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Effects of Dietary Fat and Protein on Glucoregulatory Hormones in Adolescents and Young Adults With Type 1 Diabetes.
Harray, AJ, Binkowski, S, Keating, BL, Horowitz, M, Standfield, S, Smith, G, Paramalingam, N, Jones, T, King, BR, Smart, CEM, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e205-e213
Abstract
CONTEXT Dietary fat and protein impact postprandial hyperglycemia in people with type 1 diabetes, but the underlying mechanisms are poorly understood. Glucoregulatory hormones are also known to modulate gastric emptying and may contribute to this effect. OBJECTIVE Investigate the effects of fat and protein on glucagon-like peptide (GLP-1), glucagon-dependent insulinotropic polypeptide (GIP) and glucagon secretion. METHODS 2 crossover euglycemic insulin clamp clinical trials at 2 Australian pediatric diabetes centers. Participants were 12-21 years (n = 21) with type 1 diabetes for ≥1 year. Participants consumed a low-protein (LP) or high-protein (HP) meal in Study 1, and low-protein/low-fat (LPLF) or high-protein/high-fat (HPHF) meal in Study 2, all containing 30 g of carbohydrate. An insulin clamp was used to maintain postprandial euglycemia and plasma glucoregulatory hormones were measured every 30 minutes for 5 hours. Data from both cohorts (n = 11, 10) were analyzed separately. The main outcome measure was area under the curve of GLP-1, GIP, and glucagon. RESULTS Meals low in fat and protein had minimal effect on GLP-1, while there was sustained elevation after HP (80.3 ± 16.8 pmol/L) vs LP (56.9 ± 18.6), P = .016, and HPHF (103.0 ± 26.9) vs LPLF (69.5 ± 31.9) meals, P = .002. The prompt rise in GIP after all meals was greater after HP (190.2 ± 35.7 pmol/L) vs LP (152.3 ± 23.3), P = .003, and HPHF (258.6 ± 31.0) vs LPLF (151.7 ± 29.4), P < .001. A rise in glucagon was also seen in response to protein, and HP (292.5 ± 88.1 pg/mL) vs LP (182.8 ± 48.5), P = .010. CONCLUSION The impact of fat and protein on postprandial glucose excursions may be mediated by the differential secretion of glucoregulatory hormones. Further studies to better understand these mechanisms may lead to improved personalized postprandial glucose management.
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Pancreatic β-Cell Function Is Associated with Augmented Counterregulation to In-Exercise Hypoglycemia in Type 1 Diabetes.
McCarthy, O, Pitt, J, Eckstein, ML, Moser, O, Bain, SC, Bracken, RM
Medicine and science in sports and exercise. 2021;(7):1326-1333
Abstract
PURPOSE This study aimed to investigate the influence of residual β-cell function on counterregulatory hormonal responses to hypoglycemia during acute physical exercise in people with type 1 diabetes (T1D). A secondary aim was to explore relationships between biomarkers of pancreatic β-cell function and indices of glycemia following acute exercise including the nocturnal period. METHODS This study involved an exploratory, secondary analysis of data from individuals with T1D who partook in a four-peroid, randomized, cross-over trial involving a bout of evening exercise followed by an overnight stay in a clinical laboratory facility. Participants were split into two groups: (i) a stimulated C-peptide level of ≥30 pmol⋅L-1 (low-level secretors [LLS], n = 6) or (ii) <30 pmol⋅L-1 (microsecretors [MS], n = 10). Pancreatic hormones (C-peptide, proinsulin, and glucagon), catecholamines (epinephrine [EPI] and norepinephrine [NE]), and metabolic biomarkers (blood glucose, blood lactate, and β-hydroxybutyrate) were measured at rest, during exercise with and without a hypoglycemic (blood glucose ≤3.9 mmol⋅L-1) episode, and throughout a 13-h postexercise period. Interstitial glucose monitoring was used to assess indices of glycemic variability. RESULTS During in-exercise hypoglycemia, LLS presented with greater sympathoadrenal (EPI and NE P ≤ 0.05) and ketone (P < 0.01) concentrations. Glucagon remained similar (P = 0.09). Over exercise, LLS experienced larger drops in C-peptide and proinsulin (both P < 0.01) as well as greater increases in EPI (P < 0.01) and β-hydroxybutyrate (P = 0.03). LLS spent less time in the interstitial-derived hypoglycemic range acutely postexercise and had lower glucose variability throughout the nocturnal period. CONCLUSION Higher residual β-cell function was associated with greater sympathoadrenal and ketonic responses to exercise-induced hypoglycemia as well as improved glycemia leading into and throughout the nocturnal hours. Even a minimal amount of residual β-cell function confers a beneficial effect on glycemic outcomes during and after exercise in people with T1D.
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Evening and overnight closed-loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.
Kovatchev, BP, Kollar, L, Anderson, SM, Barnett, C, Breton, MD, Carr, K, Gildersleeve, R, Oliveri, MC, Wakeman, CA, Brown, SA
The Lancet. Digital health. 2020;(2):e64-e73
Abstract
BACKGROUND Automated closed-loop control (CLC), known as the "artificial pancreas" is emerging as a treatment option for Type 1 Diabetes (T1D), generally superior to sensor-augmented insulin pump (SAP) treatment. It is postulated that evening-night (E-N) CLC may account for most of the benefits of 24-7 CLC; however, a direct comparison has not been done. METHODS In this trial (NCT02679287), adults with T1D were randomised 1:1 to two groups, which followed different sequences of four 8-week sessions, resulting in two crossover designs comparing SAP vs E-N CLC and E-N CLC vs 24-7 CLC, respectively. Eligibility: T1D for at least 1 year, using an insulin pump for at least six months, ages 18 years or older. Primary hypothesis: E-N CLC compared to SAP will decrease percent time <70mg/dL (3.9mmol/L) measured by continuous glucose monitoring (CGM) without deterioration in HbA1c. Secondary Hypotheses: 24-7 CLC compared to SAP will increase CGM-measured time in target range (TIR, 70-180mg/dL; 3.9-10mmol/L) and will reduce glucose variability during the day. FINDINGS Ninety-three participants were randomised and 80 were included in the analysis, ages 18-69 years; HbA1c levels 5.4-10.6%; 66% female. Compared to SAP, E-N CLC reduced overall time <70mg/dL from 4.0% to 2.2% () resulting in an absolute difference of 1.8% (95%CI: 1.2-2.4%), p<0.0001. This was accompanied by overall reduction in HbA1c from 7.4% at baseline to 7.1% at the end of study, resulting in an absolute difference of 0.3% (95% CI: 0.1-0.4%), p<0.0001. There were 5 severe hypoglycaemia adverse events attributed to user-directed boluses without malfunction of the investigational device, and no diabetic ketoacidosis events. INTERPRETATION In type 1 diabetes, evening-night closed-loop control was superior to sensor-augmented pump therapy, achieving most of the glycaemic benefits of 24-7 closed-loop.
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Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies.
Peters, AL, McGuire, DK, Danne, T, Kushner, JA, Rodbard, HW, Dhatariya, K, Sawhney, S, Banks, P, Jiang, W, Davies, MJ, et al
Diabetes care. 2020;(11):2713-2720
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Abstract
OBJECTIVE To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.
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Association Between Body Composition and Blood Glucose During Exercise and Recovery in Adolescent and Adult Patients With Type 1 Diabetes.
Tagougui, S, Goulet-Gelinas, L, Taleb, N, Messier, V, Suppere, C, Rabasa-Lhoret, R
Canadian journal of diabetes. 2020;(2):192-195
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Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients With Type 1 and Type 2 Diabetes Mellitus.
Toyoshima, J, Saito, M, Kaibara, A, Isaka, H, Sakatani, T
Clinical therapeutics. 2020;(9):1787-1798.e3
Abstract
PURPOSE To characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM. METHODS The PK (AUC24h of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (Emax) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM. FINDINGS Data from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC24h of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean Emax and AUC24h producing 50% of Emax (EX50) were 45.1 mL/min (95% CI, 37.0-53.2 mL/min) and 2160 ng·h/mL (95% CI, 929-3390 ng·h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model. IMPLICATIONS The PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. ClinicalTrials.gov identifiers: NCT01023945 and NCT02529449.
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High-protein meals require 30% additional insulin to prevent delayed postprandial hyperglycaemia.
Paterson, MA, Smart, CEM, Howley, P, Price, DA, Foskett, DC, King, BR
Diabetic medicine : a journal of the British Diabetic Association. 2020;(7):1185-1191
Abstract
AIM: To determine the amount of additional insulin required for a high-protein meal to prevent postprandial hyperglycaemia in individuals with type 1 diabetes using insulin pump therapy. METHODS In this randomized cross-over study, 26 participants aged 8-40 years, HbA1c < 65 mmol/mol (8.1%), received a 50 g protein, 30 g carbohydrate, low-fat (< 1 g) breakfast drink over five consecutive days at home. A standard insulin dose (100%) was compared with additional doses of 115, 130, 145 and 160% for the protein, in randomized order. Doses were commenced 15-min pre-drink and delivered over 3 h using a combination bolus with 65% of the standard dose given up front. Postprandial glycaemia was assessed by 4 h of continuous glucose monitoring. RESULTS The 100% dosing resulted in postprandial hyperglycaemia. From 120 min, ≥ 130% doses resulted in significantly lower postprandial glycaemic excursions compared with 100% (P < 0.05). A 130% dose produced a mean (sd) glycaemic excursion that was 4.69 (2.42) mmol/l lower than control, returning to baseline by 4 h (P < 0.001). From 120 min, there was a significant increase in the risk of hypoglycaemia compared with control for 145% [odds ratio (OR) 25.4, 95% confidence interval (CI) 5.5-206; P < 0.001) and 160% (OR 103, 95% CI 19.2-993; P < 0.001). Some 81% (n = 21) of participants experienced hypoglycaemia following a 160% dose, whereas 58% (n = 15) experienced hypoglycaemia following a 145% dose. There were no hypoglycaemic events reported with 130%. CONCLUSIONS The addition of 30% more insulin to a standard dose for a high-protein meal, delivered using a combination bolus, improves postprandial glycaemia without increasing the risk of hypoglycaemia.
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A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations.
Reutens, AT, Jandeleit-Dahm, K, Thomas, M, Salim, A, De Livera, AM, Bach, LA, Colman, PG, Davis, TME, Ekinci, EI, Fulcher, G, et al
Contemporary clinical trials. 2020;:105892
Abstract
PURPOSE Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DESIGN This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. PRIMARY OUTCOME MEASURES Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. CONCLUSION This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.
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Lipoatrophy in children, adolescents and adults with insulin pump treatment: Is there a beneficial effect of insulin glulisine?
Kordonouri, O, Biester, T, Weidemann, J, Ott, H, Remus, K, Grothaus, J, Pisarek, N, Hartmann, R, Adolph, K, Lange, K, et al
Pediatric diabetes. 2020;(7):1285-1291
Abstract
AIM: To investigate whether zinc-free insulin is an effective treatment option for lipoatrophy. METHODS Controlled, randomized, open-label parallel study in young people with type 1 diabetes, pump treatment and lipoatrophy at injection sites. Participants underwent dermatological examination and evaluation of affected areas using ultrasound and magnetic resonance imaging (MRI). After randomization, half of themswitched to insulin glulisine (intervention group) for 6 months. The control group continued their treatment with zinc-containing insulin and switched to insulin glulisine 6 months later. Both groups were followed-up until month 12. Primary endpoint was the increase of the relative thickness of the subcutaneous fat layer of the most atrophic site at 6 months as documented by MRI. RESULTS Fourteen participants were included into the study. While relative thickness of subcutaneous fat tissue was comparable between intervention (-60% [-98.8 - -17.6], n = 7) and control group (-50% [-72.7 - -1.0], P = .511; median (range), n = 7)at baseline, it improved in the intervention (-14.3% [-85.7-83.3] vs -31.3% (-66.7-0), P = .031), but not in the control group (P = .125) after 6 months. At 12 months, relative fat thickness (P = .003), number (P = .015) and size of most atrophic sites (P = .001) were improved in the intervention group. Number (P = .018) and size of most atrophic sites (P = .008) were also reduced in the control group between 6 and 12 months. CONCLUSIONS Although the present pilot study is based on a small sample, the data give first hint that the use of the zinc-free insulin glulisine may be beneficial in people with diabetes, pump and lipoatrophy.
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A single-blind, randomised, crossover study to reduce hypoglycaemia risk during postprandial exercise with closed-loop insulin delivery in adults with type 1 diabetes: announced (with or without bolus reduction) vs unannounced exercise strategies.
Tagougui, S, Taleb, N, Legault, L, Suppère, C, Messier, V, Boukabous, I, Shohoudi, A, Ladouceur, M, Rabasa-Lhoret, R
Diabetologia. 2020;(11):2282-2291
Abstract
AIMS/HYPOTHESIS For individuals living with type 1 diabetes, closed-loop insulin delivery improves glycaemic control. Nonetheless, maintenance of glycaemic control during exercise while a prandial insulin bolus remains active is a challenge even to closed-loop systems. We investigated the effect of exercise announcement on the efficacy of a closed-loop system, to reduce hypoglycaemia during postprandial exercise. METHODS A single-blind randomised, crossover open-label trial was carried out to compare three strategies applied to a closed-loop system at mealtime in preparation for exercise taken 90 min after eating at a research testing centre: (1) announced exercise to the closed-loop system (increases target glucose levels) in addition to a 33% reduction in meal bolus (A-RB); (2) announced exercise to the closed-loop system and a full meal bolus (A-FB); (3) unannounced exercise and a full meal bolus (U-FB). Participants performed 60 min of exercise at 60% [Formula: see text] 90 min after eating breakfast. The investigators were not blinded to the interventions. However, the participants were blinded to the sensor glucose readings and to the insulin infusion rates throughout the intervention visits. RESULTS The trial was completed by 37 adults with type 1 diabetes, all using insulin pumps: mean±SD, 40.0 ± 15.0 years of age, HbA1c 57.1 ± 10.8 mmol/mol (7.3 ± 1.0%). Reported results were based on plasma glucose values. During exercise and the following 1 h recovery period, time spent in hypoglycaemia (<3.9 mmol/l; primary outcome) was reduced with A-RB (mean ± SD; 2.0 ± 6.2%) and A-FB (7.0 ± 12.6%) vs U-FB (13.0 ± 19.0%; p < 0.0001 and p = 0.005, respectively). During exercise, A-RB had the least drop in plasma glucose levels: A-RB -0.3 ± 2.8 mmol/l, A-FB -2.6 ± 2.9 mmol/l vs U-FB -2.4 ± 2.7 mmol/l (p < 0.0001 and p = 0.5, respectively). Comparison of A-RB vs U-FB revealed a decrease in the time spent in target (3.9-10 mmol/l) by 12.7% (p = 0.05) and an increase in the time spent in hyperglycaemia (>10 mmol/l) by 21% (p = 0.001). No side effects were reported during the applied strategies. CONCLUSIONS/INTERPRETATION Combining postprandial exercise announcement, which increases closed-loop system glucose target levels, with a 33% meal bolus reduction significantly reduced time spent in hypoglycaemia compared with the other two strategies, yet at the expense of more time spent in hyperglycaemia. TRIAL REGISTRATION ClinicalTrials.gov NCT0285530 FUNDING JDRF (2-SRA-2016-210-A-N), the Canadian Institutes of Health Research (354024) and the Fondation J.-A. DeSève chair held by RR-L.