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Aims/hypothesis: Consumption of excess carbohydrates to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. The objective of this trial was to evaluate the efficacy, safety and feasibility of pen-administered low-dose dasiglucagon for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions., Methods: Twenty-four adults with insulin pump-treated type 1 diabetes (HbA 1c ≤70 mmol/mol [8.5%]) completed a randomised, open-label, two-period crossover study with 2 week periods. During the usual care and dasiglucagon intervention (DASI) periods, participants managed impending and manifested episodes of hypoglycaemia with regular carbohydrate consumption or pen-administered low-dose (80 μg) s.c. dasiglucagon, respectively. Glycaemic control was evaluated using continuous glucose monitoring (Dexcom G6) and event registration of prevention and treatment episodes., Results: Compared with usual care, the mean difference (95% CI) in the DASI period for time in (3.9-10.0 mmol/l) and below (<3.9 mmol/l) range was 2.4 %-points (-0.7, 5.5) and -0.5 %-points (-1.2, 0.2), respectively. In the DASI period, recovery rate (time from hypoglycaemia treatment to euglycaemia) was 44% (11, 87) faster while total daily carbohydrate intake was reduced by 11% (-18, -3). Dasiglucagon use was safe and well tolerated with mild nausea being the most frequent adverse effect. Among the participants, 96% (p<0.0001) were likely to include dasiglucagon in their future routine management of hypoglycaemia., Conclusions/interpretation: Use of low-dose dasiglucagon to prevent and treat non-severe hypoglycaemia during free-living conditions was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction., Trial Registration: ClinicalTrials.gov NCT04764968 FUNDING: The study was an investigator-initiated trial. Zealand Pharma supplied the investigational drug and device and provided financial support for the conduct of the trial., (© 2023. The Author(s).)

Objective: To compare the efficacy of low-dose subcutaneous dasiglucagon with oral glucose for prevention of insulin-induced hypoglycemia in people with type 1 diabetes., Research Design and Methods: Twenty adults with type 1 diabetes using multiple daily injection or insulin pump therapy completed a phase 2, randomized, three-arm crossover study. On each study visit, an individualized subcutaneous insulin bolus was administered aiming for a plasma glucose (PG) concentration of 3.0 mmol/L (54 mg/dL). When a PG concentration of 4.5 mmol/L (81 mg/dL) was reached, 15 g oral glucose (CHO) from dextrose tablets, 80 µg dasiglucagon (D80), or 120 µg dasiglucagon (D120) was administered. PG was measured frequently for the following 180 min., Results: Hypoglycemia (<3.9 mmol/L [70 mg/dL]) occurred in 10 participants after CHO, in 5 after D80, and in 4 after D120 (CHO vs. D80, P = 0.096; CHO vs. D120, P = 0.034). Time spent in hypoglycemia (<3.9 mmol/L [70 mg/dL]) was 14%, 7%, and 6% for CHO, D80, and D120, respectively (P = 0.273). The median time (95% CI) from intervention to first increase in PG of 1.1 mmol/L (20 mg/dL) was 30 (25-50), 15 (15-20), and 15 (15-20) minutes for CHO, D80, and D120, respectively (CHO vs. D80, P = 0.006; CHO vs. D120, P = 0.003). Episodes of nausea were numerically, but not significantly, higher after dasiglucagon administration. No significant differences in visual analog scale-assessed adverse effects were observed between interventions., Conclusions: Low-dose dasiglucagon safely and effectively prevented insulin-induced hypoglycemia with a faster glucose-elevating profile than oral glucose., (© 2022 by the American Diabetes Association.)

Introduction: People with type 1 diabetes are recommended to exercise regularly. However, limited evidence exists on how frequency and duration of exercise affect the risk of hypoglycemia. The study aimed to compare the percentage of time spent in hypoglycemia between two 5-day periods with different frequency and duration of physical activity., Research Design and Methods: In this outpatient randomized crossover study, 26 participants aged 18-65 years with type 1 diabetes for ≥2 years and insulin pump use for ≥1 year were included. After a 7-day observation period, participants completed two 5-day intervention periods separated by a washout period of at least 14 days. One period included five exercise sessions on 5 consecutive days (5S), each consisting of 4 min of resistance training and 30 min of aerobic exercise. Another period included two exercise sessions on 2 days with at least 2 days in between (2S), each consisting of 10 min of resistance training and 75 min of aerobic exercise. During each period, participants performed in total 150 min of aerobic exercise and 20 min of resistance training and wore continuous glucose monitors (Dexcom G6) and accelerometers (ActiGraph wGT3X-BT)., Results: Twenty insulin pump-treated adults (10 women) with type 1 diabetes completed the study. The baseline median (range) age was 48 (24-64) years, glycated hemoglobin 55 (44-66) mmol/mol, diabetes duration 24 (8-57) years, and body mass index 28.4 (22.3-35.8) kg/m 2 . No differences were observed between 5S and 2S in the percentage (mean±SD) of time spent below 3.9 mmol/L (3.5%±2.8% vs 4.5%±4.2%, p=0.28), time spent in 3.9-10.0 mmol/L (65.3%±15.0% vs 68.5%±13.6%, p=0.31), time spent above 10.0 mmol/L (31.2%±16.4% vs 27.3%±14.5%, p=0.15), mean glucose (8.7±1.3 mmol/L vs 8.5±1.2 mmol/L, p=0.33) and glycemic variability (35.8%±5.3% vs 35.8%±6.6%, p=0.97)., Conclusions: Time spent in hypoglycemia was comparable between the two 5-day periods with different duration and frequency of physical activity., Trial Registration Number: NCT04089462., Competing Interests: Competing interests: IIKS has received speaker grants from Roche Diabetes Care and Rubin Medical. SS has served on the continuous glucose monitoring advisory board of Roche Diabetes Care. KN serves as adviser for Medtronic, Abbott and Novo Nordisk A/S, owns shares in Novo Nordisk A/S, has received research grants from Novo Nordisk A/S, Zealand Pharma, Medtronic and Roche Diabetes Care, and has received fees for speaking from Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Novo Nordisk A/S, Zealand Pharma and Dexcom. AGR declares no duality of interest associated with his contribution to this manuscript., (© 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.)

Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Type 1 diabetes is a chronic disease caused by an autoimmune destruction of the insulin-producing cells in the pancreas, leading to a condition with insulin deficiency and elevated blood glucose levels. Individuals with type 1 diabetes are therefore recommended to frequently inject insulin subcutaneously to keep near-normal blood glucose levels, preventing the progression and onset of diabetes-related complications, i.e. kidney failure, blindness, amputation, stroke and heart attack. Unfortunately, the intensified insulin therapy is associated with risk of hypoglycemia- impeding individuals from reaching recommended treatment goals. In this PhD thesis, we hypothesized that low-dose glucagon may complement existing insulin therapy in improving glucose control by treating and preventing mild hypoglycemia.
 The aim was to determine whether low-dose glucagon could treat insulin-induced mild hypoglycemia sufficiently, and to investigate conditions that might impair the efficacy of glucagon. We showed that the glucose response to low-dose glucagon was dose-dependent but was impaired during high blood levels of insulin, after one week of low carbohydrate diet and perhaps 8-9 hours after ethanol intake. These findings are clinically relevant when blood glucose levels are controlled through insulin and glucagon delivery., (Articles published in the Danish Medical Journal are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: Currently, no consensus exists on a model describing endogenous glucose production (EGP) as a function of glucagon concentrations. Reliable simulations to determine the glucagon dose preventing or treating hypoglycemia or to tune a dual-hormone artificial pancreas control algorithm need a validated glucoregulatory model including the effect of glucagon., Methods: Eight type 1 diabetes (T1D) patients each received a subcutaneous (SC) bolus of insulin on four study days to induce mild hypoglycemia followed by a SC bolus of saline or 100, 200, or 300 µg of glucagon. Blood samples were analyzed for concentrations of glucagon, insulin, and glucose. We fitted pharmacokinetic (PK) models to insulin and glucagon data using maximum likelihood and maximum a posteriori estimation methods. Similarly, we fitted a pharmacodynamic (PD) model to glucose data. The PD model included multiplicative effects of insulin and glucagon on EGP. Bias and precision of PD model test fits were assessed by mean predictive error (MPE) and mean absolute predictive error (MAPE)., Results: Assuming constant variables in a subject across nonoutlier visits and using thresholds of ±15% MPE and 20% MAPE, we accepted at least one and at most three PD model test fits in each of the seven subjects. Thus, we successfully validated the PD model by leave-one-out cross-validation in seven out of eight T1D patients., Conclusions: The PD model accurately simulates glucose excursions based on plasma insulin and glucagon concentrations. The reported PK/PD model including equations and fitted parameters allows for in silico experiments that may help improve diabetes treatment involving glucagon for prevention of hypoglycemia.

Objective: This study compared the ability of glucagon to restore plasma glucose (PG) after mild hypoglycemia in patients with type 1 diabetes on an isocaloric high-carbohydrate diet (HCD) versus a low-carbohydrate diet (LCD)., Research Design and Methods: Ten patients with insulin pump-treated type 1 diabetes randomly completed 1 week of the HCD (≥250 g/day) and 1 week of the LCD (≤50 g/day). After each week, mild hypoglycemia was induced by a subcutaneous insulin bolus in the fasting state. When PG reached 3.9 mmol/L, 100 µg glucagon was given subcutaneously, followed by 500 µg glucagon 2 h later., Results: Compared with the HCD, the LCD resulted in lower incremental rises in PG after the first (mean ± SEM: 1.3 ± 0.3 vs. 2.7 ± 0.4 mmol/L, P = 0.002) and second glucagon bolus (4.1 ± 0.2 vs. 5.6 ± 0.5 mmol/L, P = 0.002). No differences were observed between the diets regarding concentrations of insulin, glucagon, and triglycerides., Conclusions: The LCD reduces the treatment effect of glucagon on mild hypoglycemia. Carbohydrate intake should be considered when low-dose glucagon is used to correct hypoglycemia., (© 2017 by the American Diabetes Association.)

Hypoglycemia can lead to seizures, unconsciousness, or death. Insulin pump treatment reduces the frequency of severe hypoglycemia compared with multiple daily injections treatment. The addition of a continuous glucose monitor, so-called sensor-augmented pump (SAP) treatment, has the potential to further limit the duration and severity of hypoglycemia as the system can detect and in some systems act on impending and prevailing low blood glucose levels. In this narrative review we summarize the available knowledge on SAPs with and without automated insulin suspension, in relation to hypoglycemia prevention. We present evidence from randomized trials, observational studies, and meta-analyses including nonpregnant individuals with type 1 diabetes mellitus. We also outline concerns regarding SAPs with and without automated insulin suspension. There is evidence that SAP treatment reduces episodes of moderate and severe hypoglycemia compared with multiple daily injections plus self-monitoring of blood glucose. There is some evidence that SAPs both with and without automated suspension reduces the frequency of severe hypoglycemic events compared with insulin pumps without continuous glucose monitoring.

Abstract: Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin‐dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose–insulin–glucagon model was used to describe seven virtual patients with insulin pump‐treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba‐insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre‐defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125‐μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba‐insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model‐based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin‐dependent glucagon dosing regimen for treatment of insulin‐induced mild hypoglycaemia in patients with type 1 diabetes. [ABSTRACT FROM AUTHOR]

The aim of the present study was to assess the effects of a high carbohydrate diet ( HCD) vs a low carbohydrate diet ( LCD) on glycaemic variables and cardiovascular risk markers in patients with type 1 diabetes. Ten patients (4 women, insulin pump-treated, median ± standard deviation [s.d.] age 48 ± 10 years, glycated haemoglobin [ HbA1c] 53 ± 6 mmol/mol [7.0% ± 0.6%]) followed an isocaloric HCD (≥250 g/d) for 1 week and an isocaloric LCD (≤50 g/d) for 1 week in random order. After each week, we downloaded pump and sensor data and collected fasting blood and urine samples. Diet adherence was high (225 ± 30 vs 47 ± 10 g carbohydrates/d; P < .0001). Mean sensor glucose levels were similar in the two diets (7.3 ± 1.1 vs 7.4 ± 0.6 mmol/L; P = .99). The LCD resulted in more time with glucose values in the range of 3.9 to 10.0 mmol/L (83% ± 9% vs 72% ± 11%; P = .02), less time with values ≤3.9 mmol/L (3.3% ± 2.8% vs 8.0% ± 6.3%; P = .03), and less glucose variability (s.d. 1.9 ± 0.4 vs 2.6 ± 0.4 mmol/L; P = .02) than the HCD. Cardiovascular markers were unaffected, while fasting glucagon, ketone and free fatty acid levels were higher at end of the LCD week than the HCD week. In conclusion, the LCD resulted in more time in euglycaemia, less time in hypoglycaemia and less glucose variability than the HCD, without altering mean glucose levels. [ABSTRACT FROM AUTHOR]