HypothesisShould minimal blood glucose variability become the gold standard of glycemic control?
Introduction
The Diabetes Complications and Control Trial (DCCT) revolutionized diabetes care by confirming the association between hyperglycemia and late diabetic complications (DCCT Research Group, 1993). Glycosylated hemoglobin (A1C) constituted the primary parameter in the study because it provides an integrated measure of glycemic exposure. Considered the “gold standard” of glycemic control, A1C remains the preeminent benchmark of successful therapy, with levels ≤7% deemed appropriate for reducing the risk of vascular complications (American Diabetes Association, 2004). Yet, the possibility that more subtle aspects of glucose homeostasis, beyond those represented by A1C, could affect the development or progression of microvascular complications was raised by the DCCT investigators themselves. In a 1995 report evaluating the association of A1C levels before and during the DCCT with the risk of retinopathy progression in patients receiving either conventional or intensive therapy, the authors surmised that updated mean A1C is “not the most complete expression of the degree of glycemia” and that the risk of complications may be more highly dependent on other factors (DCCT Research Group, 1995). Their statement rested largely on the observation that the risks of retinopathy progression associated with a given level of mean A1C differed significantly between intensively and conventionally treated patients after 5 to 9 years (P<.01; Fig. 1). Participants in the intensive treatment group exhibited minimal change in the risk of progression to retinopathy over time, whereas their conventionally treated counterparts experienced a marked escalation of risk, despite comparable A1Cs.
Our speculative explanation for this phenomenon was that there was a greater frequency and magnitude of glycemic excursions in conventionally treated patients, who received fewer insulin injections than did patients in the intensive group. We further postulated that an increased magnitude of glycemic variability would generate more reactive oxygen species (ROS) in complications-prone cells because hyperglycemia-induced oxidative stress, resulting from the overproduction of ROS by the mitochondrial electron-transport chain, is the chief underlying mechanism of glucose-mediated vascular damage (Brownlee, 2001). The ability to quantify oxidative stress in relation to glycemia has provided added insight into the ways in which acute increases in blood glucose, via the production of ROS, affect aspects of physiologic homeostasis. Based on this emerging evidence, we hypothesize that glucose variability, considered in combination with A1C, is a more reliable indicator of blood glucose control and the risk for long-term complications than mean A1C alone.
Section snippets
Evidence of the importance of glycemic variability
Although ROS cannot be measured directly, these unstable molecules interact with biological macromolecules such as proteins, lipids, and DNA, to generate numerous oxidative products (Betteridge, 2000). Of these, nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) have been evaluated to determine the extent of vascular damage induced by periodic versus continuous exposure to high glucose (Ceriello et al., 2002, Quagliaro et al., 2003). Examination of downstream targets of ROS, such as cell
Assessing the quality of glycemic control
The results of the aforementioned studies lend weight to our hypothesis that glycemic variability—both postprandial and throughout the day—may be an important but underappreciated mechanism resulting in ROS accumulation and micro- and macrovascular disease acceleration. It is possible that neglecting the prognostic significance of large glycemic variability could lead to the misestimation of the risk for diabetic complications, even if the mean A1C levels fall within or near normal range. Thus,
Testing the hypothesis
Our hypothesis can be tested from two perspectives. In one study, newly diagnosed patients with Type 2 diabetes would be randomized to one of two treatment arms: The first group would receive one injection of insulin glargine at bedtime, the second, a multiple injection regimen of insulin glargine at bedtime plus mealtime insulin (lispro or aspart) three times per day. Blood glucose would be monitored frequently to determine the degree of glycemic variability between the two groups. The study
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