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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 (HbA1c ≤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.
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Diabetes Mellitus Tipo 1 , Hipoglicemia , Adulto , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Estudos Cross-Over , Hipoglicemiantes/efeitos adversos , Automonitorização da Glicemia , Glicemia , Hipoglicemia/tratamento farmacológico , Hipoglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , InsulinaRESUMO
AIMS: Insulin pump self-management is important for glycaemic outcomes. We aimed to investigate associations between self-management factors and HbA1c. METHODS: Adult insulin pump users with type 1 diabetes (n = 770) completed an online questionnaire. The latest HbA1c and demographics were extracted from national registries. Associations between HbA1c and self-management (use of advanced features, timing of infusion set change, timing of meal bolus, data-upload and pump settings adjustments) were investigated using backward selected linear regression models. RESULTS: Of the 699 responders eligible for this study, 60% were women; the median age and diabetes duration were 49 and 25 years, respectively. Significant associations with HbA1c were found for changing infusion set every 0-4 days relative to 5-10 days (-5 mmol/mol (-0.4%), p = 0.003), and for never/rarely missing a bolus (-6 mmol/mol (-0.5%), p < 0.001) relative to often missing a bolus. Timing insulin 10-15 min before meal relative to after meal start was also associated with lower HbA1c (-3 mmol/mol (-0.3%), p = 0.023). Self-adjusting pump settings showed the strongest association with lower HbA1c (-6 mmol/mol (-0.6%), p < 0.001) relative to health care professionals doing all adjustments. CONCLUSION: Self-adjusting insulin pump settings, optimal timing and few omissions of meal boluses, and timely change of infusion set are associated with lower HbA1c.
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Diabetes Mellitus Tipo 1 , Autogestão , Adulto , Humanos , Feminino , Masculino , Insulina/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas , Sistemas de Infusão de Insulina , Glicemia , Hipoglicemiantes/uso terapêuticoRESUMO
AIMS: To profile acute glycaemic dynamics during graded exercise testing (GXT) and explore the influence of glycaemic indicators on the physiological responses to GXT in adults with type 1 diabetes using insulin pump therapy. METHODS: This was a retrospective analysis of pooled data from four clinical trials with identical GXT protocols. Data were obtained from 45 adults with type 1 diabetes using insulin pumps [(30 females); haemoglobin A1c 59.5 ± 0.5 mmol/mol (7.6 ± 1.0%); age 49.7 ± 13.0 years; diabetes duration 31.2 ± 13.5 years; VÌO2peak 29.5 ± 8.0 ml/min/kg]. Integrated cardiopulmonary variables were collected continuously via spiroergometry. Plasma glucose was obtained every 3 min during GXT as well as the point of volitional exhaustion. Data were assessed via general linear modelling techniques with age and gender adjustment. Significance was accepted at p ≤ .05. RESULTS: Despite increasing duration and intensity, plasma glucose concentrations remained similar to rest values (8.8 ± 2.3 mmol/L) throughout exercise (p = .419) with an overall change of +0.3 ± 1.1 mmol/L. Starting glycaemia bore no influence on subsequent GXT responses. Per 1% increment in haemoglobin A1c there was an associated decrease in VÌO2peak of 3.8 ml/min/kg (p < .001) and powerpeak of 0.33 W/kg (p < .001) concomitant with attenuations in indices of peripheral oxygen extraction [(O2 pulse) -1.2 ml/beat, p = .023]. CONCLUSION: In adults with long-standing type 1 diabetes using insulin pump therapy, circulating glucose remains stable during a graded incremental cycle test to volitional exhaustion. Glycaemic indicators are inversely associated with aerobic rate, oxygen economy and mechanical output across the exercise intensity spectrum. An appreciation of these nexuses may help guide appropriate decision making for optimal exercise management strategies.
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Diabetes Mellitus Tipo 1 , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Glicemia/análise , Teste de Esforço , Hemoglobinas Glicadas , Insulina/uso terapêutico , Oxigênio/uso terapêutico , Estudos Retrospectivos , MasculinoRESUMO
AIMS: To present secondary outcome analyses of liraglutide treatment in overweight adults with insulin pump-treated type 1 diabetes (T1D), focusing on changes in body composition and dimensions, and to evaluate changes in food intake to identify potential dietary drivers of liraglutide-associated weight loss. MATERIALS AND METHODS: A 26-week randomized placebo-controlled study was conducted to investigate the efficacy and safety of liraglutide 1.8 mg daily in 44 overweight adults with insulin pump-treated T1D and glucose levels above target, and demonstrated significant glycated haemoglobin (HbA1c)- and body weight-reducing effects. For secondary outcome analysis, dual X-ray absorptiometry scans were completed at Weeks 0 and 26, and questionnaire-based food frequency recordings were obtained at Weeks 0, 13 and 26 to characterize liraglutide-induced changes in body composition and food intake. RESULTS: Total fat and lean body mass decreased in liraglutide-treated participants (fat mass -4.6 kg [95% confidence interval {CI} -5.7; -3.5], P < 0.001; lean mass -2.5 kg [95% CI -3.2;-1.7], P < 0.001), but remained stable in placebo-treated participants (fat mass -0.3 kg [95% CI -1.3;0.8], P = 0.604; lean mass 0.0 kg [95% CI -0.7;0.7]; P = 0.965 [between-group P values <0.001]). Participants reduced their energy intake numerically more in the liraglutide arm (-1.1 MJ [95% CI -2.0;-0.02], P = 0.02) than in the placebo arm (-0.9 MJ [95% CI -2.0;0.1], P = 0.22), but the between-group difference was statistically insignificant (P = 0.42). However, energy derived from added sugars decreased by 27% in the liraglutide arm compared with an increase of 14% in the placebo arm (P = 0.004). CONCLUSIONS: Liraglutide lowered fat and lean body mass compared with placebo. Further, liraglutide reduced intake of added sugars. However, no significant difference in total daily energy intake was detected between liraglutide- and placebo-treated participants.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Insulinas , Adulto , Composição Corporal , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Açúcares/uso terapêutico , Resultado do TratamentoRESUMO
The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.
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Adjuvantes de Vacinas/uso terapêutico , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Infecções por Orthomyxoviridae/prevenção & controle , Desenvolvimento de Vacinas/métodos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Adjuvantes de Vacinas/administração & dosagem , Adjuvantes de Vacinas/química , Adjuvantes de Vacinas/farmacologia , Administração Intranasal , Animais , COVID-19/prevenção & controle , Vacinas contra COVID-19/síntese química , Vacinas contra COVID-19/uso terapêutico , Células Cultivadas , Embrião de Galinha , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/química , Vacinas contra Influenza/farmacologia , Interferon Tipo I/genética , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prevenção Primária/métodos , SARS-CoV-2/imunologiaRESUMO
Education is essential in insulin pump therapy, but literature in the field is limited. We systematically reviewed insulin pump education programmes and their effects in two situations as follows: (1) basic education at the start of insulin pump therapy, providing the study design enabled us to separate the effects of insulin pump therapy itself from the effects of education and (2) re-education of experienced pump users. Population: individuals ≥16 years with type 1 diabetes using insulin pumps with or without continuous glucose monitoring. Systematic searches were run in MEDLINE, Embase, CINAHL and ERIC. Original studies reporting an effect of insulin pump education programmes were included if published in English between January 1999 and May 2019. Of 988 potentially relevant studies, 48 were assessed in full text. Nine studies fulfilled the inclusion criteria, including one randomised controlled trial. Educational approaches and settings were sparsely described in all studies, and the content was usually reported as teaching points. Two studies considered basic education, reporting evaluations of knowledge and application skills, and programme satisfaction. The remaining seven studies referred to re-education. Two studies measured severe hypoglycaemic events before and after a re-education intervention, both reporting a significant event reduction. HbA1c decreased significantly in three of four studies. Two studies reported increased knowledge and improved application skills. In conclusion, this review indicates benefits from basic education and from re-education. The strength of the conclusions is limited by the low number of studies and study designs. High-quality studies are needed comparing different approaches for insulin pump education.
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Diabetes Mellitus Tipo 1 , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Insulina/uso terapêutico , Sistemas de Infusão de InsulinaRESUMO
Identifying determinants of low-dose glucagon efficacy is important to optimise its utilization for prevention and treatment of hypoglycaemia in individuals with type 1 diabetes. The study objective was to investigate whether the preceding glucose decline rate affects glucose response to low-dose glucagon administration. Ten adults with insulin pump-treated type 1 diabetes were included in this randomized, single-blind, two-way crossover study. Using a hyperinsulinaemic clamp technique, plasma glucose levels were reduced with either a rapid or slow decline rate while maintaining fixed insulin levels. When the plasma glucose level reached 3.9 mmoL/L, insulin and glucose infusions were discontinued and 150 µg subcutaneous glucagon was administered, followed by 120 minutes of plasma glucose monitoring. The positive incremental area under the glucose curve after administration of low-dose glucagon did not differ between the rapid-decline and slow-decline visits (mean ± SEM: 220 ± 49 vs. 174 ± 31 mmoL/L x min; P = 0.21). Similarly, no differences in total area under the glucose curve, peak plasma glucose, incremental peak plasma glucose, time-to-peak plasma glucose or end plasma glucose were observed. Thus, preceding glucose decline rate did not significantly affect the glucose response to low-dose glucagon.
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Diabetes Mellitus Tipo 1 , Glucagon , Adulto , Glicemia , Automonitorização da Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Método Duplo-Cego , Glucose , Humanos , Hipoglicemiantes , Insulina , Método Simples-CegoRESUMO
To achieve strict glycaemic control and avoid chronic diabetes complications, individuals with type 1 diabetes (T1D) are recommended to follow an intensive insulin regimen. However, the risk and fear of hypoglycaemia often prevent individuals from achieving the treatment goals. Apart from early insulin suspension in insulin pump users, carbohydrate ingestion is the only option for preventing and treating non-severe hypoglycaemic events. These rescue treatments may give extra calories and cause overweight. As an alternative, the use of low-dose glucagon to counter hypoglycaemia has been proposed as a tool to raise glucose concentrations without adding extra calories. Previously, the commercially available glucagon formulations required reconstitution from powder to a solution before being injected subcutaneously or intramuscularly-making it practical only for treating severe hypoglycaemia. Several companies have developed more stable formulations that do not require the time-consuming reconstitution process before use. As well as treating severe hypoglycaemia, non-severe and impending hypoglycaemia can also be treated with lower doses of glucagon. Once available, low-dose glucagon can be either delivered manually, as an injection, or automatically, by an infusion pump. This review focuses on the role and perspectives of using glucagon to treat and prevent hypoglycaemia in T1D.
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AIM: To investigate the efficacy of adding the glucagon-like peptide-1 receptor agonist liraglutide to continuous subcutaneous insulin infusion (CSII) in overweight or obese persons with type 1 diabetes and non-optimal glycaemic control. MATERIALS AND METHODS: A 26-week, randomized, double-blind, placebo-controlled trial including 44 overweight or obese adults with type 1 diabetes randomized 1:1 to liraglutide 1.8 mg once daily (QD) or placebo added to CSII treatment. The primary endpoint was change in haemoglobin A1c (HbA1c). Secondary endpoints included change in insulin dose, CSII settings, glycaemic variability, body weight and patient-reported outcome measures. Finally, adverse effects including hypoglycaemic events were registered. RESULTS: HbA1c was reduced by 5 mmol/mol (0.5%) from a baseline of 66 mmol/mol (8.2%) in patients treated with liraglutide compared with a non-significant change of +2.3 mmol/mol (0.2%) from a baseline of 66 mmol/mol (8.1%) in patients treated with placebo (between-group difference 7 mmol/mol [0.7%], P < 0.001). Liraglutide reduced total insulin dose by 8 units/day or 16% of total insulin dose (P = 0.008). Mean body weight was reduced by 6.3 kg (P < 0.001) compared with placebo. Concomitantly, time spent in glycaemic target range 4-10 mmol/L (71-180 mg/dL) increased while the risk of hypoglycaemia did not differ between groups at the end of treatment. CONCLUSION: Liraglutide treatment reduced HbA1c, total daily insulin dose and body weight without increasing the risk of hypoglycaemia in CSII-treated patients with type 1 diabetes and insufficient glycaemic control. Liraglutide may be considered a potential add-on therapy to insulin in this subgroup of patients.
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Diabetes Mellitus Tipo 1 , Hiperglicemia , Adulto , Peso Corporal , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Hemoglobinas Glicadas , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Liraglutida/uso terapêutico , Sobrepeso/complicações , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: This study aimed to compare the increase in plasma glucose after a subcutaneous injection of 200 µg glucagon given after 45 min of cycling with resting (study 1) and to investigate the effects of glucagon when injected before compared with after 45 min of cycling (study 2). We hypothesised that: (1) the glucose response to glucagon would be similar after cycling and resting; and (2) giving glucagon before the activity would prevent the exercise-induced fall in blood glucose during exercise and for 2 h afterwards. METHODS: Fourteen insulin-pump-treated individuals with type 1 diabetes completed three visits in a randomised, placebo-controlled, participant-blinded crossover study. They were allocated by sealed envelopes. Baseline values were (mean and range): HbA1c 54 mmol/mol (43-65 mmol/mol) or 7.1% (6.1-8.1%); age 45 years (23-66 years); BMI 26 kg/m2 (21-30 kg/m2); and diabetes duration 26 years (8-51 years). At each visit, participants consumed a standardised breakfast 2 h prior to 45 min of cycling or resting. A subcutaneous injection of 200 µg glucagon was given before or after cycling or after resting. The glucose response to glucagon was compared after cycling vs resting (study 1) and before vs after cycling (study 2). RESULTS: The glucose response to glucagon was higher after cycling compared with after resting (mean ± SD incremental peak: 2.6 ± 1.7 vs 1.8 ± 2.0 mmol/l, p = 0.02). As expected, plasma glucose decreased during cycling (-3.1 ± 2.8 mmol/l) but less so when glucagon was given before cycling (-0.9 ± 2.8 mmol/l, p = 0.002). The number of individuals reaching glucose values ≤3.9 mmol/l was the same on the 3 days. CONCLUSIONS/INTERPRETATION: Moderate cycling for 45 min did not impair the glucose response to glucagon compared with the glucose response after resting. The glucose fall during cycling was diminished by a pre-exercise injection of 200 µg glucagon; however, no significant difference was seen in the number of events of hypoglycaemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT02882737 FUNDING: The study was funded by the Danish Diabetes Academy founded by Novo Nordisk foundation and by an unrestricted grant from Zealand Pharma.
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Glicemia/análise , Diabetes Mellitus Tipo 1/terapia , Exercício Físico , Glucagon/administração & dosagem , Sistemas de Infusão de Insulina , Adulto , Idoso , Estudos Cross-Over , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Cetonas/sangue , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Descanso , Triglicerídeos/sangue , Adulto JovemRESUMO
AIMS: To compare the effects of a low carbohydrate diet (LCD < 100 g carbohydrate/d) and a high carbohydrate diet (HCD > 250 g carbohydrate/d) on glycaemic control and cardiovascular risk factors in adults with type 1 diabetes. MATERIALS AND METHODS: In a randomized crossover study with two 12-week intervention arms separated by a 12-week washout, 14 participants using sensor-augmented insulin pumps were included. Individual meal plans meeting the carbohydrate criteria were made for each study participant. Actual carbohydrate intake was entered into the insulin pumps throughout the study. RESULTS: Ten participants completed the study. Daily carbohydrate intake during the two intervention periods was (mean ± standard deviation) 98 ± 11 g and 246 ± 34 g, respectively. Time spent in the range 3.9-10.0 mmol/L (primary outcome) did not differ between groups (LCD 68.6 ± 8.9% vs. HCD 65.3 ± 6.5%, P = 0.316). However, time spent <3.9 mmol/L was less (1.9 vs. 3.6%, P < 0.001) and glycaemic variability (assessed by coefficient of variation) was lower (32.7 vs. 37.5%, P = 0.013) during LCD. No events of severe hypoglycaemia were reported. Participants lost 2.0 ± 2.1 kg during LCD and gained 2.6 ± 1.8 kg during HCD (P = 0.001). No other cardiovascular risk factors, including fasting levels of lipids and inflammatory markers, were significantly affected. CONCLUSIONS: Compared with an intake of 250 g of carbohydrate per day, restriction of carbohydrate intake to 100 g per day in adults with type 1 diabetes reduced time spent in hypoglycaemia, glycaemic variability and weight with no effect on cardiovascular risk factors.
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Diabetes Mellitus Tipo 1/dietoterapia , Dieta com Restrição de Carboidratos , Adulto , Glicemia/análise , Estudos Cross-Over , Carboidratos da Dieta/administração & dosagem , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Redução de Peso/fisiologiaRESUMO
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.
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Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 1/dietoterapia , Dieta com Restrição de Carboidratos , Adulto , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/dietoterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
PURPOSE: Induction of cell-mediated immune (CMI) responses is crucial for vaccine-mediated protection against difficult vaccine targets, e.g., Chlamydia trachomatis (Ct). Adjuvants are included in subunit vaccines to potentiate immune responses, but many marketed adjuvants stimulate predominantly humoral immune responses. Therefore, there is an unmet medical need for new adjuvants, which potentiate humoral and CMI responses. The purpose was to design an oil-in-water nanoemulsion adjuvant containing a synthetic CMI-inducing mycobacterial monomycoloyl glycerol (MMG) analogue to concomitantly induce humoral and CMI responses. METHODS: The influence of emulsion composition was analyzed using a systematic approach. Three factors were varied: i) saturation of the oil phase, ii) type and saturation of the applied surfactant mixture, and iii) surfactant mixture net charge. RESULTS: The emulsions were colloidally stable with a droplet diameter of 150-250 nm, and the zeta-potential correlated closely with the net charge of the surfactant mixture. Only cationic emulsions containing the unsaturated surfactant mixture induced concomitant humoral and CMI responses upon immunization of mice with a Ct antigen, and the responses were enhanced when squalene was applied as the oil phase. In contrast, emulsions with neutral and net negative zeta-potentials did not induce CMI responses. The saturation degree of the oil phase did not influence the adjuvanticity. CONCLUSION: Cationic, MMG analogue-containing nanoemulsions are potential adjuvants for vaccines against pathogens for which both humoral and CMI responses are needed.
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Adjuvantes Imunológicos/química , Imunidade Celular , Imunidade Humoral , Nanopartículas/química , Óleos/química , Tensoativos/química , Animais , Contagem de Linfócito CD4 , Portadores de Fármacos , Liberação Controlada de Fármacos , Emulsões , Feminino , Humanos , Imunoglobulina G/sangue , Camundongos Endogâmicos C57BL , Monoglicerídeos/química , Mycobacterium/imunologia , Tamanho da Partícula , Propriedades de Superfície , Vacinas de Subunidades AntigênicasRESUMO
Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information Criterion; a bootstrap analysis for practical identifiability; a simulation exercise for predictability. The simplest model fit poorly to the data (R2 = 0.53), had the highest Akaike score, and worst prediction. Goodness of fit improved with increasing model complexity (R2 = 0.85-0.92) but Akaike scores were similar for these models. Complexity increased practical non-identifiability, where small changes in the dataset caused large variation (CV > 10%) in identified parameters in the most complex models. Best prediction was achieved in a relatively simple model. Some model complexity was necessary to achieve good data fit but further complexity introduced practical non-identifiability and worsened prediction capability. The best model used two linear subcutaneous compartments, an interstitial and plasma compartment, and two identified variables for interstitial clearance and subcutaneous transfer rate. This model had optimal performance trade-off with reasonable fit (R2 = 0.85) and parameterisation, and best prediction and practical identifiability (CV < 2%).
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Insulina Aspart/farmacocinética , Modelos Cardiovasculares , Adulto , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Infusões Subcutâneas , Insulina Aspart/administração & dosagem , Insulina Aspart/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Automated insulin delivery (AID) systems offer promise in improving glycemic outcomes for individuals with type 1 diabetes. However, data on those who struggle with suboptimal glycemic levels despite insulin pump and continuous glucose monitoring (CGM) are limited. We conducted a randomized controlled trial to assess the effects of an AID system in this population. METHODS: Participants with hemoglobin A1c (HbA1c) ≥ 58 mmol/mol (7.5%) were allocated 1:1 to 14 weeks of treatment with the MiniMed 780G system (AID) or continuation of usual care (UC). The primary endpoint was change in time in range (TIR: 3·9-10·0 mmol/L) from baseline to week 14. After this trial period, the UC group switched to AID treatment while the AID group continued using the system. Both groups were monitored for a total of 28 weeks. RESULTS: Forty adults (mean ± SD: age 52 ± 11 years, HbA1c 67 ± 7 mmol/mol [8.3% ± 0.6%], diabetes duration 29 ±13 years) were included. After 14 weeks, TIR increased by 18.7% (95% confidence interval [CI] = 14.5, 22.9%) in the AID group and remained unchanged in the UC group (P < .0001). Hemoglobin A1c decreased by 10.0 mmol/mol (95% CI = 7.0, 13.0 mmol/mol) (0.9% [95% CI = 0.6%, 1.2%]) in the AID group but remained unchanged in the UC group (P < .0001). The glycemic benefits of AID treatment were reproduced after the 14-week extension phase. There were no episodes of severe hypoglycemia or diabetic ketoacidosis during the study. CONCLUSIONS: For adults with type 1 diabetes not meeting glycemic targets despite use of insulin pump and CGM, transitioning to an AID system confers considerable glycemic benefits.
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By reducing carbohydrate intake, people with type 1 diabetes may reduce fluctuations in blood glucose, but the evidence in this area is sparse. The aim of this study was to investigate glucose metrics during a one-week low-carbohydrate-high-fat (HF) and a low-carbohydrate-high-protein (HP) diet compared with an isocaloric high-carbohydrate (HC) diet. In a randomized, three-period cross-over study, twelve adults with insulin-pump-treated type 1 diabetes followed an HC (energy provided by carbohydrate: 48%, fat: 33%, protein: 19%), HF (19%, 62%, 19%), and an HP (19%, 57%, 24%) diet for one week. Glucose values were obtained during intervention periods using a Dexcom G6 continuous glucose monitoring system. Participant characteristics were: 33% females, median (range) age 50 (22-70) years, diabetes duration 25 (11-52) years, HbA1c 7.3 (5.5-8.3)% (57 (37-67) mmol/mol), and BMI 27.3 (21.3-35.9) kg/m2. Glycemic variability was lower with HF (30.5 ± 6.2%) and HP (30.0 ± 5.5%) compared with HC (34.5 ± 4.1%) (PHF-HC = 0.009, PHP-HC = 0.003). There was no difference between groups in mean glucose (HF: 8.7 ± 1.1, HP: 8.2 ± 1.0, HC: 8.7 ± 1.0 mmol/L, POverall = 0.08). Time > 10.0 mmol/L was lower with HP (22.3 ± 11.8%) compared with HF (29.4 ± 12.1%) and HC (29.5 ± 13.4%) (PHF-HP = 0.037, PHC-HP = 0.037). In conclusion, a one-week HF and, specifically, an HP diet improved glucose metrics compared with an isocaloric HC diet.
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Diabetes Mellitus Tipo 1 , Glucose , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Estudos Cross-Over , Automonitorização da Glicemia , Glicemia , Dieta com Restrição de GordurasRESUMO
INTRODUCTION: The study aimed to investigate independent and combined associations between insulin delivery method (insulin pump therapy (IPT) vs multiple daily injections (MDI)), glucose monitoring method (intermittently scanned continuous glucose monitoring (isCGM) and real-time continuous glucose monitoring (rtCGM) vs blood glucose metre (BGM)) and diabetes distress (DD) in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We combined data from two Danish questionnaire-based surveys, the Steno Tech Survey (n=1591) and the Type 1 Diabetes Distress Scale (T1-DDS) validation survey (n=4205), in which individuals aged ≥18 years with T1D were invited to participate. The 28-item T1-DDS was used to measure DD and DD scores were categorised as little or no distress (score <2.0), moderate distress (2.0-2.9) and high distress (score ≥3.0). Associations between insulin delivery, glucose monitoring methods and DD were assessed using linear regression. RESULTS: Among 2068 adults with T1D who responded to one of the surveys, the use of IPT was associated with a lower total T1-DDS score (-0.09, 95% CI 0.16 to -0.03) compared with MDI and adjusted for glucose monitoring method. The use of CGM was associated with a higher total T1-DDS score (0.11, 95% CI 0.05 to 0.18) compared with BGM and adjusted for the insulin delivery method. IPT was still associated with a lower T1-DDS score, regardless of being combined with BGM (-0.17, 95% CI -0.28 to -0.06) or CGM (-0.13, 95% CI -0.21 to -0.05), compared with MDI with CGM. No association was found between the type of CGM (isCGM vs rtCGM) and DD among either IPT or MDI users when restricting analysis to individuals using CGM. CONCLUSIONS: Among Danish adults with T1D, the use of IPT was associated with lower levels of DD, while CGM use was associated with higher levels of DD. DD should be addressed when introducing people with T1D to diabetes technology, CGM in particular. TRIAL REGISTRATION NUMBER: NCT04311164 (Results).
Assuntos
Diabetes Mellitus Tipo 1 , Adulto , Humanos , Adolescente , Diabetes Mellitus Tipo 1/terapia , Hipoglicemiantes , Automonitorização da Glicemia , Estudos Transversais , Glicemia/análise , Hemoglobinas Glicadas , Insulina , DinamarcaRESUMO
Design of inhalable mRNA therapeutics is promising because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences the expression of mRNA-encoded protein in the lungs, and (iii) the route of administration (nasal versus pulmonary) affects mRNA delivery in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of protein expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inmore durable protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.
Assuntos
Nanopartículas , Sistema Respiratório , Animais , Camundongos , Lipossomos , RNA Mensageiro , LipídeosRESUMO
Successful oral delivery of liposomes requires formulations designed to withstand harsh gastrointestinal conditions, e.g., by converting to solid-state followed by loading into gastro-resistant delivery devices. The hypothesis was that the use of dextran-trehalose mixtures for spray drying would improve the rehydration kinetics of dried liposomes. The objectives were to determine the protective capacity of trehalose-dextran dehydration precursors and to increase the concentration of liposomes in the dry formulation volume. The study successfully demonstrated that 8.5% dextran combined with 76.5% trehalose protected CAF®04 liposomes during drying, with the liposome content maintained at 15% of the dry powder. Accordingly, the rehydration kinetics were slightly improved in formulations containing up to 8.5% dextran in the dry powder volume. Additionally, a 2.4-fold increase in lipid concentration (3 mM vs 7.245 mM) was achieved for spray dried CAF®04 liposomes. Ultimately, this study demonstrates the significance of trehalose as a primary carrier during spray drying of CAF®04 liposomes and highlights the advantage of incorporating small amounts of dextran to tune rehydration kinetics of spray-dried liposomes.