Glucagon augments the secretion of FGF21 and GDF15 in MASLD by indirect mechanisms.

INTRODUCTION: Glucagon receptor agonism is currently explored for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The metabolic effects of glucagon receptor agonism may in part be mediated by increases in circulating levels of Fibroblast Growth Factor 21 (FGF21) and Growth Differentiation Factor 15 (GDF15). The effect of glucagon agonism on FGF21 and GDF15 levels remains uncertain, especially in the context of elevated insulin levels commonly observed in metabolic diseases. METHODS: We investigated the effect of a single bolus of glucagon and a continuous infusion of glucagon on plasma concentrations of FGF21 and GDF15 in conditions of endogenous low or high insulin levels. The studies included individuals with overweight with and without MASLD, healthy controls (CON) and individuals with type 1 diabetes (T1D). The direct effect of glucagon on FGF21 and GDF15 was evaluated using our in-house developed isolated perfused mouse liver model. RESULTS: FGF21 and GDF15 correlated with plasma levels of insulin, but not glucagon, and their secretion were highly increased in MASLD compared with CON and T1D. Furthermore, FGF21 levels in individuals with overweight with or without MASLD did not increase after glucagon stimulation when insulin levels were kept constant. FGF21 and GDF15 levels were unaffected by direct stimulation with glucagon in the isolated perfused mouse liver. CONCLUSION: The glucagon-induced secretion of FGF21 and GDF15 are augmented in MASLD and may depend on insulin. Thus, glucagon receptor agonism may augment its metabolic benefits in patients with MASLD through enhanced secretion of FGF21 and GDF15.

Automated Insulin Delivery in Adults With Type 1 Diabetes and Suboptimal HbA1c During Prior Use of Insulin Pump and Continuous Glucose Monitoring: A Randomized Controlled Trial.

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.

Diabetes Technology Meeting 2023.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.

Associations between use of diabetes technology and diabetes distress: a Danish cross-sectional survey of adults with type 1 diabetes.

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).

Lipid nanoparticles for local delivery of mRNA to the respiratory tract: Effect of PEG-lipid content and administration route.

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.

The interplay between trehalose and dextran as spray drying precursors for cationic liposomes.

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.

Sensor-Based Glucose Metrics during Different Diet Compositions in Type 1 Diabetes-A Randomized One-Week Crossover Trial.

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.

Effects of a Low-Carbohydrate-High-Protein Pre-Exercise Meal in Type 1 Diabetes-a Randomized Crossover Trial.

CONTEXT: Current guidelines for exercise-related glucose management focus on reducing bolus and/or basal insulin doses and considering carbohydrate intake. Yet far less attention has been paid to the potential role of other macronutrients alongside carbohydrates on glucose dynamics around exercise. OBJECTIVE: To investigate the effects of a low-carbohydrate-high-protein (LCHP) compared with a high-carbohydrate-low-protein (HCLP) pre-exercise meal on the metabolic, hormonal, and physiological responses to exercise in adults with insulin pump-treated type 1 diabetes. METHODS: Fourteen adults (11 women, 3 men) with insulin pump-treated type 1 diabetes (median [range] HbA1c of 50 [43-59] mmol/mol (6.7% [6.1%-7.5%]), age of 49 [25-65] years, and body mass index of 24.0 [19.3-27.1] kg/m2) completed an unblinded, 2-arm, randomized, crossover study. Participants ingested isocaloric meals that were either LCHP (carbohydrate 21%, protein 52%, fat 27%) or HCLP (carbohydrate 52%, protein 21%, fat 27%) 90 minutes prior to undertaking 45 minutes of cycling at moderate intensity. Meal insulin bolus was dosed according to meal carbohydrate content but reduced by 25%. Basal insulin rates were reduced by 35% from meal ingestion to end of exercise. RESULTS: Around exercise the coefficient of variability was lower during LCHP (LCHP: 14.5 ± 5.3 vs HCLP: 24.9 ± 7.7%, P = .001). Over exercise, LCHP was associated with a lesser drop (LCHP: Δ-1.49 ± 1.89 vs HCLP: Δ-3.78 ± 1.95 mmol/L, P = .001). Mean insulin concentration was 30% lower during exercise for LCHP compared with HCLP (LCHP: 25.5 ± 11.0 vs HCLP: 36.5 ± 15.9 mU/L, P < .001). CONCLUSION: Ingesting a LCHP pre-exercise meal lowered plasma glucose variability around exercise and diminished the drop in plasma glucose over exercise.

Associations between clinical and psychosocial factors and HbA1c in adult insulin pump users with type 1 diabetes.

AIMS: Many adults with type 1 diabetes do not achieve recommended glycemic goals despite intensive insulin therapy using insulin pumps. The aim of this study was to explore associations between clinical and psychosocial factors and HbA1c in insulin pump users to identify and prioritize areas for potential intervention. METHODS: A questionnaire-based survey covering clinical and psychosocial aspects of life with type 1 diabetes was distributed to all adult (≥ 18 years) insulin pump users in the Capital Region of Denmark. Responses were combined with data from medical records and national registries. Associations with HbA1c were modeled using regression-based machine learning. RESULTS: Of 1,591 invited individuals, 770 (48.4%) responded to the survey. Mean HbA1c among responders was 7.3% (56 mmol/mmol), and 35.6% had an HbA1c < 7.0% (53 mmol/mol). Six factors were significantly associated with HbA1c: diabetes duration (0.006% (0.1 mmol/mol) lower HbA1c per 1-year increase in diabetes duration); education (0.4% (4.3 mmol/mol) lower HbA1c with long higher education vs. primary school); insulin type (0.2% (2.2 mmol/mol) lower HbA1c with ultra-rapid-acting insulin vs. rapid-acting insulin); hypoglycemia awareness status (0.2% (2.2 mmol/mol) lower HbA1c with complete unawareness vs. full awareness); insulin device satisfaction (0.2% (2.7 mmol/mol) lower HbA1c per 1-point increase in Insulin Device Satisfaction Survey score); and diabetes distress (0.3% (3.1 mmol/mol) higher HbA1c per 1-point increase in Type 1 Diabetes Distress Scale score). CONCLUSIONS: This study identified several associations between clinical and psychosocial factors and HbA1c that may be considered when developing interventions targeted people with type 1 diabetes.

Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg.

OBJECTIVE: The aim of this study was to examine how improvement in BMI with the glucagon-like peptide-1 receptor agonist semaglutide translated to changes in BMI category in a post hoc analysis of the double-blind, phase 3a randomized controlled Semaglutide Treatment Effect in People with obesity (STEP) TEENS trial. METHODS: Adolescents with obesity received once-weekly subcutaneous semaglutide 2.4 mg or placebo plus lifestyle intervention, which comprised counseling in healthy nutrition and a goal of 60 minutes of moderate- to high-intensity physical activity per day. Achievement of an improvement in BMI category and attainment of normal-weight or overweight BMI by week 68 were analyzed using logistic regression models. RESULTS: In the overall population, 44.9% of participants receiving semaglutide achieved weight reduction resulting in reclassification to a normal-weight or overweight BMI category versus 12.1% receiving placebo at week 68 (odds ratio: 22.7; 95% CI: 7.6-67.9). The proportion of semaglutide-treated participants in obesity class III decreased from 37.3% to 13.6% but increased with placebo. The odds ratio for achieving an improvement of at least one BMI category was significantly greater with semaglutide versus placebo (23.5; 95% CI: 9.9-55.5); an improvement of at least one BMI category was seen in 73.7% of participants receiving semaglutide compared with 19.0% of participants receiving placebo. CONCLUSIONS: Semaglutide was highly effective in reducing BMI category. While on treatment, most trial participants' BMI improved by at least one category, and >40% reached a category below the obesity threshold.

Automated Insulin Delivery Around Exercise in Adults with Type 1 Diabetes: A Pilot Randomized Controlled Study.

Aim: To assess the effectiveness of an automated insulin delivery (AID) system around exercise in adults with type 1 diabetes (T1D). Methods: This was a three-period, randomized, crossover trial involving 10 adults with T1D (hemoglobin A1C; HbA1c: 8.3% ± 0.6% [67 ± 6 mmol/mol]) using an AID system (MiniMed 780G; Medtronic USA). Participants performed 45 min of moderate intensity continuous exercise 90 min after consuming a carbohydrate-based meal using three strategies: (1) a 100% dose of bolus insulin with exercise announcement immediately at exercise onset "spontaneous exercise" (SE) or a 25% reduced dose of bolus insulin with exercise announcement either (2) 90 min (AE90) or (3) 45 min (AE45) before exercise. Venous-derived plasma glucose (PG) taken in 5 and 15 min intervals over a 3 h collection period was stratified into the percentage of time spent below (TBR [<3.9 mmol/L]), time in range (TIR [3.9-10 mmol/L]), and time above range (TAR [ > 10 mmol/L]). In instances of hypoglycemia, PG data were carried forward for the remainder of the visit. Results: Overall, TBR was greatest during SE (SE: 22.9 ± 22.2, AE90: 1.1 ± 1.9, AE45: 7.8% ± 10.3%, P = 0.029). Hypoglycemia during exercise occurred in four participants in SE but one in both AE90 and AE45 (ꭓ2 [2] = 3.600, P = 0.165). In the 1 h postexercise period, AE90 was associated with higher TIR (SE: 43.8 ± 49.6, AE90: 97.9 ± 5.9, AE45: 66.7% ± 34.5%, P = 0.033), lower TBR (SE: 56.3 ± 49.6, AE90: 2.1 ± 5.9, AE45: 29.2% ± 36.5%, P = 0.041) with the greatest source of discrepancy observed relative to SE. Conclusion: In adults using an AID system and undertaking postprandial exercise, a strategy involving both bolus insulin dose reduction and exercise announcement 90 min before commencing the activity may be most effective in minimizing dysglycemia. The study was registered as a clinical trial (Clinical Trials Register; NCT05134025).

Pen-administered low-dose dasiglucagon vs usual care for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions: a Phase II, randomised, open-label, two-period crossover trial.

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.

Associations between insulin pump self-management and HbA1c in type 1 diabetes.

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.

Glycemia Around Exercise in Adults with Type 1 Diabetes Using Automated and Nonautomated Insulin Delivery Pumps: A Switch Pilot Trial.

In an in-patient switch study, 10 adults with type 1 diabetes (T1D) performed 45 min of moderate-intensity exercise on 2 occasions: (1) when using their usual insulin pump (UP) and (2) after transitioning to automated insulin delivery (AID) treatment (MiniMed™ 780G). Consensus glucose management guidelines for performing exercise were applied. Plasma glucose concentrations measured over a 3-h monitoring period were stratified into time below range (TBR, <3.9 mmol/L), time in range (TIR, 3.9-10.0 mmol/L), and time above range (TAR, >10.0 mmol/L). Overall, TBR (UP: 11 ± 21 vs. AID: 3% ± 10%, P = 0.413), TIR (UP: 53 ± 27 vs. AID: 66% ± 39%, P = 0.320), and TAR (UP: 37 ± 34 vs. AID: 31% ± 41%, P = 0.604) were similar between arms. A proportionately low number of people experienced exercise-induced hypoglycemia (UP: n = 2 vs. AID: n = 1, P = 1.00). In conclusion, switching to AID therapy did not alter patterns of glycemia around sustained moderate-intensity exercise in adults with T1D. Clinical Trial Registration number: NCT05133765.

Development of a glucagon sensitivity test in humans: Pilot data and the GLUSENTIC study protocol.

A physiological feedback system exists between hepatocytes and the alpha cells, termed the liver-alpha cell axis and refers to the relationship between amino acid-stimulated glucagon secretion and glucagon-stimulated amino acid catabolism. Several reports indicate that non-alcoholic fatty liver disease (NAFLD) disrupts the liver-alpha cell axis, because of impaired glucagon receptor signaling (glucagon resistance). However, no experimental test exists to assess glucagon resistance in humans. The objective was to develop an experimental test to determine glucagon sensitivity with respect to amino acid and glucose metabolism in humans. The proposed glucagon sensitivity test (comprising two elements: 1) i.v. injection of 0.2 mg glucagon and 2) infusion of mixed amino acids 331 mg/hour/kg) is based on nine pilot studies which are presented. Calculation of a proposed glucagon sensitivity index with respect to amino acid catabolism is also described. Secondly, we describe a complete study protocol (GLUSENTIC) according to which the glucagon sensitivity test will be applied in a cross-sectional study currently taking place. 65 participants including 20 individuals with a BMI 18.6-25 kg/m2, 30 individuals with a BMI ≥ 25-40 kg/m2, and 15 individuals with type 1 diabetes with a BMI between 18.6 and 40 kg/m2 will be included. Participants will be grouped according to their degree of hepatic steatosis measured by whole-liver magnetic resonance imaging (MRI). The primary outcome measure will be differences in the glucagon sensitivity index between individuals with and without hepatic steatosis. Developing a glucagon sensitivity test and index may provide insight into the physiological and pathophysiological mechanism of glucagon action and glucagon-based therapies.

Effects of initiating insulin pump therapy in the real world: A nationwide, register-based study of adults with type 1 diabetes.

AIMS: We aimed to estimate effects of insulin pump therapy (IPT) on HbA1c level, HbA1c variability, and risk of hospitalised diabetic ketoacidosis (DKA) and severe hypoglycaemia (SH), compared with multiple daily insulin injections (MDI). METHODS: We identified a cohort of all adults with type 1 diabetes in Denmark using national registry data and assigned each individual to either IPT (treatment) or MDI (control) from 2010 to 2020. We estimated average treatment effects on the treated (ATT) and treatment effects among population subgroups using treatment-staggered difference-in-differences. RESULTS: The cohort consisted of 26,687 individuals with a collective 243,601 person-years of observation; 38,823 (16 %) were IPT person-years. We identified an ATT for HbA1c of -0.33 % (95 % CI -0.39 to -0.27; -3.6 mmol/mol [95 % CI -4.2 to -2.9]). ATTs were larger among women and individuals who were older, had highest baseline HbA1c, and used continuous glucose monitoring. ATT for HbA1c variability (-0.016 % [-0.028 to -0.0041); -0.17 mmol/mol [95 % CI -0.30 to -0.045]) corresponded to a 6.5 % decrease in the standard deviation of HbA1c. ATTs for DKA and SH corresponded to 0.52 additional and 0.11 fewer hospitalisations per 1,000 person-years, respectively. CONCLUSIONS: IPT significantly reduced HbA1c level and variability, compared with MDI. However, it also marginally increased the risk of hospitalised DKA.

Metabolic and physiological responses to graded exercise testing in individuals with type 1 diabetes using insulin pump therapy.

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; V̇O2peak 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 V̇O2peak 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.

Challenges for perioperative glycaemic control in patients with diabetes.

In surgical patients, diabetes is associated with increased length of hospital stay and complications. Optimal glycaemic control is important to reduce complications, and enhanced recovery after surgery/fast-track protocols reduce the impact of surgery on glucose homeostasis. Guidelines for perioperative diabetes management are complex and not always supported by highest-grade evidence; this also includes guidelines for use of newer peroral antidiabetic drugs. Technology for automated insulin delivery based on continuous glucose monitoring is available and could potentially simplify and improve perioperative diabetic management, as argued in this review.

The endocrine pancreas during exercise in people with and without type 1 diabetes: Beyond the beta-cell.

Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic ß-cell mediated insulin release opposed by increments in α-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic ß-cells resulting in pronounced aberrations in glucose control. Yet beyond the beta-cell perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise.