The Development of an Exercise Advisor App for Type 1 Diabetes: Digitization Facilitates More Individualized Guidance.

Maintaining blood glucose levels in the target range during exercise can be onerous for people with type 1 diabetes (T1D). Using evidence-based research and consensus guidelines, we developed an exercise advisor app to reduce some of the burden associated with diabetes management during exercise. The app will guide the user on carbohydrate feeding strategies and insulin management strategies before, during, and after exercise and provide targeted and individualized recommendations. As a basis for the recommendations, the decision trees for the app use various factors including the type of insulin regimen, time of activity, previous insulin boluses, and current glucose level. The app is designed to meet the various needs of people with T1D for different activities to promote safe exercise practices.

Carbohydrate Requirements for Prolonged, Fasted Exercise With and Without Basal Rate Reductions in Adults With Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion.

OBJECTIVE: Exercising while fasted with type 1 diabetes facilitates weight loss; however, the best strategy to maintain glucose stability remains unclear. RESEARCH DESIGN AND METHODS: Fifteen adults on continuous subcutaneous insulin infusion completed three sessions of fasted walking (120 min at 45% VO2max) in a randomized crossover design: 50% basal rate reduction, set 90 min pre-exercise (-90min50%BRR); usual basal rate with carbohydrate intake of 0.3 g/kg/h (CHO-only); and combined 50% basal rate reduction set at exercise onset with carbohydrate intake of 0.3 g/kg/h (Combo). RESULTS: Combo had a smaller change in glucose (5 ± 47 mg/dL) versus CHO-only (-49 ± 61 mg/dL, P = 0.03) or -90min50%BRR (-34 ± 45 mg/dL). The -90min50%BRR strategy produced higher ß-hydroxybutyrate levels (0.4 ± 0.3 vs. 0.1 ± 0.1 mmol/L) and greater fat oxidation (0.51 ± 0.2 vs. 0.39 ± 0.1 g/min) than CHO-only (both P < 0.05). CONCLUSIONS: All strategies examined produced stable glycemia for fasted exercise, but a 50% basal rate reduction, set 90 min pre-exercise, eliminates carbohydrate needs and enhances fat oxidation better than carbohydrate feeding with or without a basal rate reduction set at exercise onset.

Flexible insulin therapy with a hybrid regimen of insulin degludec and continuous subcutaneous insulin infusion with pump suspension before exercise in physically active adults with type 1 diabetes (FIT Untethered): a single-centre, open-label, proof-of-concept, randomised crossover trial.

BACKGROUND: People with type 1 diabetes who use continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) often remove their pump before extended periods of exercise, but this approach might result in reduced glycaemic control and increased risk of hyperglycaemia and ketogenesis. We aimed to assess the efficacy and safety of a hybrid approach, in which basal insulin delivery was divided between CSII and a daily injection of insulin degludec. METHODS: In this single-centre, open-label, proof-of-concept, randomised crossover trial done at the LMC Diabetes & Endocrinology research centre, we recruited physically active and aerobically fit participants aged 18 years or older with type 1 diabetes who were using CSII. Participants were randomly assigned (1:1) by use of a computer-generated sequence to one of two sequences of either usual CSII, involving the continuation of the participant's usual CSII regimen, followed by crossover to hybrid CSII, in which the delivery of the participant's usual daily basal insulin dose was split (50% delivered by CSII and 50% delivered by a once-daily morning injection of 100 U/mL insulin degludec), or the opposite sequence (ie, hybrid CSII followed by crossover to usual CSII). Treatment was not masked to the investigators or participants. For each intervention, participants completed a moderate-intensity and a high-intensity in-clinic exercise session in the first week, followed by four high-intensity and two moderate-intensity home-based exercise sessions in the subsequent 3 weeks. Insulin pumps were suspended or disconnected 60 min before exercise and reconnected immediately after exercise during both treatment regimens. The coprimary outcomes were: (1) time spent in the target control range of 4·0-10·0 mmol/L blood glucose after high-intensity exercise, and (2) time spent in target control range of 4·0-10·0 mmol/L blood glucose after moderate-intensity exercise, measured by continuous glucose monitoring in the 6-h period from the start of the high-intensity and moderate-intensity in-clinic exercise sessions. Outcomes were assessed in a modified intention-to-treat population that included all participants who started both intervention phases and completed all of the in-clinic exercise visits. This trial is registered with ClinicalTrials.gov, NCT03838783, and is complete. FINDINGS: Between May 15, 2018, and March 5, 2019, we assessed 43 patients for eligibility, of whom 31 were randomly assigned to receive the usual CSII regimen (n=14) or hybrid CSII regimen (n=17) in the first phase (before crossover). The analysis population consisted of 24 participants who completed both study phases. Compared with the usual CSII regimen, participants on the hybrid CSII regimen had a significantly longer time in blood glucose range of 4-10 mmol/L during the 6-h period from the start of both moderate-intensity (mean difference 86 min [95% CI 61-147], p=0·005; percentage time in range 64% [SD 35] vs 40% [35]) and high-intensity in-clinic exercise session (60 min [11-109], p=0·01; 66% [32] vs 50% [27]). Participants on the hybrid CSII regimen also showed a higher time in blood glucose range of 4-10 mmol/L during home-based exercise sessions (mean difference 23 min [95% CI -1 to 46], p=0·055), with significantly lower time spent in hyperglycaemia than participants on the usual CSII regimen (mean difference 25 min [2-48], p=0·04). These exploratory outcomes also showed no significant difference in the amount of time spent in hypoglycaemia, nor the number of hypoglycaemic events, between the two interventions. There were three study-related adverse events reported with the usual CSII regimen (two hypotension events and one nausea event) and four with the hybrid CSII regimen (two hypotension events and two nausea events). INTERPRETATION: A hybrid regimen of injected insulin degludec and CSII (with pump removal during exercise) appears to be safe and effective in adults with type 1 diabetes who exercise regularly. This approach could offer improved glycaemic control immediately after exercise and should be further assessed in a larger-scale randomised trial. FUNDING: Novo Nordisk.

Lag Time Remains with Newer Real-Time Continuous Glucose Monitoring Technology During Aerobic Exercise in Adults Living with Type 1 Diabetes.

Background: Real-time continuous glucose monitoring (CGM) devices help detect glycemic excursions associated with exercise, meals, and insulin dosing in patients with type 1 diabetes (T1D). However, the delay between interstitial and blood glucose may result in CGM underestimating the true change in glycemia during activity. The purpose of this study was to examine CGM discrepancies during exercise and the meal postexercise versus self-monitoring of blood glucose (SMBG). Methods: Seventeen adults with T1D using insulin pump therapy and CGM completed 60 min of aerobic exercise on three occasions. A standardized meal was given 30 min postexercise. SMBG was measured during exercise and in recovery using OmniPod® Personal Diabetes Manager (PDM; Insulet, Billerica, MA) with built-in glucose meter (FreeStyle; Abbott Laboratories, Abbott Park, IL), while CGM was measured with Dexcom G4® with 505 algorithm (n = 4) or G5® (n = 13), which were calibrated with subjects' own PDM. Results: SMBG showed a large drop in glycemia during exercise, while CGM showed a lag of 12 ± 11 (mean ± standard deviation) minutes and bias of -7 ± 19 mg/dL/min during activity. Mean absolute relative difference (MARD) for CGM versus SMBG was 13 (6-22)% [median (interquartile range)] during exercise and 8 (5-14)% during mealtime. Clarke error grids showed CGM values were in zones A and B 94%-99% of the time for SMBG. Conclusion: In summary, the drop in CGM lags behind the drop in blood glucose during prolonged aerobic exercise by 12 ± 11 min, and MARD increases to 13 (6-22)% during exercise as well. Therefore, if hypoglycemia is suspected during exercise, individuals should confirm glucose levels with a capillary glucose measurement.

Improved Open-Loop Glucose Control With Basal Insulin Reduction 90 Minutes Before Aerobic Exercise in Patients With Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion.

OBJECTIVE: To reduce exercise-associated hypoglycemia, individuals with type 1 diabetes on continuous subcutaneous insulin infusion typically perform basal rate reductions (BRRs) and/or carbohydrate feeding, although the timing and amount of BRRs necessary to prevent hypoglycemia are unclear. The goal of this study was to determine if BRRs set 90 min pre-exercise better attenuate hypoglycemia versus pump suspension (PS) at exercise onset. RESEARCH DESIGN AND METHODS: Seventeen individuals completed three 60-min treadmill exercise (∼50% of VO2peak) visits in a randomized crossover design. The insulin strategies included 1) PS at exercise onset, 2) 80% BRR set 90 min pre-exercise, and 3) 50% BRR set 90 min pre-exercise. RESULTS: Blood glucose level at exercise onset was higher with 50% BRR (191 ± 49 mg/dL) vs. 80% BRR (164 ± 41 mg/dL; P < 0.001) and PS (164 ± 45 mg/dL; P < 0.001). By exercise end, 80% BRR showed the smallest drop (-31 ± 58 mg/dL) vs. 50% BRR (-47 ± 50 mg/dL; P = 0.04) and PS (-67 ± 41 mg/dL; P < 0.001). With PS, 7 out of 17 participants developed hypoglycemia versus 1 out of 17 in both BRR conditions (P < 0.05). Following a standardized meal postexercise, glucose rose with PS and 50% BRR (both P < 0.05), but failed to rise with 80% BRR (P = 0.16). Based on interstitial glucose, overnight mean percent time in range was 83%, 83%, and 78%, and time in hypoglycemia was 2%, 1%, and 5% with 80% BRR, 50% BRR, and PS, respectively (all P > 0.05). CONCLUSIONS: Overall, a 50-80% BRR set 90 min pre-exercise improves glucose control and decreases hypoglycemia risk during exercise better than PS at exercise onset, while not compromising the postexercise meal glucose control.

HDAC6 Inhibition Promotes Transcription Factor EB Activation and Is Protective in Experimental Kidney Disease.

To contend with the deleterious effects of accumulating misfolded protein aggregates or damaged organelles cells rely on a system of quality control processes, among them the autophagy-lysosome pathway. This pathway is itself controlled by a master regulator transcription factor termed transcription factor EB (TFEB). When TFEB localizes to the cell nucleus it promotes the expression of a number of genes involved in protein clearance. Here, we set out to determine (1) whether TFEB expression is altered in chronic kidney disease (CKD); (2) whether inhibition of the cytosolic deacetylase histone deacetylase 6 (HDAC6) affects TFEB acetylation and nuclear localization; and (3) whether HDAC6 inhibition, in turn, alters the natural history of experimental CKD. TFEB mRNA and protein levels were observed to be diminished in the kidneys of humans with diabetic kidney disease, accompanied by accumulation of the protein aggregate adaptor protein p62 in tubule epithelial cells. In cultured NRK-52E cells, HDAC6 inhibition with the small molecule inhibitor Tubastatin A acetylated TFEB, increasing TFEB localization to the nucleus and attenuating cell death. In a rat model of CKD, Tubastatin A prevented the accumulation of misfolded protein aggregates in tubule epithelial cells, attenuated proteinuria progression, limited tubule cell death and diminished tubulointerstitial collagenous matrix deposition. These findings point to the common occurrence of dysregulated quality control processes in CKD and they suggest that TFEB downregulation may contribute to tubule injury in CKD. They also identify a regulatory relationship between HDAC6 and TFEB. HDAC6 inhibitors and TFEB activators both warrant further investigation as treatments for CKD.