Determinants of the Risk of Diabetic Kidney Disease and Diabetic Retinopathy Independent of Glucose Exposure

Corresponding author: Bo Kyung Koo http://orcid.org/0000-0002-6489-2656 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, Korea E-mail: [email protected] The Diabetes Control and Complications Trial (DCCT) confirmed that intensive glucose control reduced the risk of diabetic mellitus retinopathy (DMR) and diabetic kidney disease (DKD) development by 76% and 34% and 44%, respectively, compared with standard treatment [1]. However, the subsequent analyses by DCCT/Epidemiology of Diabetes Interventions and Complications study group raised the issue that total glycemic exposure (glycosylated hemoglobin [HbA1c] and duration of diabetes) explains only about 11% of the variation in retinopathy risk [2]; therefore, other factors might be responsible for the remaining 89% of the variation in risk among subjects independently of HbA1c. Glycemic variability has been suggested as an independent risk factor in diabetic microvascular complications through many epidemiological studies [3]. In vitro and in vivo studies confirmed that glycemic variability induces epigenetic changes in the promoter of nuclear factor-κB [4] and increases oxidative stress leading to cellular apoptosis [5]. Furthermore, high glycemic variability is apparently associated the risk of concurrent hypoglycemia [6]; the cellular processes that occur with hyperglycemic spikes are also induced by experimental hypoglycemia [7]. Yun et al. [8] added the evidence for the significant association between glycemic variability and DKD. They specifically showed that HbA1c variability affected the development and progression of DKD in type 2 diabetic patients with advanced DMR. Although their study did not show whether there is a difference in the degree of effect of HbA1c variability on DKD according to the presence or absence of advanced DMR, both of short term and long term glucose variability have been known to also increase the risk of DMR [9]. Yun et al. [8] also showed that lipid level was another determining factor of DKD in type 2 diabetic patients with advanced DMR; however, dyslipidemia is also known to affect the risk of DMR [10] as well as DKD [11]. In addition, fenofibrate was shown to reduce DMR progression in patients with type 2 diabetes in The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [12] and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study [13], although triglyceride level could not explain the effect of fenofibrate. As the authors mentioned, the discrepancy between the severity of DMR and DKD has already been reported even in one individual [14,15]. In the study of Yun et al. [8], 37.2% of patients with advanced DMR did not have any DKD; and 31.1% of patients with severe DKD did not have advanced DMR. Furthermore, in the case of DMR, there has been evidence that DMR can develop independent of glucose exposure or glucose variability: retinal microaneurysms can be detected even in individuals with normal glucose tolerance [16] or prediabetes [17]. Genetic factors might explain the susceptibility to DMR and Editorial Complications