Development and Validation of a Nocturnal Hypoglycaemia Risk Model for Patients With Type 2 Diabetes Mellitus.

AIM: To develop and test different machine learning algorithms for predicting nocturnal hypoglycaemia in patients with type 2 diabetes mellitus. DESIGN: A retrospective study. METHODS: We collected data from dynamic blood glucose monitoring of patients with T2DM admitted to the Department of Endocrinology and Metabolism at a hospital in Shanghai, China, from November 2020 to January 2022. Patients undergone the continuous glucose monitoring (CGM) for ≥ 24 h were included in this study. Logistic regression, random forest and light gradient boosting machine algorithms were employed, and the models were validated and compared using AUC, accuracy, specificity, recall rate, precision, F1 score and the Kolmogorov-Smirnov test. RESULTS: A total of 4015 continuous glucose-monitoring data points from 440 patients were included, and 28 variables were selected to build the risk prediction model. The 440 patients had an average age of 62.7 years. Approximately 48.2% of the patients were female and 51.8% were male. Nocturnal hypoglycaemia appeared in 573 (14.30%) of 4015 continuous glucose monitoring data. The light gradient boosting machine model demonstrated the highest predictive performances: AUC (0.869), specificity (0.802), accuracy (0.801), precision (0.409), recall rate (0.797), F1 score (0.255) and Kolmogorov (0.603). The selected predictive factors included time below the target glucose range, duration of diabetes, insulin use before bed and dynamic blood glucose monitoring parameters from the previous day. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

The interdependence of targets for continuous glucose monitoring outcomes in type 1 diabetes with automated insulin delivery.

AIM: The aim was to determine the interdependence of targets for glucose management indicator (GMI), time within the ranges of 70-180 mg/dL (TIR) and 70-140 mg/dL (time in tight glucose range [TITR]), time above 180 mg/dL (TA180) and 250 mg/dL (TA250) and time below 70 mg/dL (TB70) and 54 mg/dL (TB54) and its implications for setting targets in automated insulin delivery (AID). MATERIALS AND METHODS: Real-world data from individuals with type 1 diabetes using the 780G system were used to calculate the receiver operating characteristic curves and establish interdependent targets for time in ranges based on several GMI benchmarks. Correlation, regression and principal component analysis were used to determine their association and dimensionality. RESULTS: In individuals aged >15 years (n = 41 692), a GMI <6.5% required targets of >81%, >58%, <15% and <1.9% for TIR, TITR, TA180 and TA250, respectively, with high sensitivity, specificity and accuracy (>90%), whereas these values were poor for time in hypoglycaemia and GMI, which had a modest correlation (-0.21 to -0.43). Two dimensions emerged: (1) GMI, TIR, TITR, TA180 and TA250, and (2) TB70 and TB54, explaining 95% of total variability. GMI (or TIR) and TB70 explained >81% of the variability in the remaining continuous glucose monitoring (CGM) metrics, providing accurate predictions. Individuals aged ≤15 years (n = 14 459) showed similar results. CONCLUSION: We developed a methodology to establish interdependent CGM targets for therapies with CGM data outputs. In AID with the 780G system, a GMI <7% requires time in ranges close to consensus targets. Targets for GMI, TIR, TITR, TA180 and TA250 could be reduced to targets for GMI or TIR, whereas targets for time in hypoglycaemia are not inherently tied to GMI/TIR targets.

Risk of hypoglycaemia among people with type 2 diabetes not treated with insulin: A retrospective analysis of Medicare Advantage beneficiaries.

AIMS: In 2022, the Centers for Medicare & Medicaid Services released proposed changes to Medicare's continuous glucose monitoring (CGM) coverage policy, making individuals with a history of problematic hypoglycaemia eligible for CGM coverage, irrespective of insulin use. This study estimated the burden of hypoglycaemia in Medicare Advantage beneficiaries with noninsulin-treated type 2 diabetes (T2D). MATERIALS AND METHODS: We retrospectively analysed US healthcare claims data using Optum's deidentified Clinformatics® database. Noninsulin-treated beneficiaries were identified in the 16 years from January 2007 to March 2023. Hypoglycaemia-related encounters (HREs) were those accompanied by a hypoglycaemia-specific ICD-9/10 diagnosis code in any position on the claim or the first or second position. HREs following the first claim related to T2D were reported by setting (ambulatory or inpatient/emergency department [ED]). RESULTS: HREs were identified in 689,853 (21.4%) of 3,229,695 noninsulin-treated Medicare Advantage beneficiaries, of whom 82.9% (n = 571,581) had ≥1 HRE in an ambulatory location and 26.8% (n = 184,833) in an ED/inpatient location. Use of sulfonylurea (odds ratio [OR]: 4.33 confidence interval [CI: 4.27-4.38]), evidence of end-stage kidney disease (OR: 2.87 [CI: 2.79-2.94]), hypertension (OR: 3.09 [CI: 3.04-3.15]) and retinopathy (OR: 2.94 [CI: 2.82-3.07]) were the strongest predictors of an HRE (p < 0.001). CONCLUSIONS: These findings show that HREs are prevalent in noninsulin-treated diabetes and identify a large number of patients who may benefit from CGM. Because >80% of HREs occur in the ambulatory setting and >70% occur in patients not taking sulfonylureas, primary care providers should be aware of the latest eligibility criteria for Medicare's coverage of CGM and not restrict this technology to their sulfonylurea-treated patients.

Use of glucose sensors for post-discharge care triaging of insulin-treated patients with type 2 diabetes: a feasibility study.

The use of glucose sensors to triage post-discharge follow-up was investigated among hospital inpatients with type 2 diabetes. Feasibility, utility and patient satisfaction with this model of care were studied. Feasibility was 36.5%, with 90/198 (45.5%) inpatients discharged with glucose sensors but 9.0% unable to use glucose sensors effectively. Follow-up plans were altered in 76.3% of the patients able to use the sensor technology. Patient satisfaction was high and was improved on follow-up after 6 months.

High incidence of low interstitial fluid glucose among type 2 diabetes patients with chronic kidney disease (CKD) despite adhering to appropriate glycated haemoglobin targets-has time come for robust integration of interstitial fluid glucose targets into glycaemic guidelines?

AIM: We aim to compare the burden of Level 1 (<4 mmol/L) and Level 2 (<3 mmol/L) hypoglycaemia between type 2 diabetes (T2D) patients with and without chronic kidney disease (CKD). METHODS: T2D subjects with and without CKD (eGFR<60 mL/min/1.73 m2) were recruited from a tertiary-care hospital. Subjects wore the Freestyle Libre-Pro sensor for 2 weeks. The number of hypoglycaemic events and intra-day difference in Level 1 and 2 hypoglycaemias were compared between the cohorts. RESULTS: We recruited 134 subjects: 74 with CKD (44 M:30F) and 60 without CKD (36 M:24F), with no difference in HbA1c between the two cohorts (66 ± 20 vs 64 ± 16 mmol/mol, p = 0.529). The CKD cohort had increased level 1 (OR 1.73, p = 0.011), level 2 hypoglycaemias (OR 2.16, p = 0.002), and glycaemic variability than the non-CKD cohort (35.3 ± 9.5 vs 32.3 ± 6.8%). The CKD cohort had more level 2 hypoglycaemia events nocturnally compared to day at 1.9 ± 3.1 vs. 1.4 ± 2.5 events/person within the two week sensor wearing period (p = 0.022), whereas there was no significant intra-day difference in the number of such events within the non-CKD cohort. CONCLUSIONS: The CKD cohort has a greater burden of hypoglycaemia despite being treated to similar HbA1c targets. The greater number of nocturnal events warrants safety concern. Interstitial fluid glucose targets should be incorporated into the glycaemic guidelines for T2D patients with CKD.

Mechanism and performance of choline-based ionic liquids in enhancing nasal delivery of glucagon.

Proteins and peptides have been increasingly developed as pharmaceuticals owing to their high potency and low side effects. However, their administration routes are confined to injections, such as intra-muscular and intra-venous injections, making patient compliance a challenge. Hence, non-injectable delivery systems are crucial to expanding the clinical use of proteins and peptides. In this context, two choline-based ionic liquids (ILs), namely, choline geranic acid ([Ch][Ger]) and choline citric acid ([Ch][Cit]), have been identified as promising agents for enhancing the permeation and prolonging the retention time of glucagon (GC) after intra-nasal administration. Notably, intra-nasal delivery of GC via ILs (GC/ILs) elicited rapid and smooth reversal of acute hypoglycaemia without leading to rebound hyperglycaemia in type 1 diabetic rats subjected to insulin induction. In addition, ILs could improve the transcellular transport of GC through electrostatic interaction. ILs could also transiently open inter-cellular tight junctions transiently to facilitate the paracellular transport of GC. Safety tests indicated that continuous intra-nasal delivery of ILs led to reversible changes, such as epithelial cell inflammation, goblet cell overgrowth, and impacts on the distribution of nasal cilia. However, these changes could be alleviated by the innate self-repair ability of mucosal epithelial cells. This study highlights the considerable potential of ILs for long-term nasal delivery of biomacromolecules.

Hypoglycaemia in screening oral glucose tolerance test in pregnancy with low birth weight fetus.

Maternal hypoglycemia, a condition characterized by lower than normal blood glucose levels in pregnant women, has been increasingly associated with adverse pregnancy outcomes, including low birth weight (LBW) in neonates. LBW, defined as a birth weight of less than 2500 g, can result from various factors, including maternal nutrition, health status, and metabolic conditions like hypoglycemia. Maternal hypoglycemia may affect fetal growth by altering the supply of essential nutrients and oxygen to the fetus, leading to restricted fetal development and growth. This condition poses significant risks not only during pregnancy but also for the long-term health of the child, increasing the likelihood of developmental delays, health issues, and chronic conditions later in life. Research in this area has focused on understanding the mechanisms through which maternal hypoglycemia influences fetal development, with studies suggesting that alterations in placental blood flow and nutrient transport, as well as direct effects on fetal insulin levels and metabolism, may play a role. Given the potential impact of maternal hypoglycemia on neonatal health outcomes, early detection and management are crucial to minimize risks for LBW and its associated complications. Further investigations are needed to fully elucidate the complex interactions between maternal glucose levels and fetal growth, as well as to develop targeted interventions to support the health of both mother and child. Understanding these relationships is vital for improving prenatal care and outcomes for pregnancies complicated by hypoglycemia.

The association of glycaemic risk factors and diabetes duration with risk of heart failure in people with type 2 diabetes: A systematic review and meta-analysis.

AIMS: To conduct a systematic review in order to better understand the association of glycaemic risk factors and diabetes duration with risk of heart failure (HF) in individuals with type 2 diabetes (T2D). METHODS: We identified longitudinal studies investigating the association of glycaemic factors (glycated haemoglobin [HbA1c], HbA1c variability, and hypoglycaemia) and diabetes duration with HF in individuals with T2D. Hazard ratios and odds ratios were extracted and meta-analysed using a random-effects model where appropriate. Risk of bias assessment was carried out using a modified Newcastle-Ottawa Scale. Egger's test along with the trim-and-fill method were used to assess and account for publication bias. RESULTS: Forty studies representing 4 102 589 people met the inclusion criteria. The risk of developing HF significantly increased by 15% for each percentage point increase in HbA1c, by 2% for each additional year of diabetes duration, and by 43% for having a history of severe hypoglycaemia. Additionally, variability in HbA1c levels was associated with a 20%-26% increased risk of HF for each unit increase in the metrics of variability (HbA1c standard deviation, coefficient of variation, and average successive variability). All included studies scored high in the risk of bias assessment. Egger's test suggested publication bias, with trim-and-fill analyses revealing a significant 14% increased risk of HF per percentage point increase in HbA1c. CONCLUSIONS: Glycaemic risk factors and diabetes duration significantly contribute to the heightened risk of HF among individuals with T2D. A reduction in risk of HF is anticipated with better management of glycaemic risk factors.

Detection of hypoglycaemia in type 1 diabetes through breath volatile organic compound profiling using gas chromatography-ion mobility spectrometry.

AIM: To evaluate the relationship between breath volatile organic compounds (VOCs) and glycaemic states in individuals with type 1 diabetes (T1D), focusing on identifying specific VOCs as biomarkers for hypoglycaemia to offer a non-invasive diabetes-monitoring method. MATERIALS AND METHODS: Ten individuals with T1D underwent induced hypoglycaemia in a clinical setting. Breath samples, collected every 10-15 minutes, were analysed using gas chromatography-ion mobility spectrometry (GC-IMS). Correlation analysis and machine learning models, including Partial Least Squares Discriminant Analysis (PLS-DA) and Support Vector Machine classifiers, were used to classify glycaemic states based on VOC profiles. RESULTS: Statistical analysis revealed moderate correlations between specific VOCs (e.g. isoprene, acetone) and venous blood glucose levels. Machine learning models showed high accuracy in classifying glycaemic states, with the best performance achieved by a two-class PLS-DA model showing an accuracy of 93%, sensitivity of 92% and specificity of 94%. Key biomarkers identified included isoprene, acetone, 2-butanone, methanol, ethanol, 2-propanol and 2-pentanone. CONCLUSIONS: This study shows the potential of breath VOCs to accurately classify glycaemic states in individuals with T1D. While key biomarkers such as isoprene, acetone and 2-butanone were identified, the analysis emphasizes the importance of using overall VOC patterns rather than individual compounds, which can be markers for multiple conditions. Machine learning models leveraging these patterns achieved high accuracy, sensitivity and specificity. These findings suggest that breath analysis using GC-IMS could be a viable non-invasive method for monitoring glycaemic states and managing diabetes.

Characteristics of Nocturnal Hypoglycaemic Events and Their Impact on Glycaemia.

BACKGROUND: Nocturnal hypoglycaemia is a burden for people with diabetes, particularly when treated with multiple daily injections (MDI) therapy. However, the characteristics of nocturnal hypoglycaemic events in this patient group are only poorly described in the literature. METHOD: Continuous glucose monitoring (CGM) data from 185 study participants with type 1 diabetes using MDI therapy were collected under everyday conditions for up to 13 weeks. Hypoglycaemic events were identified as episodes of consecutive CGM readings <70 mg/dl or <54 mg/dl for at least 15 minutes. Subsequently, the time <54 mg/dl (TB54), time below range (TBR), time in range (TIR), time above range (TAR), glucose coefficient of variation (CV), and incidence of hypoglycaemic events were calculated for diurnal and nocturnal periods. Furthermore, the effect of nocturnal hypoglycaemic events on glucose levels the following day was assessed. RESULTS: The incidence of hypoglycaemic events <70 mg/dl was significantly lower during the night compared to the day, with 0.8 and 3.8 events per week, respectively, while the TBR, TB54, and incidence of events with CGM readings <54 mg/dl was not significantly different. Nocturnal hypoglycaemic events <70 mg/dl were significantly longer (60 vs 35 minutes) and enveloped by less rapidly changing glucose levels. On days following nights containing hypoglycaemic events, there was a decrease in TAR, mean CGM glucose level and morning glucose levels and an increase in TB54, TBR, and CV. CONCLUSIONS: The results showed that nocturnal hypoglycaemic events are a common occurrence in persons with type 1 diabetes using MDI with significant differences between the characteristics of nocturnal and diurnal events.

Ageing well with diabetes: the role of technology.

Over the past two decades there has been a substantial rise in the adoption of diabetes therapeutic technology among children, adolescents and younger adults with type 1 diabetes, and its use is now also advocated for older individuals. Older people with diabetes are more prone to experience hypoglycaemia because of numerous predisposing factors and are at higher risk of hypoglycaemic events requiring third-party assistance as well as other adverse sequelae. Hypoglycaemia may also have long-term consequences, including cognitive impairment, frailty and disability. Diabetes in older people is often characterised by marked glucose variability related to age-associated changes such as variable appetite and levels of physical activity, comorbidities and polypharmacotherapy. Preventing hypoglycaemia and mitigating glucose excursions may have considerable positive impacts on physical and cognitive function and general well-being and may even prevent or improve frailty. Technology for older people includes continuous glucose monitoring systems, insulin pumps, automated insulin delivery systems and smart insulin pens. Clinical trials and real-world studies have shown that older people with diabetes benefit from technology in terms of glucose management, reductions in hypoglycaemic events, emergency department attendance and hospital admissions, and improvement in quality of life. However, ageing may bring physical impairments and other challenges that hinder the use of technology. Healthcare professionals should identify older adults with diabetes who may benefit from therapeutic technology and then adopt an individualised approach to education and follow-up for individuals and their caregivers. Future research should explore the impact of diabetes technology on outcomes relevant to older people with diabetes.

Use of continuous glucose monitoring when initiating glucagon-like peptide-1 receptor agonist therapy in insulin-treated diabetes.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) medications have been shown to be effective in achieving optimal glucose control and reducing all-cause death, cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, and end-stage kidney disease in individuals with type 1 (T1D) and type 2 diabetes (T2D). However, use of these medications has been associated with increased hypoglycaemia risk in patients treated with concomitant antihyperglycaemic medications. The risk is particularly high in patients with T1D due to their loss of glucagon counter-regulatory response. This article reviews the effect of GLP-1RA formulations on the development of hypoglycaemia in individuals with T1D and T2D treated with insulin therapy, discusses the benefits of continuous glucose monitoring with GLP-1RA treatment, and presents strategies for safely initiating GLP-1RA therapy in these individuals.

Glucose disturbances in very low-birthweight infants-Results from the prospective LIGHT study.

AIM: To describe glucose homeostasis disturbances (dysglycaemia) in very low-birthweight infants (<1500 g) during the admission period and explore associated risk factors. METHODS: The LIGHT (very low-birthweight infants - glucose and hormonal profile over time) study was a prospective observational cohort study that included 49 very low-birthweight infants admitted to the tertiary neonatal intensive care unit in Umeå, Sweden, during 2016-2019. All glucose concentrations (n = 3515) sampled during the admission period were registered. RESULTS: Hyperglycaemia >10 mmol/L and hypoglycaemia <2.6 mmol/L were registered in 63% and 55% of the infants, respectively. Onset of dysglycaemia occurred almost exclusively in the first postnatal week. Hyperglycaemia followed 15% of corticosteroid doses given; all were preceded by pre-existing hyperglycaemia. Pre-existing hyperglycaemia was found in 66.7% of hyperglycaemic infants who received inotrope treatment. Upon commencement, 72.5% of antimicrobial treatments given were neither preceded nor followed by hyperglycaemia. CONCLUSION: Dysglycaemia was common in very low-birthweight infants. Daily means of glucose concentrations seemed to follow a postmenstrual age-dependent pattern, decreasing towards term age suggesting a postmenstrual age-dependent developmental mechanism. The primary mechanism causing hyperglycaemia was independent of sepsis, and corticosteroid and inotrope treatments. No hypoglycaemia was registered during ongoing insulin treatment.

Severe hypoglycaemia-induced microglial inflammation damages microvascular endothelial cells, leading to retinal destruction.

Human microglia (HMC) are stress-induced inflammatory cells of the retina. It is unknown whether severe hypoglycaemia causes inflammation in microglia, affects the permeability of human retinal microvascular endothelial cells (HRMECs), and causes retinal damage. This study aimed to explore the effects of severe hypoglycaemia on retinal microglial inflammation and endothelial cell permeability and evaluate the damage caused by hypoglycaemia to the retina. The CCK-8 assay was used to measure cell viability. Western blotting was used to detect IL-1ß, IL-6, TNF- α, claudin-1, and occludin expression. ELISA was used to detect IL-1ß, IL-6, and TNF- α. Transmission electron microscopy (TEM) and haematoxylin and eosin staining were used to observe the retinal structure. Immunohistochemistry and immunofluorescence staining assays were also used to detect IL-1ß, IL-6, TNF- α, claudin-1, and occludin expression. Severe hypoglycaemia promoted inflammation in HMC3 cells. Inflammation caused by hypoglycaemia leads to the decreased expression of tight junction proteins. In vivo, severe hypoglycaemia induced structural damage to the retina, increased the expression of inflammatory factors, and decreased the expression of tight junction proteins. Our results suggest that severe hypoglycaemia leads to acute retinal inflammation, affecting the permeability of HRMECs and causing retinal damage.

A Case Report: Hypoglycaemic Unawareness Associated With Insulinoma.

Hypoglycaemic unawareness (HU) is more frequently described in relation to diabetics in the literature. We have noted that there is also an increasing reporting of HU in insulinoma cases. We report a hospital presentation for an incidental finding of hypoglycaemic unawareness in a gentleman in his fifties who was eventually diagnosed with insulinoma following biochemical studies, radiologic evaluation and histologic evaluation of an excised lesion between the pancreas and the spleen. We have reviewed existing literature evidence regarding the possible aetiologies and management options for this occurrence. More research studies to identify the epidemiology of this association and the determination of a protocol for increased detection of patients with insulinoma who display HU will need to be done.

Role of age and sex in the incidence of adverse effects among diabetic patients treated with glipizide.

Glipizide is an antidiabetic drug that belongs to a class of medication known as sulfonylureas. It is considered one of the highly prescribed antidiabetic drugs for the treatment of type II diabetes in patients following a kidney transplant. It lowers blood glucose levels by causing the release of insulin from ß-cells in the pancreas. Its main metabolizing pathway is through the liver. It has several adverse effects, which range from an upset stomach to glipizide-induced haemolytic anaemia and hypoglycaemia. These adverse effects may be spontaneous, or they could have a genetic cause. The present study aimed to assess and document the incidence of glipizide-induced adverse reactions among patients prescribed the drug. The present retrospective case-control study used the electronic medical records of patients prescribed glipizide for the past 3 years. These records were reviewed to extract and document cases and/or signs of glipizide-induced adverse reactions. The results revealed that the incidence of adverse effects was higher among female patients (odds ratio, 2.40, P<0.001). Moreover, the results revealed that the likelihood of developing adverse drug reactions among patients <40 years of age was higher than in older patients (P>0.05). The outcomes of the present study are expected to prompt future studies to take sex and age into consideration, in an aim to improve treatment outcomes, reduce adverse events and decrease the burden of unnecessary costs for healthcare systems. Recommendations also include genetic screening prior to administering the medication, educating the patients and caregivers on the possibility of adverse drug reactions, and routine follow-up. This issue is of utmost importance to achieve the optimal outcomes with the minimal detrimental effects.

Spontaneous Hypoglycaemia due to Insulin Autoimmune Syndrome in Six Cases, Response to Steroid Therapy and Rituximab.

Introduction: Dr. Hirata of Japan first described insulin autoimmune syndrome (IAS) in 1970. Seven hundred ninety-five cases of this rare syndrome have been reported from Japan and China and 29 from India. IAS has the following characteristic features 1) severe spontaneous attacks of hyperinsulinemic hypoglycaemia, 2) high total immunoreactive insulin levels, 3) elevated insulin autoantibody (IAA) titres, 4) no prior exposure to exogenous insulin, and 5) no pathological abnormalities of the pancreatic islet cells. Methods: We treated six cases of IAS with high doses of prednisolone for 4-6 weeks and then gradually reduced the doses. Diagnosis of IAS was established by documenting Whipple's triad of symptoms and signs of hypoglycaemia, blood sugar <55 mg/dl, improvement of symptoms with dextrose infusion, inappropriately increased insulin levels >3 uU/ml, C-peptide levels >0.6 ng/ml, and increased titres of anti-insulin autoantibodies. Insulinoma and non-pancreatic tumours were ruled out by CECT (contrast-enhanced computerised tomography) or MRI (magnetic resonance imaging) of the abdomen and if necessary endoscopic ultrasonography and gallium 68 Dotanoc PET (positron enhanced tomography). Autoimmune screening and serum electrophoresis were done to rule out multiple myeloma. Monitoring of the patient's blood sugars was done by the laboratory, glucometer readings, and a freestyle libre glucose monitoring system. Results: Remission of hypoglycaemic episodes, hyperglycaemic episodes, and marked reduction of serum insulin and insulin autoantibodies in four out of six patients with diet therapy and steroids. Two patients resistant to steroids were treated with rituximab successfully. Patient 6 developed serious complications of cytomegalovirus and Pneumocystis carnii after rituximab, which were treated successfully. Conclusion: A careful history including recent infections, medications, and vaccinations provides vital clues in the evaluation. An increased awareness of IAS will prevent unnecessary and costly investigations and surgery. Although it is often self-remitting, steroids are contributory in severe cases. Immunosuppressives are used successfully in cases refractory to steroids. Continuous glucose monitoring system (CGMS), by freestyle libre glucose monitoring system, provided real-time blood sugar values, total time in hypoglycaemia, and total time in the range (TIR), which proved very valuable in managing IAS patients. Low CGMS values should be corroborated clinically and with laboratory or glucometer values.

Clinical Profile and Efficacy of Long-Acting Octreotide in Hyperinsulinemic Hypoglycaemia.

Introduction: Hyperinsulinemic hypoglycaemia (HH) is characterised by unregulated insulin secretion, leading to persistent non-ketotic hypoglycaemia with a lack of alternate fuel that induces a severe risk for brain damage and neurodevelopmental abnormalities. Octreotide, a somatostatin analogue, has been effectively administered as subcutaneous injections or depot preparations in diazoxide-unresponsive HH. Methods: Children and infants with HH receiving short-acting octreotide injections were included. Anthropometric values, hypoglycaemic episodes, HbA1C, and side effects were noted from the records and were followed up for 12 months. Informed written consent was obtained from the parents before administration of a single dose of LAR (long-acting octreotide). Based on home-based glucose monitoring (HBGM), the dosage of LAR was modified, and short-acting octreotide was eventually withdrawn. The patients shared the injection's cost for cost-effectiveness. HH affects the quality of life (QoL) if not diagnosed and controlled adequately. A QoL questionnaire was given before starting LAR and after 6 months of receiving LAR, and the changes were noted accordingly. Results: Twenty-two patients were diagnosed with HH, of which 11 infants and children were included in the study. Mutations were identified in 7 (63.63%) children. Daily octreotide could be tapered and stopped with the addition of sirolimus in one patient with an increasing dose of LAR to maintain euglycaemia. The hypoglycaemic episodes decreased with increasing dose of LAR with a decrease in the severity. Eight (72.7%) patients showed an improved lifestyle on LAR quantified through a QoL questionnaire. Conclusion: LAR was found effective in reducing hypoglycaemic episodes with no adverse effects. The patient's parent's satisfaction was higher. Given its high cost, this trial achieved cost-effectiveness by sharing a single sitting of LAR injection.

Effective and safe use of sirolimus in hyperinsulinemic hypoglycaemia refractory to medical and surgical therapy: a case series and review of literature.

OBJECTIVES: Hyperinsulinemic hypoglycaemia (HH) presents significant management challenges, especially in cases refractory to standard therapies. This case series aims to report the efficacy and safety of sirolimus, an mTOR inhibitor, as an adjunctive therapy in persistent HH, noting that current clinical guidelines caution its use outside of research. CASE PRESENTATION: We report a case series from two paediatric endocrinology centres across Australia, describing use of sirolimus in four infants with persistent HH refractory to conventional treatments or post near-total pancreatectomy. Retrospective chart reviews provided clinical and biochemical data, documenting each patient's sirolimus dosing, treatment responses, and adverse events. CONCLUSIONS: Sirolimus emerged as a useful and safe adjunct, enabling hospital discharge, and demonstrating efficacy even at lower serum trough levels. Despite safety concerns, including recurrent viral infections in one patient, sirolimus was generally well-tolerated. We advocate for implementing risk mitigation strategies, including a multidisciplinary approach, and maintaining lower sirolimus trough levels than previously recommended. Careful consideration of sirolimus is warranted in select cases of severe diffuse HH, emphasising ongoing monitoring for adverse effects and further research to refine treatment guidelines.

Nutritional Management of Patients with Fatty Acid Oxidation Disorders.

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy (total MCT+LCT ratio = 20-35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation.