Prevention of hypoglycemia is an important strategy for glycemic management in patients with type 1 diabetes mellitus (T1D). Hypoglycemia is difficult to recognize at night while sleeping, particularly when using multiple daily injection (MDI) insulin therapy rather than sensor-augmented insulin-pump therapy. Therefore, it is possible that patients with T1D are at higher risk of nocturnal hypoglycemia when insulin is administered using an MDI regimen. We investigated nocturnal hypoglycemia in 50 pediatric patients with T1D on MDI insulin therapy using data from an intermittently scanned continuous glucose monitoring (isCGM) system. Hypoglycemia was observed on 446 of the 1,270 nights studied. Most of the hypoglycemic episodes were severe (blood glucose <54 mg/dL). On nights when hypoglycemia occurred, the blood glucose concentrations measured using finger-stick blood glucose monitoring (FSGM) before sleep and the next morning were lower than nights when hypoglycemia did not occur. However, few values were below the normal blood glucose range, suggesting that FSGM alone may be insufficient to detect nocturnal hypoglycemia. Approximately 7% of time was spent below the normal glucose range during the 10 hours from 21:00 to 7:00 the next morning. This result suggests that the patients on MDI insulin therapy could end up spending more time in hypoglycemia than is recommended by the American Diabetes Association (time below range <4.0% of time per day). Monitoring glucose levels overnight using an isCGM sensor may improve glycemic management via automatic detection of blood glucose peaks and troughs.

SEVERE HYPOGLYCEMIA and chronic hyperglycemia are known to affect brain development [1, 2]. Adequate glycemic control is necessary to support cognitive development and reduce the risk of diabetic complications during childhood and adolescence [3]. For those people with diabetes, an effective method for monitoring their blood glucose is required to achieve or maintain glycemic control. Currently, continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems can be used for this purpose, in addition to finger-stick glucose monitoring (FSGM). FSGM can be used several times during the day to measure blood glucose concentration. However, it is painful, time consuming, and costly. Additionally, measurements at a single point in time do not reveal the direction or speed of any change in blood glucose. Therefore, CGM is emerging as a more informative and convenient method for self-monitoring of blood glucose for children and adolescents with type 1 diabetes mellitus (T1D).

Patients with diabetes may have difficulty recognizing the onset of hypoglycemic symptoms, particularly while sleeping. Furthermore, when patients are treated with multiple daily injection (MDI) insulin therapy, the risk of hypoglycemia can be higher than in those who are treated with a sensor-augmented pump (SAP). Therefore, patients on an MDI insulin regimen need adequate blood glucose monitoring.

The purpose of this study was to investigate nighttime hypoglycemia in Japanese pediatric patients who have T1D, received MDI insulin therapy, and were assessed using isCGM.

The subjects enrolled in this study were 50 Japanese pediatric patients (23 males, median age 13 years) with T1D. This study is a subgroup analysis of a cohort of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) initiated in 2018. It is the largest cohort of pediatric patients with T1D in Japan—71 hospitals and clinics participated, and 1,155 patients were registered—followed from infancy to adolescence. The JSGIT was founded in 1994 with the objective of establishing a large cohort registry for prospective studies to investigate and improve the therapy and management of pediatric patients with T1D. The patients were treated with MDI insulin therapy and had their blood glucose monitored using isCGM (FreeStyle Libre, Alameda, California, USA).

This was a retrospective cross-sectional, observational study. Sensor glucose (SG) values for any single 28-day period, including the day of a hospital visit from March 2020 to October 2021, were collected from the Libre Reader used by each patient. The primary endpoints were as follows:

1) The frequency, severity, and length of nighttime hypoglycemia.

2) The association between nighttime hypoglycemia and FSGM values before dinner (before dinner glucose: BDG), at bedtime (bedtime glucose: BTG), and early in the morning before breakfast (morning fasting glucose: MFG; Fig. 1).

Fig. 1

Definition of the study observational period

FSGM measurements represented during each period were defined as: (1) BDG = the BG value measured at the time closest to 18:00 from 16:00 to 20:00; (2) BTG = the BG value at the latest time from 20:00 to 24:00; and (3) MFG = the BG value at the earliest time from 6:00 to 10:00

BDG, before dinner glucose; BG, blood glucose; BTG, bedtime glucose; FSGM, finger-stick glucose monitoring; MFG, morning fasting glucose; NT-TBR, nighttime-time below range; isCGM, intermittently scanned continuous glucose monitoring

3) Patients’ awareness of nighttime hypoglycemia that occurred early in the morning.

4) The percentage of the nighttime-time below range (NT-TBR; duration of SG ≤70 mg/dL during 10-hour night period).

Secondary endpoints were as follows:

1) The associations between NT-TBR and metabolic markers (glycated hemoglobin [HbA1c] and glycoalbumin). Associations between NT-TBR and the number of isCGM measurements, and the rate of FSGM during the observation period (from 16:00 to 10:00 the next morning [Fig. 1]).

2) The associations between NT-TBR and the dose per bodyweight, type of basal insulin, and administration time (bedtime or others) of basal insulin.

Time is reported in a 24-hour format. Nighttime was defined as a 10-hour period from 21:00 to 7:00 the next morning. The severity of hypoglycemia was determined in accordance with SG values: level 1 (>54 mg/dL to ≤70 mg/dL), level 2 (≤54 mg/dL), and level 3 (hypoglycemia complicated by unconsciousness or convulsions, which required external help to administer carbohydrates or glucagon) [4]. BTG values that may have caused the consumption of a late-night snack before sleep were excluded from the analysis. Hypoglycemia awareness could occur when patients confirmed hypoglycemia using the recorded SG scan or FSGM values. Hypoglycemia unawareness was documented when hypoglycemia had naturally recovered before the first SG scan or FSGM in the morning, or when neither the SG scan nor FSGM was performed, despite the hypoglycemia episode lasting beyond 7:00 the next morning. An awareness of nocturnal hypoglycemia that lasted beyond 4:00 the next morning was included in our analysis; this approach was based on our pilot study data that showed the frequency of nighttime hypoglycemia peaked between 4:00 and 5:00 and decreased thereafter (data not shown). The NT-TBR in each case and the length of the individual hypoglycemic episode were measured. The rate of FSGM was calculated using BDG, BTG, and MFG monitoring performed 3 times a day for 28 days; values from 84 measurements overall were equivalent to 100%.

The results are expressed as median (interquartile range). The BDG, BTG, and MFG concentrations determined using FSGM measurements were divided into groups based on the presence or absence of nighttime hypoglycemia. The patients were divided into groups by sex, type of basal insulin, and administration time of basal insulin. Wilcoxon’s rank sum test was used to assess the difference between groups. The Spearman correlation coefficient was used to examine the association between NT-TBR and diabetes-related metabolic parameters, the number of isCGM measurements, and the rate of FSGM. Statistical analyses were performed using STATA/IC ver. 16.1 (StataCorp LLC., College Station, Texas, USA). P-values <0.05 were considered statistically significant for all analyses.

This study was approved by the Ethics Committee of Niigata City General Hospital (No. 17-062) and by each participating institute in accordance with the ethical guidelines and recommendations of the Declaration of Helsinki in 1995. Written informed consent was obtained from all patients or their guardians.

Data for analyses were collected from 50 subjects for a total of 1,270 nights. The clinical characteristics of the participants are summarized in Table 1. The median age of children at their hospital visit was 13 years (11–16 years), and HbA1c and glycoalbumin measurements were 8.2% (7.5–8.6%) and 24.2% (21.0–27.3%), respectively. Hypoglycemia was detected in 48 children during the 28-day observation period. The SG values obtained from their Libre Readers were captured over 27 (25–28) days.

Over 1,270 nights of monitoring, a total of 552 episodes of hypoglycemia were observed during 446 nights (35%). No observation of hypoglycemia was recognized as a level 3 episode (Table 2). The frequency of hypoglycemia increased between 23:00 and 5:00 the next morning, then gradually decreased until 7:00 (Fig. 2A). The ratio of level 1: level 2 hypoglycemia was at a nadir between 4:00 and 6:00, followed by a sharp increase between 6:00 and 7:00 (Fig. 2B). These data also indicate that the frequency and severity of nighttime hypoglycemia was highest between 4:00 and 6:00 and was followed by a spontaneous improvement from 6:00 onward.

Fig. 2

The total frequency and severity of nighttime hypoglycemia

(A) The cumulative frequency of level 1 and 2 nighttime hypoglycemia. For example, when a hypoglycemic episode started during 4:00–5:00 and lasted until 6:00–7:00, and the lowest blood glucose concentrations observed during each time increment were 60, 50, and 60 mg/dL, respectively; two level 1 episodes (4:00–5:00 and 6:00–7:00), and one level 2 episode (5:00–6:00) were counted. (B) The ratio of level 1 to level 2 hypoglycemia, where lower values indicate a higher percentage of severe hypoglycemia.

The BDG, BTG, and MFG concentrations determined using FSGM measurements in the presence or absence of nighttime hypoglycemia were compared (Fig. 3). BTG and MFG concentrations were significantly lower on the day of a nighttime episode of hypoglycemia. However, the median BTG and MFG concentrations on those days were generally within the appropriate range for BTG (121 mg/dL [72–199] mg/dL) and MFG (101 mg/dL [75–148] mg/dL), respectively.

Fig. 3

Difference in FSGM with and without nighttime hypoglycemia at various times

The Wilcoxon rank sum test was used for statistical comparisons.

+, presence of hypoglycemia; –, absence of hypoglycemia; BDG, before dinner glucose; BTG, bedtime glucose; FSGM, finger-stick glucose monitoring; IQR, interquartile range; MFG, morning fasting glucose; n.s., not significant; p, probability value

Patients’ awareness of nighttime hypoglycemia occurred early in the morning as follows: (1) among the 267 episodes of confirmed hypoglycemia lasting beyond 4:00, we determined awareness of 113 episodes (113 episodes corresponded to hypoglycemia measured using an SG scan or FSGM); (2) among the remaining 154 episodes during which unawareness of hypoglycemia was judged to have occurred, 119 recoveries occurred before the first SG scan or FSGM measurement in the morning and 35 episodes were not monitored by SG scan or FSGM at all.

The NT-TBR of the patients was 7% (3–15%) and the episodes of hypoglycemia lasted 93 minutes (45–212 minutes; Fig. 4). The correlations between NT-TBR and age, HbA1c, glycoalbumin, number of isCGM measurements, FSGM rate, and basal insulin use according to body weight are summarized in Table 3. Age was positively correlated with NT-TBR (ρ = 0.30) and negatively correlated with isCGM measurements (ρ = –0.40). HbA1c and glycoalbumin were each negatively correlated with NT-TBR (ρ = –0.52 and ρ = –0.67, respectively).

Fig. 4

Histograms depicting NT-TBR and length of the episodes of hypoglycemia

NT-TBR, nighttime time-below range; IQR, interquartile range

There were no significant differences in NT-TBR associated with basal insulin type (insulin detemir, 4 cases; glargine, 4 cases; and glargine XR, 9 cases) versus degludec (33 cases) or administration timing (bedtime, 25 cases versus other times, 25 cases).

T1D is a chronic disease that requires lifelong insulin therapy. Severe hypoglycemia associated with insulin use often occurs during sleep, mostly late in the evening and early in the morning [5]. A previous study of nighttime hypoglycemia using CGM showed that it was a frequent occurrence [6]. However, based on a later report, 163 of the 176 subjects who were included in that study used an insulin pump. In recent years, the utility of SAPs equipped to suspend basal insulin to reduce the risk of severe hypoglycemia has increased. For this reason, we limited our investigation to children treated with MDI insulin therapy.

In our study, the frequency of nighttime hypoglycemia began to increase at 23:00 and reached its maximum between 4:00 and 5:00 the next morning. The ratio of level 1: level 2 hypoglycemia showed that abnormally low blood glucose worsened and was at its most severe between 4:00 and 6:00; thereafter, level 1 hypoglycemia increased relative to level 2 hypoglycemia. In summary, nighttime hypoglycemia was most frequent and severe in the early morning between 4:00 and 6:00.

With regard to the relationship between FSGM and nighttime hypoglycemia, BTG and MFG were significantly lower on days when an episode of hypoglycemia occurred. However, these values approached an almost normal range, despite an episode of nighttime hypoglycemia during that day. The cause can be partially explained by discrepancies between the SG and FSGM values. In other words, a false episode of hypoglycemia may have been included. However, our results showed that patients remained unaware of more than half of the episodes of hypoglycemia that occurred in the morning, and those episodes tended to recover spontaneously before a SG scan or the FSGM monitoring occurred in the morning.

In non-diabetic subjects in the early morning hours, insulin secretion increases slightly to prevent hyperglycemia due to an abnormally increased rate of hepatic gluconeogenesis induced by insulin antagonizing hormones. However, in patients with diabetes, depending on the type of insulin and the method of administration, exogenous insulin seems to be less effective in the early morning hours; therefore, it does not always suppress an early morning spike in blood glucose, otherwise known as the ‘dawn phenomenon’ [7] which can partially contribute to the spontaneous improvement of nighttime hypoglycemia. This may have masked nighttime hypoglycemia.

Overall, it is important to note that patients may not be able to predict or detect nighttime hypoglycemia using BTG or MFG measurements. Reports indicate that MFG are lower on days when nighttime hypoglycemia episodes occur (i.e., 118 mg/dL compared with 179 mg/dL on days when hypoglycemia is absent), although fasting glucose levels could not be used to predict the presence of nocturnal hypoglycemia with high precision [8]. For bedtime glucose levels, one study showed that the incidence of hypoglycemia doubled from 22% to 45% when bedtime glucose levels were below 100 mg/dL based on CGM [9]. However, previous studies of nighttime hypoglycemia have failed to determine the glucose level at bedtime that reliably predicts the risk of hypoglycemia. In our study, both BTG and MFG, grouped according to the presence of hypoglycemia, overlapped considerably. We propose that checking the trend of nighttime SG values is a reliable way to confirm the presence of nocturnal hypoglycemia. Patients should be educated to check the trend of SG values at night to either avert nocturnal hypoglycemia unawareness or an underestimation of the incidence of hypoglycemia.

The 2022 consensus guidelines of the American Diabetes Association recommend a daily TBR goal of less than 4% (i.e., 1 hour) at level 1 and less than 1% (15 minutes) at level 2, in non-high-risk groups (i.e., those who are young and without complications), regardless of the type (1 or 2) of diabetes mellitus [10]. Although the NT-TBR reflects a limited TBR of 10 hours, it was longer than the recommended daily TBR. Considering the dangers of hypoglycemia, TBR should be managed more stringently. It is another reason why patients with diabetes should monitor nocturnal episodes of hypoglycemia in a reliable manner.

In our study, NT-TBR was negatively correlated with HbA1c and glycoalbumin. However, both the glycoalbumin and HbA1c of the participants were within an adequate range and it was difficult to predict nighttime hypoglycemia using these parameters.

A weak, positive correlation was observed between age and NT-TBR, and the correlation between age and the number of isCGM measurements was negative. The lower number of isCGM measurements in older participants could indirectly affect the increase in hypoglycemia.

Our study did not show differences in NT-TBR by insulin type or administration time. Several studies have shown that insulin degludec is less likely to cause hypoglycemia than insulin glargine or insulin detemir in patients with T1D [11, 12]. In our study, 33 out of 50 patients used degludec and the number of patients using other types of insulin was comparatively small. This could be a possible reason why we did not find a significant difference between degludec and other basal insulins. Nevertheless, it should be noted that episodes of nocturnal hypoglycemia were not uncommon, despite two-thirds of the patients receiving degludec treatment.

Notably, SG values acquired from Libre Readers can be less than actual BG values, particularly for values in the hypoglycemic range and thus hypoglycemia may have been overestimated [13]. In fact, some SG data indicative of hypoglycemia showed a large discrepancy between corresponding FSMG values, signifying the possibility of false readings for what would otherwise have been considered episodes of hypoglycemia. Although we excluded such data from our analyses, we were unable to exclude them completely because the FSGM values were not routinely confirmed. Considering this limitation of the isCGM device, patients should be encouraged to perform FSGM without delay to confirm their exact blood glucose concentrations when hypoglycemia–based on SG values–has been observed.

Hypoglycemia reportedly suppresses the secretion of counterregulatory hormones, resulting in autonomic symptoms being less perceptible during hypoglycemia [14-16]. Therefore, nighttime hypoglycemia can further exacerbate the risk of hypoglycemia unawareness. Prevention of nocturnal hypoglycemia is of the utmost importance and patients would benefit from being educated on the use of isCGM to better manage overnight blood glucose concentrations.

Because this research was designed to represent a retrospective observational study, data indicative of SG values could not be collected from all patients at participating sites.

Our patients were encouraged to perform FSGM at least three times a day: i.e., before each meal or bedtime, in addition when they recognized hypoglycemia or hyperglycemia. Although many of them performed measurements as instructed, it was assumed that some patients took measurements only when they noticed abnormal blood glucose levels. Therefore, we were unable to eliminate the possibility that such biased values were included in the analysis. For BDG, BTG, and MFG, we evaluated the FSGM values measured at a defined time; however, it is unclear whether those values were reflective of the correct time, particularly when multiple FSGM values were collected at points in approximately real-time.

As previously mentioned, the SG values obtained from Libre Readers could overestimate hypoglycemic episodes. Well-designed prospective studies are desirable to accurately investigate the reality of nocturnal hypoglycemia.

A survey conducted by the JSGIT in pediatric Japanese patients with T1D who were treated with MDI insulin therapy found that nighttime hypoglycemia occurred rather frequently, and most patients remained unaware of nighttime episodes. For adequate glycemic management, it is necessary to educate patients on the benefits of FSGM concomitant with isCGM so that they can confirm the occurrence of hypoglycemic events. When low SG values are observed, patients should have been able to review the trend of nocturnal SG levels to verify the presence of hypoglycemia that might otherwise go undetected.

This study was supported by grants from the Japan Diabetes Foundation, Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics and The Ministry of Health Labor and Welfare (No. 19K10658). We would like to express our deepest gratitude to all the T1D patients, their families and all the members of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). The members of the JSGIT are as follows: Akemi Koike, Koike Child Clinic; Aki Nishii, JR Sendai Hospital; Yusuke Tanahashi, Asahikawa Medical College; Akira Endo, Iwata City Hospital; Eishin Ogawa, Teikyo University; Emiko Tachikawa, Tokyo Women’s Medical University School of Medicine; Hanako Tajima, Nippon Medical School; Tomohiro Hori, Gifu University; Makoto Anzo, Kawasaki Municipal Hospital; Hiroki Matsuura, Shinshu University; Hiroko Kadowaki, Sanno Hospital; Katsuya Aizu, Saitama Children’s Medical Center; Hisakazu Nakajima, Kyoto Prefectural University of Medicine; Yumiko Kotani, Tokushima University School of Medicine; Ichiro Yokota, Shikoku Medical Center for Children and Adults; Ikuko Takahashi, Akita University Graduate School of Medicine; Ikuma Fujiwara, Tohoku University Hospital; Jiro Iwamoto, Aso-Izuka Hospital; Junichi Nagaishi, Tottori Municipal Hospital; Junko Ito, Toranomon Hospital; Junichi Arai, Hosogi Hospital; Kanako Ishii and Kenji Ihara, Kyushu University School of Medicine; Kanshi Minamitani, Teikyo University Chiba Medical Center; Kaori Sasaki, Tokyo Women’s Medical University Yachiyo Medical Center; Kazuhiko Jinno, Hiroshima Prefectural Hospital; Keiichi Hanaki, Tottori Prefectural Kousei Hospital; Yohei Ogawa, Niigata University Graduate School of Medical and Dental Sciences; Yuki Abe, Niigata City General Hospital; Kenichi Miyako, Fukuoka Children’s Hospital; Kentaro Shiga, Yokohama City University Medical Center; Kimitoshi Nakamura, Kumamoto University School of Medicine; Kisho Kobayashi, University of Yamanashi Faculty of Medicine; Kohei Sato, Sapporo Factory Kids Clinic; Koji Takemoto, Ehime University Graduate School of Medicine; Kosei Hasegawa, Okayama University School of Medicine; Mahoko Hurujyo, Okayama Medical Center; Masanori Adachi, Kanagawa Children’s Medical Center; Masaru Inoue, Okayama Red Cross General Hospital; Michiko Okajima, Kanazawa University School of Medicine; Hitomi Koyama, Dokkyo Medical University; Nobuyuki Kikuchi, Department of Pediatrics, Yokohama City Minato Red Cross Hospital; Kazuteru Kitsuda, Noriyuki Takubo and Shigeyuki Ohtsu, Kitasato University School of Medicine; Reiko Horikawa, National Center for Child Health and Development; Rika Kizu, Yokosuka Kyosai Hospital; Ryuzo Takaya, Osaka Medical College; Sachiko Kitanaka, The University of Tokyo School of Medicine; Shinichiro Miyagawa; National Hospital Organization Kure Medical Center; Shinji Kadoya, Nishinomiya Municipal Central Hospital; Haruo Mizuno, Nagoya City University; Shoji Nakayama, Mominoki Hospital; Shun Soneda, St. Marianna University School of Medicine; Susumu Kanzaki, Tottori University Faculty of Medicine; Susumu Konda, Konda Children’s Clinic; Tadayuki Ayabe, Dokkyo Medical University Koshigaya Hospital; Takahiro Mochizuki, Osaka Police Hospital; Takao Fujisawa, National Mie Hospital; Tokuo Mukai, Asahikawa-Kosei General Hospital; Tomoyuki Hotubo, Sapporo Pediatric Endocrinology Clinic; Kohji Tsubouchi: Department of Pediatrics, Chuno Kosei Hospital; Toshi Tatematsu, Chubu Rosai Hospital; Toshihisa Okada, Kumamoto Hatsuiku Clinic; Toshikazu Takahashi, Takahashi Clinic; Tsutomu Ogata, Hamamatsu University School of Medicine; Utako Sato, Tokyo Hitachi Hospital; Yasusada Kawata, Kyushyu Rosai Hospital; Yoshiya Ito, Kitami Red Cross Hospital; Goro Sasaki: Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital; Yukiyo Yamamoto: Department of Pediatrics, University of Occupational and Environmental Health; Tomoyuki Kawamura, Osaka City University Graduate School of Medicine; Tatsuhiko Urakami: Department of Pediatrics, Nihon University School of Medicine; Toru Kikuchi and Shin Amemiya: Department of Pediatrics, Saitama Medical University; Shigetaka Sugihara: Department of Pediatrics, Tokyo Women’s Medical University Medical Center East.

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