Recent developments in continuous and intermittently scanned continuous glucose monitoring systems provide not only more efficient regulation of type 1 diabetes treatment, but also new information on glycemic parameters from the time of diagnosis. In this study, by using intermittently scanned glucose monitoring systems, the glycemic parameters of children with type 1 diabetes who are in RP and those who are not in RP were compared. As expected, the glycemic parameters in the RP were found to be closer to the target levels but were far from those of non-diabetic subjects (10). It was found that while CP levels did have an effect on glycemic parameters during the honeymoon period, there was no correlation between PI levels and glycemic parameters. In terms of glycemic parameters during the honeymoon period, the CP level had a significant correlation with the TIR value. CP seems to be a useful biochemical tool, while PI was not a sensitive biochemical parameter.
New parameters are needed to define the honeymoon or preserved beta-cell reserve period. Although several studies (11-13) focused on the honeymoon period and investigated honeymoon-related factors, data related to the glycemic parameters during the honeymoon period are limited. Meng et al. examined the relationship between blood glucose fluctuations during various phases of diabetes and oxidative stress and showed that the mean glucose, glucose SD, the mean amplitude of glycemic excursions (MAGE) and incremental area under the blood glucose curve (IAUC) levels during the honeymoon period were lower than those during the acute metabolic disturbance and long-standing phases (14). Similarly, in our study, the mean sensor glucose level, SD value, CV value, time-in-range, time in hyperglycemia were found to be lower in the honeymoon group, suggesting a better metabolic control (Table 2). While the mean CV of 32.3% was lower than the target value of 36% in the CGMS consensus, (6) the mean SD value was higher than that found in a recent study analyzing the CGMS data of healthy children (9). In addition, time spent in level 1 hypoglycemia was found to be similar in the honeymoon vs. non-honeymoon groups, indicating that glycemic control in RP is restricted.
CP is a useful and widely used method of assessing pancreatic beta-cell function. The formula for IDAA1c was derived using a higher CP cut-off value of 300 pmol/L. Therefore, although it previously played a role in defining the honeymoon phase, (3), it is no longer used to define the honeymoon phase. Venous blood CP levels can be measured in the random, fasting, or stimulated state. Random samples are taken at any time during the day without consideration of recent food intake, whereas fasting samples are taken after an 8 to 10 hours fast (8). In the present study, serum CP levels were measured in the random state, and as expected the mean CP level was significantly higher in the honeymoon group than in the non-honeymoon group. Although CP is a widely accepted biochemical parameter for pancreatic beta-cell reserve, data on the association between CP levels and glycemic parameters are very limited. In the present study, the presence of a correlation between CP levels and glycemic parameters was evaluated. In the honeymoon group, the mean CP level was inversely correlated with the mean sensor glucose and SD glucose whereas it positively correlated with TIR. These findings support that CP might be a relevant biochemical parameter in the honeymoon phase. However, the presence of a positive correlation between CP and time in both level 1 hypoglycemia and level 1 hyperglycemia in the non-honeymoon group suggests that CP is not a reliable parameter when it is low.
Recent studies reported an increased risk of developing 5-year T1D in antibody-positive first-degree relatives having an increased PI / CP ratio (15). Similarly, the PI/CP ratio was found to be higher at the time of diagnosis of diabetes compared with the control group (16). Although PI is used as a beta-cell stress marker, two recent studies showed that PI secretion was maintained for a long time and that the level of CP was still detectable in individuals with T1D (17,18). In our study, both the PI level and PI / CP ratio were significantly higher in the honeymoon group. In the non-honeymoon group, however, two children had CP levels below the measurable limit despite detectable PI levels and two children had PI levels below the measurable limit despite measurable CP levels. Due to the small size of the patient groups, it is difficult to comment on the differences in the maintenance of CP and PI secretions. In this study, no significant correlation was detected between proinsulin levels and glycemic parameters in any group, suggesting that proinsulin is not as clinically reliable as CP in the management of diabetes.
One of the main limitations of our study was the random measurement of CP and PI levels. These measures may have been affected by the degree of fasting, which was not taken into account because we recruited patients during scheduled outpatient follow-up visits. Measurements of stimulated CP and PI secretions using tests such as a mixed-meal tolerance test may be beneficial, as well. However, this study design would require more inconvenience to the participants and their families. Moreover, Watkins et al conducted a research by random sampling for the CP and PI measurement in order to evaluate the β-cell function in persons with T1D (5) and Leighton et al in their review article had stated that venous blood CP levels can be measured in the random, fasting, or stimulated state (8). Another limitation was the lack of simultaneous blood glucose measurements with the use of isCGMS which does not require calibration. The accuracy of isCGMS was reported to be lower during hypoglycemia than during euglycemia and hyperglycemia (19). However, time spent in level 1 hypoglycemia was not high and similar in both groups. Despite these limitations, we feel that this pilot study is important as it is the first study to evaluate glycemic parameters in the honeymoon period with the use of isCGMS data and to examine the relationship between these parameters and Beta-cell reserve markers CP and PI. There is no doubt that a future study with larger patient numbers would show more generalizable results.
In conclusion, although the glycemic profile during the honeymoon period was better than that in the non-honeymoon group, the glycemic variability during this period was not as low as expected. It is also important to continue efforts to improve and maintain metabolic control during the honeymoon period. Subcutaneous insulin infusion or automated insulin delivery systems may help to achieve better glycemic control in the remission phase as well. CP seems to be a useful biochemical tool, while PI was not a sensitive biochemical parameter. Further studies are needed to determine if PI might prove to be a useful parameter in clinical follow-up.