Bihormonal fully closed-loop system for the treatment of type 1 diabetes: a real-world multicentre, prospective, single-arm trial in the Netherlands.

BACKGROUND: Management of insulin administration for intake of carbohydrates and physical activity can be burdensome for people with type 1 diabetes on hybrid closed-loop systems. Bihormonal fully closed-loop (FCL) systems could help reduce this burden. In this trial, we assessed the long-term performance and safety of a bihormonal FCL system. METHODS: The FCL system (Inreda AP; Inreda Diabetic, Goor, Netherlands) that uses two hormones (insulin and glucagon) was assessed in a 1 year, multicentre, prospective, single-arm intervention trial in adults with type 1 diabetes. Participants were recruited in eight outpatient clinics in the Netherlands. We included adults with type 1 diabetes aged 18-75 years who had been using flash glucose monitoring or continuous glucose monitors for at least 3 months. Study visits were integrated into standard care, usually every three months, to evaluate glycaemic control, adverse events, and person-reported outcomes. The primary endpoint was time in range (TIR; glucose concentration 3·9-10·0 mmol/L) after 1 year. The study is registered in the Dutch Trial Register, NL9578. FINDINGS: Between June 1, 2021, and March 2, 2022, we screened 90 individuals and enrolled 82 participants; 78 were included in the analyses. 79 started the intervention and 71 were included in the 12 month analysis. Mean age was 47.7 (SD 12·4) years and 38 (49%) were female participants. The mean preintervention TIR of participants was 55·5% (SD 17·2). After 1 year of FCL treatment, mean TIR was 80·3% (SD 5·4) and median time below range was 1·36% (IQR 0·80-2·11). Questionnaire scores improved on Problem Areas in Diabetes (PAID) from 30·0 (IQR 18·8-41·3) preintervention to 10·0 (IQR 3·8-21·3; p<0·0001) at 12 months and on World Health Organization-Five Well-Being Index (WHO-5) from 60·0 (IQR 44·0-72·0) preintervention to 76·0 (IQR 60·0-80·0; p<0·0001) at 12 months. Five serious adverse events were reported (one cerebellar stroke, two severe hypoglycaemic, and two hyperglycaemic events). INTERPRETATION: Real-world data obtained in this trial demonstrate that use of the bihormonal FCL system was associated with good glycaemic control in patients who completed 1 year of treatment, and could help relieve these individuals with type 1 diabetes from making treatment decisions and the burden of carbohydrate counting. FUNDING: Inreda Diabetic.

The effect of antecedent hypoglycaemia on ß2-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the ß2-adrenergic receptor.

AIMS/HYPOTHESIS: Homozygosity for glycine at codon 16 (GlyGly) of the ß(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on ß(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the ß(2)-adrenergic receptor. METHODS: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the ß(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)). RESULTS: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased ß(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in ß(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047). CONCLUSION/INTERPRETATION: Antecedent hypoglycaemia did not affect ß(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in ß(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00160056.

[Physical risks whilst walking the Nijmegen Four Days Marches in 2007: electrolyte imbalance in 1 in 5 walkers]. / Fysieke risico's tijdens het lopen van de Nijmeegse Vierdaagse in 2007: elektrolytendisbalans bij 1 op de 5 wandelaars.

OBJECTIVE: To determine the physiological impact and health risks for walkers during the Nijmegen (the Netherlands) Four Days Marches in 2007, the largest walking event in the world with more than 45,000 participants. DESIGN: Observational study. METHODS: 66 volunteers were randomly selected and counterbalanced for distance walked and gender in this observational study. Subjects walked 30 km (n = 20; 10 men), 40 km (n = 25; 14 men) or 50 km (n = 21; 10 men) per day, for 4 consecutive days. Core body temperature, fluid intake, changes in body weight, plasma sodium concentrations and energy usage were measured before and after the marches. RESULTS: During this event, ambient temperatures ranged from 11.0 degrees C to a maximum 25.4 degrees C expressed as 'wet bulb globe temperature' (WBGT). Heart rate (+38 beats per minute) and core body temperature (+0.8 degree C) significantly increased in all subjects during each day (about 9 hours walking per day at an average of 4.6 km/h), but hyperthermia was not diagnosed (definition: > 39.0 degrees C). Average fluid intake varied between 2.6 and 3.3 l/d with a range of 0.3-12 l/d. The relative change in body weight associated with this was -3.1 to +4.3%. Mean plasma sodium concentration decreased from 142.4 to 140.6 mmol/l over each walking day. The plasma sodium correlated negatively with fluid intake (r = -0.32; p < o.001), change in body weight (r = -0.13; p < 0.05), and walking time (r = -0.37; p < 0.001). A high prevalence of hyponatraemia (5%) and hypernatraemia (16%) was observed; extrapolating these findings to the entire field a large group (about 10,000) would have been at risk with this electrolyte imbalance. CONCLUSION: This study showed that walking the Four Days Marches in Nijmegen with mild ambient conditions led to one in five participants incurring disturbances in fluid and electrolyte balance. Nonetheless, the participants were well able to keep their increasing core temperature within safe limits. Apart from the frequent electrolyte imbalance, the fluid intake varied strongly between individuals.

Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes.

Iatrogenic hypoglycaemia is a well-known complication of insulin therapy in patients with diabetes mellitus and a limiting factor for glycaemic control. In a setting of endogenous insulin deficiency (type 1 and advanced type 2 diabetes), one episode of hypoglycaemia reduces both counterregulatory hormone responses to and subjective awareness of subsequent hypoglycaemia, thus impairing physiological defences against hypoglycaemia. This phenomenon may lead to a vicious cycle of recurrent hypoglycaemia and glucose counterregulatory failure, of which hypoglycaemia unawareness (i.e. the inability to perceive symptoms of hypoglycaemia) is the clinical representative. The underlying mechanism of hypoglycaemia-induced counterregulatory failure has not yet been disclosed. Patients with clinical hypoglycaemia unawareness are at high risk of severe hypoglycaemia that requires third-party assistance. Management options include avoidance of hypoglycaemic events and optimisation of insulin therapy to limit deterioration of glycaemic control associated with hypoglycaemia avoidance. Several counterregulatory-stimulating agents have been found to improve hypoglycaemic awareness in small clinical trials, but none have been tested in sufficiently large randomised studies to justify their use in daily practice. More research is required to elucidate the pathogenesis of counterregulatory failure and to develop adequate treatment strategies.

Acute pancreatitis after a course of clarithromycin.

We present a case of acute pancreatitis after a course of clarithromycin. An 84-year-old woman died of suspected pneumonia and cardiac failure. Autopsy surprisingly revealed acute pancreatitis. Except for the use of clarithromycin no other cause for her acute pancreatitis was obvious. Pancreatitis induced by clarithromycin has been reported twice in the English literature so far. There are, however, a few reports on acute pancreatitis associated with other macrolide antibiotics, such as erythromycin and roxithromycin.

Sulphadoxine/pyrimethamine: an appropriate first-line alternative for the treatment of uncomplicated falciparum malaria in Ghanaian children under 5 years of age.

OBJECTIVE: To assess whether chloroquine (CQ) still is an appropriate first-line drug for the treatment of uncomplicated falciparum malaria in Ghana and whether sulphadoxine/pyrimethamine (SP) could be a good alternative. METHOD: The parasitological, clinical and haematological responses to CQ and SP were studied in children < 5 years of age according to a modified WHO 28-day in vivo protocol. A total of 142 children attending the outpatients department meeting the inclusion criteria were randomly assigned to the CQ (n=72) or SP (n=70) group. RESULTS: In the CQ group, 15 children (20.8%) exhibited early clinical failure (within 3 days) compared with only 1 (1.4%) in the SP group (P < 0.01). The clinical failure rate before day 14 (early treatment failure plus late treatment failure before day 14) also showed a marked advantage in favour of the SP group (1.4 against 29.2%). The median time to clinical failure was 11.5 days in the CQ group and 26 days in the SP group (P < 0.01). Of the 72 children treated with CQ, 9 (12.5%) had RIII resistance and 19 (26.4%) had RII resistance. A total of 36 (50.0%) were sensitive to CQ. From the 70 children treated with SP, none had RIII or RII resistance. There was no difference in haematological response between the two treatment groups. CONCLUSION: Although there is little concordance on when to change treatment policy, the high resistance to CQ in this study supports the change to another first-line drug for children under 5 years of age. SP seems to be a good alternative, although a high RII and RIII resistance against this drug has already been reported in the coastal zones of Ghana.