
- 55.Hirsch IB. Professional flash continuous glucose monitoring as a supplement to A1C in primary care. Postgrad Med. 2017;1–10.Google Scholar
- 57.Lind M, Polonsky W, Hirsch IB, Heise T, Bolinder J, Dahlqvist S, et al. Continuous glucose monitoring vs conventional therapy for glycemic control in adults with type 1 diabetes treated with multiple daily insulin injections: the GOLD randomized clinical trial. JAMA. 2017;317(4):379–87. https://doi.org/10.1001/jama.2016.19976.CrossRefPubMedGoogle Scholar
- 58.Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, et al. Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections: a randomized trial. Ann Intern Med. 2017;167(6):365–74. https://doi.org/10.7326/M16-2855.CrossRefPubMedGoogle Scholar
- 61.Yeoh EC, Lim BK, Fun S, Tong J, Yeoh LY, Sum CF, et al. Efficacy of self-monitoring of blood glucose versus retrospective continuous glucose monitoring in improving glycaemic control in diabetic kidney disease patients. Nephrology (Carlton). 2016. https://doi.org/10.1111/nep.12978.
- 62.•• Hirsch IB, Verderese CA. Professional continuous flash glucose monitoring with ambulatory glucose profile reporting to supplement A1c: rationale and practical implementation. Endocr Pract. 2017. This article explains flash glucose monitoring, its clinical use, data interpretation, and benefits for use in patients with type 1 and type 2 diabetes.Google Scholar
- 63.Bolinder J, Antuna R, Geelhoed-Duijvestijn P, Kroger J, Weitgasser R. Novel glucose-sensing technology and hypoglycaemia in type 1 diabetes: a multicentre, non-masked, randomised controlled trial. Lancet. 2016;388(10057):2254–63. https://doi.org/10.1016/S0140-6736(16)31535-5.CrossRefPubMedGoogle Scholar
- 64.Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Use of flash glucose-sensing technology for 12 months as a replacement for blood glucose monitoring in insulin-treated type 2 diabetes. Diabetes Ther. 2017;8(3):573–86. https://doi.org/10.1007/s13300-017-0255-6.CrossRefPubMedPubMedCentralGoogle Scholar