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.

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.

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.

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.

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.

Vulnerable Hours of the Day for Severe Iatrogenic Hypoglycaemia in Type 2 Diabetes: A Single-Centre Retrospective Study.

INTRODUCTION: Iatrogenic hypoglycaemia is an event that should be avoided in the treatment of diabetes, but the pathophysiology thereof has been poorly examined and reported. There is no established method for preventing iatrogenic hypoglycaemia and the current approach is a reactive response following onset of the disease. In this study, we aimed to explore the existence of 'hypoglycaemia-vulnerable hours of the day' in patients with type 2 diabetes, with the ultimate goal of preventing the onset of iatrogenic hypoglycaemia by clarifying the time when severe hypoglycaemia is likely to occur. METHODS: Of the 553,201 patients who visited the Critical Care and Emergency Center of Aizawa Hospital between 2008 and 2019, patients with proven hypoglycaemia (blood glucose level <3.0 mmol/L) and those using insulin or oral hypoglycaemic agents for the treatment of type 2 diabetes were included: 146 insulin users and 148 oral hypoglycaemic agent users. Cosinor analysis was employed to identify hypoglycaemia-vulnerable hours of the day. RESULTS: Patients with type 2 diabetes and severe hypoglycaemia had two peaks: at 8:00 and 18:00-19:00. Hypoglycaemia was observed as quadra-peaked in insulin users and double-peaked in oral hypoglycaemic agent users. Single-cosinor analysis revealed that the cycle was 5.83 hours (R=0.417) in insulin users, whereas it was 11.0 hours (R=0.717) in oral hypoglycaemic agent users. In insulin users, a significant periodicity of six hours (P=0.003) was observed in the cosinor detection analysis, and a significant correlation (P<0.05) was present in the cosinor percent rhythmicity analysis. In contrast, in oral hypoglycaemic agent users, a significant periodicity of 11 hours (P=0.03) was ascertained in the cosinor detection analysis, and there was a significant correlation (P<0.001) in the cosinor percent rhythmicity analysis. There were different hypoglycaemia-vulnerable hours of the day in the patients with type 2 diabetes, suggesting an interaction between disease pathophysiology and pharmacology. CONCLUSIONS: These results can help elucidate the trend of the development of iatrogenic hypoglycaemia and contribute to the prevention of the onset thereof.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Dysglycaemia in Ebola virus disease: a retrospective analysis from the 2018 to 2020 outbreak.

BACKGROUND: Ebola virus disease (EVD) is associated with multisystem organ failure and high mortality. Severe hypoglycaemia is common, life-threatening, and correctable in critically ill patients, but glucose monitoring may be limited in EVD treatment units. METHODS: We conducted a retrospective review of patients admitted to EVD treatment units in Butembo and Katwa, Eastern DRC. Glucose measurements were done using a handheld glucometer at the bedside or using the Piccolo xpress Chemistry Analyzer on venous samples. FINDINGS: 384 patients (median age 30 years (interquartile range, IQR, 20-45), 57% female) and 6422 glucose measurements (median 11 per patient, IQR 4-22) were included in the analysis. Severe hypoglycaemia (≤2.2 mmol/L) and hyperglycaemia (>10 mmol/L) were recorded at least once during the ETU admission in 97 (25%) and 225 (59%) patients, respectively. A total of 2004 infusions of glucose-containing intravenous solutions were administered to 302 patients (79%) with a median cumulative dose of 175g (IQR 100-411). The overall case fatality rate was 157/384 (41%) and was 2.2-fold higher (95% CI 1.3-3.8) in patients with severe hypoglycaemia than those without hypoglycaemia (p = 0.0042). In a multivariable Cox proportional hazards model, periods of severe hypoglycaemia (adjusted hazard ratio (aHR) 6.2, 95% CI 3.2-12, p < 0.0001) and moderate hypoglycaemia (aHR 3.0, 95% CI 1.9-4.8, p < 0.0001) were associated with elevated mortality. INTERPRETATION: Hypoglycaemia is common in EVD, requires repeated correction with intravenous dextrose solutions, and is associated with mortality. FUNDING: This study was not supported by any specific funding.

Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight. METHODS: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes. RESULTS: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced. CONCLUSIONS/INTERPRETATION: These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.

Case report: Exceptional transmission of congenital hyperinsulinism from a focal CHI mother to her diffuse CHI dichorionic diamniotic twins.

We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was performed at the age of three weeks. Later, histological analysis of her pancreas in a research setting revealed a focal form of CHI. Genetic testing was not available at that time. The patient developed pancreatic exocrine deficiency and insulin-dependent diabetes at the age of 9 years. In 2016, a genetic test revealed a missense heterozygous variant in the ABCC8 gene inherited from her father and classified as having a recessive inheritance. The geneticist concluded that the risk of CHI for her offspring would be low (1/600), making pregnancy favourable. As there was no consanguinity in the family, testing the future father was deemed unnecessary (carrier frequency 1/150 in the general population). The pregnancy occurred spontaneously in 2020 and at a gestational age of 28 weeks, the mother went into premature labour. An emergency C-section was performed in April 2021 resulting in the birth of bichorial bi-amniotic male twins. Following birth, both newborns experienced persistent severe hypoglycaemia which required glucagon treatment and intravenous glucose infusion initially, followed by Diazoxide from day 51 after birth, without satisfactory response. Continuous intravenous Octreotide treatment was introduced on day 72. Due to the recurrence of hypoglycaemia episodes despite reaching maximum doses of Octreotide, from day 92 the treatment was switched to Pasireotide. Genetic tests revealed the same genotypes for both infants: the exon 39 missense variant (c.4716C>A; p.Ser1572Arg) inherited from their mother and a truncating variant in exon 28 (c.3550del; p.Val1184*), inherited from their asymptomatic father. As a result of inheriting two recessive variants of the ABCC8 gene, the children were diagnosed with a diffuse form of CHI, consistent with the diazoxide-unresponsive presentation. This situation is very rare outside consanguinity. This case emphasises the significance of genetic counselling for individuals with a history of rare diseases outside the context of consanguinity, as there is a potential risk of recurrence. Prenatal diagnosis can lead to better outcomes for affected neonates, as well as help families make informed decisions about future pregnancies.

Once-weekly insulin icodec compared with daily basal insulin analogues in type 2 diabetes: Participant-level meta-analysis of the ONWARDS 1-5 trials.

AIM: To perform a participant-level post hoc meta-analysis of Phase 3a trials in type 2 diabetes (T2D) to characterize the hypoglycaemia safety and glycaemic efficacy of once-weekly insulin icodec (icodec). MATERIALS AND METHODS: All ONWARDS 1-5 randomized participants were pooled as overall T2D, insulin-naive, an insulin-experienced subgroups, and by once-daily trial comparator (degludec or glargine U100). The main outcomes included incidence and rates of clinically significant and severe hypoglycaemia. Additional endpoints included change in glycated haemoglobin (HbA1c) from baseline and HbA1c target achievement without clinically significant or severe hypoglycaemia. RESULTS: The meta-analysis comprised 3765 participants (1882 icodec vs. 1883 comparators). In the overall T2D pool, clinically significant hypoglycaemia incidence was similar in the icodec group versus the comparator group (17.9% vs. 16.2%, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.94, 1.38); however, rates were low but significantly higher in the icodec group (1.15 vs. 1.00 episodes/participant-year of exposure, estimated rate ratio 1.51 [95% CI 1.24, 1.85]). Fewer severe hypoglycaemic episodes occurred with icodec than with comparators (8 vs. 18). A greater reduction in HbA1c occurred with icodec versus comparators, irrespective of subgroup (estimated treatment difference range [-0.10 to -0.29%]; all p < 0.05). Across subgroups, except for the insulin-experienced subgroup, the odds of achieving HbA1c <53 mmol/mol (7.0%) without clinically significant or severe hypoglycaemia were greater with icodec than with comparators (OR range 1.30-1.55; all p < 0.05). CONCLUSIONS: Icodec was associated with a similar incidence but higher rates of clinically significant hypoglycaemia (equating to one additional hypoglycaemic episode every 6 years) and fewer severe hypoglycaemic episodes versus comparators. Our findings also confirmed the greater efficacy of icodec that was demonstrated in the ONWARDS trial programme.

The impact of hypoglycaemia on daily functioning among adults with diabetes: a prospective observational study using the Hypo-METRICS app.

AIMS/HYPOTHESIS: The aim of this work was to examine the impact of hypoglycaemia on daily functioning among adults with type 1 diabetes or insulin-treated type 2 diabetes, using the novel Hypo-METRICS app. METHODS: For 70 consecutive days, 594 adults (type 1 diabetes, n=274; type 2 diabetes, n=320) completed brief morning and evening Hypo-METRICS 'check-ins' about their experienced hypoglycaemia and daily functioning. Participants wore a blinded glucose sensor (i.e. data unavailable to the participants) for the study duration. Days and nights with or without person-reported hypoglycaemia (PRH) and/or sensor-detected hypoglycaemia (SDH) were compared using multilevel regression models. RESULTS: Participants submitted a mean ± SD of 86.3±12.5% morning and 90.8±10.7% evening check-ins. For both types of diabetes, SDH alone had no significant associations with the changes in daily functioning scores. However, daytime and night-time PRH (with or without SDH) were significantly associated with worsening of energy levels, mood, cognitive functioning, negative affect and fear of hypoglycaemia later that day or while asleep. In addition, night-time PRH (with or without SDH) was significantly associated with worsening of sleep quality (type 1 and type 2 diabetes) and memory (type 2 diabetes). Further, daytime PRH (with or without SDH), was associated with worsening of fear of hyperglycaemia while asleep (type 1 diabetes), memory (type 1 and type 2 diabetes) and social functioning (type 2 diabetes). CONCLUSIONS/INTERPRETATION: This prospective, real-world study reveals impact on several domains of daily functioning following PRH but not following SDH alone. These data suggest that the observed negative impact is mainly driven by subjective awareness of hypoglycaemia (i.e. PRH), through either symptoms or sensor alerts/readings and/or the need to take action to prevent or treat episodes.

Assessing the influence of insulin type (ultra-rapid vs rapid insulin) and exercise timing on postprandial exercise-induced hypoglycaemia risk in individuals with type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The relationship between pre-meal insulin type, exercise timing and the risk of postprandial exercise-induced hypoglycaemia in people living with type 1 diabetes is unknown. We aimed to evaluate the effects of exercise timing (60 vs 120 min post meal) and different insulin types (aspart vs ultra-rapid aspart) on hypoglycaemic risk. METHODS: This was a four-way crossover randomised trial including 40 individuals with type 1 diabetes using multiple daily injections (mean HbA1c 56 mmol/mol [7.4%]). Participants, who were recruited from the Montreal Clinical Research Institute, undertook 60 min cycling sessions (60% of V ˙ O 2 peak ) after breakfast (60 min [EX60min] or 120 min [EX120min] post meal) with 50% of their usual insulin dose (aspart or ultra-rapid aspart). Eligibility criteria included age ≥18 years old, clinical diagnosis of type 1 diabetes for at least 1 year and HbA1c ≤80 mmol/mol (9.5%). Participants were allocated using sequentially numbered, opaque sealed envelopes. Participants were masked to their group assignment, and each participant was allocated a unique identification number to ensure anonymisation. The primary outcome was change in blood glucose levels between exercise onset and nadir. RESULTS: Prior to exercise onset, time spent in hyperglycaemia was lower for EX60min vs EX120min (time >10.0 mmol/l: 56.6% [1.2-100%] vs 78.0% [52.7-97.9%]; p<0.001). The glucose reduction between exercise onset and nadir was less pronounced with EX60min vs EX120min (-3.8±2.7 vs -4.7±2.5 mmol/l; p<0.001). A similar number of hypoglycaemic events occurred during both exercise timings. Blood glucose between exercise onset and nadir decreased less with ultra-rapid aspart compared with aspart (-4.1±2.3 vs -4.4±2.8 mmol/l; p=0.037). While a similar number of hypoglycaemic events during exercise were observed, less post-exercise hypoglycaemia occurred with ultra-rapid aspart (n=0, 0%, vs n=15, 38%; p=0.003). No interactions between insulin types and exercise timings were found. CONCLUSIONS/INTERPRETATION: EX60min blunted the pre-exercise glucose increase following breakfast and was associated with a smaller glucose reduction during exercise. Ultra-rapid aspart led to a smaller blood glucose reduction during exercise and might be associated with diminished post-exercise hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03659799 FUNDING: This study was funded by Novo Nordisk Canada.

A deprescribing programme aimed to optimise blood glucose-lowering medication in older people with type 2 diabetes mellitus, the OMED2-study: the study protocol for a randomised controlled trial.

BACKGROUND: Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients. METHODS: We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy - Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness. DISCUSSION: This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023.

Addressing recurrent hypoglycaemia through thoracic surgical intervention: understanding Doege-Potter syndrome, a rarity in syndromes.

Doege-Potter syndrome (DPS), a rare paraneoplastic phenomenon characterised by non-islet cell tumour hypoglycaemia (NICTH), presents clinicians with intricate diagnostic and therapeutic challenges. This comprehensive review consolidates current understanding, clinical presentations, diagnostic modalities, therapeutic interventions, and emerging trends in managing DPS. The pathophysiology of DPS revolves around dysregulated insulin-like growth factors (IGF), particularly IGF-2, produced by mesenchymal tumours, notably solitary fibrous tumours (SFT). Clinical manifestations encompass recurrent hypoglycaemic episodes, often distinct from typical hypoglycaemia, with implications for insulin and counterregulatory hormone levels. Diagnosis necessitates a multidisciplinary approach integrating biochemical assays, imaging studies, and histopathological confirmation of the underlying neoplasm. Surgical resection remains the cornerstone of treatment, complemented by adjunctive therapies to manage persistent hypoglycaemia. Prognosis is influenced by successful tumour resection and long-term surveillance for recurrence. A patient-centred approach, incorporating supportive services and multidisciplinary care, is essential for optimal outcomes in individuals affected by DPS.

Association between maternal blood lipids and neonatal hypoglycaemia in pregnancy with gestational diabetes mellitus: a cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) prevalence is on the rise globally. Offspring of diabetic mothers face increased risk of neonatal hypoglycaemia (NH), and women with GDM have abnormal lipid profiles. However, there is no consensus on the link between maternal blood lipids and NH in infants from mothers with GDM. This study aimed to explore how maternal blood lipids affect NH. METHODS: A retrospective cohort study was conducted at the First Affiliated Hospital of Sun Yat-sen University. Information on participants' baseline characteristics and maternal metabolic profiles of glucose and lipids was collected. Significant variables from the univariate analysis were included in logistic regression, which was used to construct the predictive model for NH. A nomogram was constructed for visualizing the model and assessed using the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Neonatal capillary blood glucose (CBG) decreased rapidly in the first hour after birth, increased gradually from the first to the second hour, and then remained stable. In the NH group, 86.11% (502/583) of hypoglycaemia cases occurred within the first two hours after birth. Multivariate logistic regression suggested that the lipid indices of maternal apoprotein B/apoprotein A1 (Apo-B/Apo-A1) (odds ratio (OR) = 1.36, 95% confidence intervals (CIs): 1.049-1.764, P = 0.02) and apoprotein E (Apo-E) (OR = 1.014, 95% CIs: 1.004-1.024, P = 0.004) were positively associated with NH in neonates from mothers with GDM. Triglycerides (TGs) (OR = 0.883, 95% CIs: 0.788-0.986, P = 0.028) were inversely associated with NH. Maternal glycated haemoglobin (HbA1c), age, twin pregnancy and caesarean delivery also had predictive value of NH. The AUC of the nomogram derived from these factors for the prediction model of NH was 0.657 (95% CIs: 0.630-0.684). CONCLUSIONS: The present study revealed that the Apo-B/Apo-A1 and Apo-E levels were associated with an increased risk of NH. A nomogram was developed to forecast the risk of NH in babies born to mothers with GDM, incorporating maternal blood lipids, HbA1c, age, twin pregnancy, and caesarean section. The trajectory of glycaemia for neonates indicates the need for intensive CBG monitoring within 2 h of birth for neonates from mothers with GDM.

Combined sepsis- and renal dysfunction-induced hypoglycaemia in an older patient taking cibenzoline.

Key Clinical Message: An 86-year-old geriatric patient with sepsis presented cibenzoline-induced hypoglycaemia, although within the boundary range of cibenzoline blood concentration. Abstract: An 86-year-old geriatric patient taking cibenzoline for ametropic hypertrophic cardiac tendinopathy was admitted to our hospital for the treatment of sepsis. Upon admission, blood cibenzoline levels of 400.1 ng/mL were observed. Antibiotic therapy was initiated and cibenzoline was discontinued. On Day 16, cibenzoline was administered orally at a reduced dose of 50 mg/day. Several days after restarting cibenzoline, the patient developed hypoglycaemia (64 mg/dL), prompting the administration of 20% glucose. The present case demonstrates a rational timeline for cibenzoline administration, considering the patient's renal dysfunction and sepsis. Clinicians should exercise caution when managing older patients with severe infections who are receiving cibenzoline, and should consider the possibility of blood glucose fluctuations regardless of cibenzoline blood levels. Further research is warranted to better understand and address the potential side effects of cibenzoline administration in geriatric populations.