Background It is well established that the risk of developing the microvascular complications of diabetes is intimately related to the glycemic control of an individual. HbA1c (A1C) is used as a surrogate marker for glycemia, and it has an exponential relationship between rising blood glucose and the risk of either developing or worsening retinopathy, nephropathy, and neuropathy. It is not clear whether glycemic instability may confer a risk to complications that is in addition to that predicted by the mean glucose value alone. There is firm evidence that postprandial glycemia is a stronger risk marker for the large-vessel (macrovascular) complications of diabetes than fasting or preprandial concentrations. However, little is known about the relative contribution of pre- and postprandial glycemia to the likelihood of developing microvascular complications.

Hypothesis This study has analyzed the DCCT data to determine the relative contribution of pre- and post-prandial glycemia to the development of microvascular complications and also to establish whether the degree of instability of glucose control has any additional influence on this risk. Pre- and post-prandial glycemia contributes to the development of microvascular complications. Instability of glucose control has additional influence on this risk. AIM

Study Subject The publicly available DCCT database: the 1,441 participants with type 1 diabetes 1-day glucose profiles A blood glucose profile was taken at 3-monthly intervals by a laboratory Blood glucose was assessed at seven points throughout the day prebreakfast (we assumed a time of 0700), postbreakfast (0830), prelunch (1200), postlunch (0130), presupper (1800), postsupper (1930), and bedtime (2200)

Definition of events RETINOPATHY Severity of retinopathy was determined by the 25-point Early Diabetic Retinopathy Treatment Study interim score. The development and progression of sustained retinopathy was defined as a change from baseline of three or more units on the Early Diabetic Retinopathy Treatment Study score on any two successive annual evaluations. NEPHROPATHY Nephropathy was defined as an increase in AER ≧ 40 mg/24 h (28 μg/min) on any annual evaluation providing that the baseline AER was<40 mg/dl (28μg/min).

Method Mean blood glucose was calculated by the area under the curve (AUC) using the trapezoidal rule in accordance with Rohlfing et al. Instability of blood glucose (within-day SD) was calculated as the SD of daily blood glucose around the mean from each quarterly visit. Variability in MBG over time was estimated as the SD of the MBG (AUC) measurements measured at each quarter. Mean preprandial glucose was taken as the average of prebreakfast, prelunch, and presupper and mean postprandial glucose as the average of postbreakfast, postlunch, and postsupper. The relationship between each risk factor and the development of diabetes complications was assessed by Cox regression from which hazard ratios (HRs) and 95% CIs were calculated.

Cox Regression 打ち切り症例を含む生存データについて、従属変数に事象発生までの時間を使 用する有用な回帰モデルが 1972 年 David Cox によって紹介され、比例ハザードモ デルあるいは Cox のモデルと呼ばれている。

CONCLUSIONS This study has shown that the variability in blood glucose around a patient’s mean value has no influence on the development or progression of either retinopathy or nephropathy in type 1 diabetes. We have also found that neither pre- nor postprandial glucose concentrations preferentially contribute to the risk of microvascular disease. The relative glycemic instability of patients on insulin did not seem to confer a higher probability of microvascular disease. Their findings are also consistent with a recent study using DCCT data that found that glycemic instability had little influence on the A1C value of a patient.

Discussion Kilpatrick et al. have answered a longawaited question. Other questions remain open: ・ What about glucose variability and risk of macroangiopathy in type 1 diabetes? ・ Do the results obtained for microangiopathy apply to macrovascular disease as well, which in type 1 diabetes has recently been shown to respond to A1C similarly to microangiopathy? ・ Most importantly, what about type 2 diabetes? ・ Can we extrapolate the concept of Kilpatrick et al. in type 1 to type 2 diabetic subjects and their micro- and macroangiopathic complications? ・ Should we value only A1C in type 2 diabetes and not intraday glucose variability as some studies indicate, thus neglecting the postprandial hyperglycemia and glycemic excursions? At present, we have no answers.

SUMMARY This study has shown that pre- and postprandial glucose values are equally predictive of the microvascular complications of type 1 diabetes and that blood glucose variability does not appear to be an additional factor in their development.

Clinical Implication After this study, the goals of treatment are going to be simplified. Subjects with type 1 diabetes should be more concentrated in keeping A1C at the recommended target rather than worrying because of intraday ups and downs in blood glucose. The everyday fundamental work of selecting the appropriate dose of insulin based on blood glucose monitoring, diet, and physical activity is important.,too. It is the key to success for the long-term maintainance of near normoglycemia as indicated by the DCCT. Doctors (and the entire diabetes team including the type 1 diabetic patient) should not be worried if intraday variability in blood glucose remains elevated in some subjects compared with others, as long as A1C is at the target. After the article by Kilpatrick et al., two therapeutic goals in treatment of type 1 diabetes remain: 1) keep A1C<7.0% and 2) reduce the risk for minor hypoglycemia as much as possible. However, if A1C is maintained <7.0% and hypoglycemia is prevented, the remaining fluctuations of blood glucose are unlikely to play a role in long- term complications according to the conclusions of Kilpatrick et al.