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This pilot study explores the relationship between nocturnal hypoglycemia (NH) and subjective sleep quality in people with type 1 diabetes (T1D). Twenty-seven adults with T1D wore a Freestyle Libre Pro CGM and recorded subjective sleep quality daily, as assessed by a single Likert scale question. Frequency, duration, area under the curve (AUC) of NH (00:00-06:00) defined as sensor glucose below threshold (< 3.9 mmol/L; < 3 mmol/L) for ≥ 15 min, nocturnal mean glucose, Time in Range (3.9-10 mmol/L), and coefficient of variation were calculated. Twenty-seven adults, 18 (66.7%) women, with median (IQR) age of 27 (26, 32) years and HbA1c of 7.6 (7.1, 8.1) participated. Nights with NH < 3.9 mmol/L resulted in a lower (worse) sleep score than nights without NH [Mean (SD): 3.3 (1.2) vs 3.5 (1.0), p = 0.03). A higher frequency and longer duration but not AUC [adjusted OR (95% CI) 0.52 (0.38, 0.72), 0.961 (0.932, 0.991), 0.999 (0.998, 1.001) respectively)], of NH < 3.9 mmol/L, were associated with a lower sleep score. NH < 3.0 mmol/L metrics were not associated with sleep quality. Recurrent NH < 3.9 mmol/L, rather than prolonged NH < 3.0 mmol/L, seems associated with subjective sleep quality, implying that those with the highest burden of NH are likely unaware of it., (© 2023. The Author(s).)

Introduction: Given that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX., Method: A real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH., Result: Among 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. Median CLD [DZX, 15 days (6-27) vs. WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than the WW group [62.5 days (9-198) vs. 16 days (6-27), P < 0.001]., Conclusion: CLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chandran, Jaya-Bodestyne, Rajadurai, Saffari, Chua and Yap.)

Background: There is a lack of clarity of what constitutes the starting point of a clinical pathway for infants at-risk of hypoglycaemia. Glucose-centric pathways (GCP) identify low glucose in the first 2 hours of life that may not represent clinical hypoglycaemia and can lead to inappropriate glucose management with infusions and medications., Objective: To study the impact of a feed-centric pathway (FCP) on the number of admissions for hypoglycaemia to level 2 special care nursery (SCN) and the need for parenteral glucose/medications, compared to GCP., Methods: This project was conducted over 2 years, before and after switching from a GCP to FCP in our institution. FCP involves skin-to-skin care, early breast feeding, checking glucose at 2 hours and use of buccal glucose. The primary outcome was the number of SCN admissions for hypoglycaemia. Secondary outcomes include the number of infants needing intravenous glucose, medications and length of SCN stay., Results: Of 23 786 live births, 4438 newborns were screened. We screened more infants at-risk for hypoglycaemia using the FCP (GCP:1462/11969, 12.2% vs FCP:2976/11817, 25.1%) but significantly reduced SCN admissions (GCP:246/1462, 16.8% vs FCP:102/2976, 3.4%; p<0.0001). Fewer but proportionally more FCP newborns required intravenous glucose (GCP: 136/246, 55% vs FCP: 88/102, 86%; p=0.000). Compared with GCP, FCP reduced the total duration of stay in SCN by 104 days per annum, reducing the cost of care. However, the mean length of SCN stay for FCP was higher (GCP:2.43 days vs FCP:3.49 days; p=0.001). There were no readmissions for neonatal hypoglycaemia to our institution., Conclusion: The use of FCP safely reduced SCN admissions, averted avoidable escalation of care and helped identify infants who genuinely required intravenous glucose and SCN care, allowing more efficient utilisation of healthcare resources., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hyperinsulinemic hypoglycemia (HH) has the potential to cause acute neurologic dysfunction and neurodevelopmental impairment. Parieto-occipital neuronal injuries have been reported in hypoglycemic infants, but intraparenchymal hemorrhage is rare. On day 5 of life, a late preterm infant was transferred to our care with recurrent asymptomatic hypoglycemia. Prior to arrival, plasma glucose levels were at a median of 1.25 mmol/L (22.5 mg/dL) in the first 6 hours of life, and he required a glucose infusion rate (GIR) of 22.6 mg/kg/min. Hyperinsulinism was confirmed in the presence of detectable insulin, low ketones, and fatty acid when hypoglycemic. A left grade 4 intraventricular hemorrhage (IVH) was noted in the cranial ultrasound scan during the workup for sepsis on the day of admission. However, magnetic resonance imaging of the brain on day 7 of life revealed extensive bilateral IVH. On day 9, he was initiated on diazoxide, and HH resolved within 48 to 72 hours, allowing increment of feeds while weaning GIR. Ventricular drain for post-hemorrhagic ventriculomegaly was advised but not performed. At 3 months, post-hemorrhagic ventriculomegaly was stable, and there were early signs of neurodevelopmental delay. After discontinuing diazoxide at 4 months of age, he passed an 8-hour fasting study confirming the resolution of HH. Severe hypoglycemia has been associated with cerebral hyperperfusion in preterm infants and potentially could cause IVH. Close monitoring and prompt intervention in preterm infants to prevent severe hypoglycemia are paramount. In addition to long-term neurodevelopmental follow-up, infants with recurrent hypoglycemia may benefit from neuroimaging and thereby early intervention if required.

Background: Hypoglycemia is the major impediment to therapy intensification in diabetes. Although higher individualized HbA1c targets are perceived to reduce the risk of hypoglycemia in those at risk of hypoglycemia, HbA1c itself is a poor predictor of hypoglycemia. We assessed the use of glycemic variability (GV) and glycemic indices as independent predictors of hypoglycemia., Methods: A retrospective observational study of 60 type 1 and 100 type 2 diabetes subjects. All underwent professional continuous glucose monitoring (CGM) for 3-6 days and recorded self-monitored blood glucose (SMBG). Indices were calculated from both CGM and SMBG. Statistical analyses included regression and area under receiver operator curve (AUC) analyses., Results: Hypoglycemia frequency (53.3% vs. 24%, P < 0.05) and %CV (40.1% ± 10% vs. 29.4% ± 7.8%, P < 0.001) were significantly higher in type 1 diabetes compared with type 2 diabetes. HbA1c was, at best, a weak predictor of hypoglycemia. %CV CGM , Low Blood Glucose Index (LBGI) CGM , Glycemic Risk Assessment Diabetes Equation (GRADE)Hypoglycemia CGM , and Hypoglycemia Index CGM predicted hypoglycemia well. %CV CGM and %CV SMBG consistently remained a robust discriminator of hypoglycemia in type 1 diabetes (AUC 0.88). In type 2 diabetes, a combination of HbA1c and %CV SMBG or LBGI SMBG could help discriminate hypoglycemia., Conclusion: Assessment of glycemia should go beyond HbA1c and incorporate measures of GV and glycemic indices. %CV SMBG in type 1 diabetes and LBGI SMBG or a combination of HbA1c and %CV SMBG in type 2 diabetes discriminated hypoglycemia well. In defining hypoglycemia risk using GV and glycemic indices, diabetes subtypes and data source (CGM vs. SMBG) must be considered.

Hyperinsulinaemic hypoglycaemia in small-for-gestational age infants usually presents in the first two postnatal days. We present a preterm, small-for-gestational age infant who had hyperinsulinaemic hypoglycaemia on day 13 of life. A female twin infant weighing 1390 g was born at 32(+6) weeks of gestation. Her glycaemic profile was normal till day 13 of life, after which she was noted to be lethargic and hypoglycaemic and had hyperinsulinism, hypoketonaemia and hypofattyacidaemia, requiring high glucose infusion rate to maintain normoglycaemia, while negative for septic markers and metabolic screen. Initially, there was no response to diazoxide and the genetic studies for ABCC8 and KCNJ11 gene mutations were negative. Delayed response to diazoxide was followed by complete resolution of hypoglycaemia in 5 months. This case highlights the importance of glucose monitoring in small-for-date infants for hypoglycaemia till they achieve full feeds and gain weight. Early recognition and appropriate management of hypoglycaemia in this group of infants have important implications for neurodevelopmental outcome.

Diazoxide (DZX) remains the first-line medication for the treatment of prolonged and persistent forms of hyperinsulinemic hypoglycemia (HH). In nearly 40%–50% of cases of HH, the genetic mechanism is unidentified. Almost half of the infants with permanent or genetic causes are DZX sensitive, but hypersensitivity to DZX is extremely rare, and the mechanism is poorly understood. Here, we report for the first time a case of DZX hypersensitivity in a neonate with HH who inherited a novel HNF1A variant from the mother. A term, male large-for-gestational-age infant of a diabetic mother presented with early onset of severe, recurrent hypoglycemia. Critical blood samples when hypoglycemic confirmed HH. Diazoxide was initiated at conventional doses of 5 mg/kg/day, which resulted in hyperglycemia (blood glucose, 16.6 mmol/L) within 48 h. Glucose infusion was rapidly weaned off. DZX was withheld and eventually stopped. Following 3 days of milk feeds alone with a normal glucose profile, suspecting a resolution of HH, he underwent a 6-h fasting study and passed. While on glucose monitoring in the hospital, he again developed hypoglycemic episodes, and the critical blood samples confirmed HH. DZX was restarted at a lower dose of 3 mg/kg/day, which required further down-titration to 0.7 mg/kg/day before steady euglycemia was obtained. No more episodes of hypo or hyperglycemia occurred, and he passed a safety fasting study before discharge. Molecular genetic testing identified a novel HNF1A mutation in the mother–child dyad, whereas the father tested negative. We concluded that the HH phenotype due to this novel HNF1A mutation can be mutation specific and require a very low dose of DZX. Clinicians should observe closely for the risk of diabetic ketoacidosis and hyperglycemic hyperosmolar state while initiating DZX therapy. [ABSTRACT FROM AUTHOR]

Introduction: Given that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX. Method: A real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH. Result: Among 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. MedianCLD [DZX, 15 days (6-27) vs.WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than theWWgroup [62.5 days (9-198) vs. 16 days (6-27), P < 0.001]. Conclusion: CLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS. [ABSTRACT FROM AUTHOR]

Recurrent and profound hypoglycemia is a leading cause of neonatal brain injury. Small-for-gestational-age infants are at risk of hypoglycemia due to substrate deficiency and hyperinsulinism. Inappropriate insulin secretion by the β-cells of the pancreas results in hypoglycemia, neuronal energy deprivation, and parieto-occipital brain injury. Hypoglycemic neuronal injury is increasingly being identified as a trigger for infantile spasms, even though the underlying pathophysiological mechanisms remain elusive. A term, small-for-gestational-age male infant developed severe symptomatic hypoglycemia on day 3 of life. He required a high glucose infusion rate (14 mg/kg/min) to maintain normoglycemia. Critical blood samples showed inappropriate insulin levels while hypoglycemic and hypoketonemic, consistent with a diagnosis of hyperinsulinemic hypoglycemia. Blood glucose levels normalized with a diazoxide dose of 5 mg/kg/day. Gradually, glucose infusion was weaned with increasing oral feeds while maintaining prefeed capillary blood glucose levels. While at home, his glucose profile remained stable on the self-weaning dose of diazoxide. He passed a resolution fasting study at 4 months of age after weaning off diazoxide. He developed left gaze preference at 2.5 months of age while on treatment for hyperinsulinemic hypoglycemia but developed infantile spasms at 5 months that was confirmed with an electroencephalogram (EEG). Gaze preference may be epileptic, even in the absence of seizures. Spasms were well controlled with high-dose prednisolone therapy. At the age of 6 years, he has a mild fine motor delay and learning disabilities. Early diagnosis and treatment of infantile spasms have a better prognosis. Identifying gaze preference as a predating sign of occipital lobe epilepsy, EEG monitoring, and, if required, treatment could have possibly averted the genesis of infantile spasms. [ABSTRACT FROM AUTHOR]

Background: Complex changes of glycemia that occur in diabetes are not fully captured by any single measure. The Comprehensive Glucose Pentagon (CGP) measures multiple aspects of glycemia to generate the prognostic glycemic risk (PGR), which constitutes the relative risk of hypoglycemia combined with long-term complications. We compare the components of CGP and PGR across type 1 and type 2 diabetes. Methods: Participants: n = 60 type 1 and n = 100 type 2 who underwent continuous glucose monitoring (CGM). Mean glucose, coefficient of variation (%CV), intensity of hypoglycemia (INThypo), intensity of hyperglycemia (INThyper), time out-of-range (TOR <3.9 and >10 mmol/L), and PGR were calculated. PGR (median, interquartile ranges [IQR]) for diabetes types, and HbA1c classes were compared. Results: While HbA1c was lower in type 1 (type 1 vs. type 2: 8.0 ± 1.6 vs. 8.6 ± 1.7, P = 0.02), CGM-derived mean glucoses were similar across both groups (P > 0.05). TOR, %CV, INThypo, and INThyper were all higher in type 1 [type 1 vs. type 2: 665 (500, 863) vs. 535 (284, 823) min/day; 39% (33, 46) vs. 29% (24, 34); 905 (205, 2951) vs. 18 (0, 349) mg/dL × min2; 42,906 (23,482, 82,120) vs. 30,166 (10,276, 57,183) mg/dL × min2, respectively, all P < 0.05]. Across each HbA1c class, the PGR remained consistently and significantly higher in type 1. While mean glucose remained the same across HbA1c classes, %CV, TOR, INThyper, and INThypo were significantly higher for type 1. Even within the same HbA1c class, the variation (IQR) of each parameter in type 1 was wider. The PGR increased across diabetes groups; type 2 on orals versus type 2 on insulin versus type 1 (PGR: 1.6 vs. 2.2 vs. 2.9, respectively, P < 0.05). Conclusion: Composite indices such as the CGP capture significant differences in glycemia independent of HbA1c and mean glucose. The use of such indices must be explored in both the clinical and research settings. [ABSTRACT FROM AUTHOR]

A neonatologist plays a critical role in the management of babies with hypoglycemia. Although neonatal hypoglycemia has been conventionally defined as glucose ≤2.5 mmol/L, levels ≤2.8 mmol/L among neonates raise concerns of neuroglycopenia, supporting the Pediatric Endocrine Societies' suggestion to target plasma glucose levels >2.8 mmol/L in at-risk infants <48 h of age and >3.3 mmol/L for those aged >48 h. The neonatologist needs to identify at-risk babies and enroll them into a pathway that ensures safe, physiological transition to extrauterine life. Physiological transition constitutes early enteral feeding, navigating the glucose nadir while maintaining mother–child bonding. Smooth umbilical to enteral transition of glucose homeostasis following birth needs adequate glycogen stores and appropriate counter-regulatory hormone responses. When stores are inadequate and counter-regulatory responses fail, glucose regulation becomes more dependent on appropriate β-cell responses. However, β-cell dysregulation may cause inappropriate insulin secretion when hypoglycemic (hyperinsulinemic hypoglycemia [HH]) that can be transient, prolonged, or persistent. The majority comprise transient and prolonged forms of HH that recover in days to weeks with feeds or short-term parenteral glucose infusion or rarely with use of KATP channel agonist, diazoxide. The minority with persistent forms may have genetic mutations in at least 12 genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, and PGMM2) and need medical and/or surgical intervention, as well as long-term multidisciplinary specialist care. Although there is complexity to a management framework that begins in the first hours to days of life, a gentle, physiological, and phased approach can lead to better outcomes. This review article describes such an approach. [ABSTRACT FROM AUTHOR]

Glucose is an essential substrate for mammalian cells; in particular, the brain needs glucose continuously as a primary source of energy. Hypoglycemia is the most common biochemical finding in the neonatal period. However, despite the common occurrence, there is still controversy on the definition of hypoglycemia in the newborn period. This has led to the development of guidelines designed to identify infants "at-risk" and the implementation of an "operational threshold" for physicians to consider intervention. In healthy term infants, the optimal hormonal and metabolic adaptations during the immediate neonatal period ensure an adequate energy substrate for the vital organs, whereas the abnormal glucose homeostasis observed in preterm and growth-retarded infants is multifactorial in origin. For these high-risk infants, it is important to identify, screen, and prevent significant hypoglycemia. Detailed investigations are warranted in infants with severe and persistent hypoglycemia. Neonatal hypoglycemia is a major cause of brain injury. The speculated mechanisms of cellular injury include excitatory neurotoxins active at N-methyl-D-aspartate receptors, increased mitochondrial free radical generation with initiation of apoptosis and altered cerebral energetic characteristics. This hypoglycemic brain injury predominantly affects parieto-occipital regions causing cognitive, sensory, psychomotor, and behavioral deficits in children. This state of the art review article covers the fetal--neonatal metabolic adaptation, glucose homeostasis in normal and abnormal conditions, management strategies, and late neurological sequelae of hypoglycemia. [ABSTRACT FROM AUTHOR]

Hyperinsulinaemic hypoglycaemia in small-for-gestational age infants usually presents in the first two postnatal days. We present a preterm, small-for-gestational age infant who had hyperinsulinaemic hypoglycaemia on day 13 of life. A female twin infant weighing 1390 g was born at 32+6 weeks of gestation. Her glycaemic profile was normal till day 13 of life, after which she was noted to be lethargic and hypoglycaemic and had hyperinsulinism, hypoketonaemia and hypofattyacidaemia, requiring high glucose infusion rate to maintain normoglycaemia, while negative for septic markers and metabolic screen. Initially, there was no response to diazoxide and the genetic studies for ABCC8 and KCNJ11 gene mutations were negative. Delayed response to diazoxide was followed by complete resolution of hypoglycaemia in 5 months. This case highlights the importance of glucose monitoring in small-for-date infants for hypoglycaemia till they achieve full feeds and gain weight. Early recognition and appropriate management of hypoglycaemia in this group of infants have important implications for neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]