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Association between family history, early growth and the risk of beta cell autoimmunity in children at risk for type 1 diabetes.
Pacaud, D, Nucci, AM, Cuthbertson, D, Becker, DJ, Virtanen, SM, Ludvigsson, J, Ilonen, J, Knip, M, ,
Diabetologia. 2021;(1):119-128
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AIMS/HYPOTHESIS The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. METHODS In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. RESULTS Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. CONCLUSIONS/INTERPRETATION The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth. TRIAL REGISTRATION ClinicalTrials.gov NCT00179777 Graphical abstract.
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Soluble Klotho Is Decreased in Children With Type 1 Diabetes and Correlated With Metabolic Control.
Zubkiewicz-Kucharska, A, Wikiera, B, Noczyńska, A
Frontiers in endocrinology. 2021;:709564
Abstract
UNLABELLED Klotho concentration may be considered as a prognostic factor in the development of chronic complications of diabetes. Moreover, decrease in sKlotho concentration may contribute to beta cell apoptosis and type 1 diabetes development. The aim of this study was to evaluate if sKlotho protein concentration in children with type 1 diabetes (T1D) and its correlation with classical risk factors of chronic complications of diabetes: dysglycemia and endothelial dysfunction. MATERIAL AND METHODS In a cross-section single center study the levels of soluble Klotho protein in 80 T1D (37 boys) and 34 healthy children (controls, 15 boys). Micro- and macroangiopathy were excluded and renal function was normal in all participants. Serum sKlotho, sICAM-1, sVCAM-1 and E-selectin levels were measured. RESULTS The concentration of sKlotho was lower in T1D than in the controls (2041.9 ± 1017.6 pg/mL vs. 2790.3 ± 1423.9 pg/mL, p=0.0113). sICAM-1, sVCAM-1 and E-selectin concentrations were comparable in patients and controls. In T1D, sKlotho was not correlated with the duration of diabetes. Klotho and E-selectin were correlated with HbA1c (r=-0.31, P=0.0066 and r=0.25, P=0.0351, respectively), but not with AVBG and blood glucose SD. Correlations of sKlotho with total cholesterol (r=0.31, P=0.0129), HDL-cholesterol (r=0.43, P=0.0011) and LDL-cholesterol (r=0.28, P=0.0412), but not with triglycerides, were found. Likewise, Klotho was not correlated with sICAM-1, sVCAM-1, and E-selectin concentrations. CONCLUSIONS This study reports the significantly lower level of s-Klotho in children with type 1 diabetes, correlated with HbA1c and HDL cholesterol, but not with the adhesion molecules concentrations nor the duration of the disease. Negative correlation between the levels of HbA1c and soluble Klotho may suggest its possible involvement in the development of chronic diabetes complications.
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Safety and glycemic outcomes of do-it-yourself AndroidAPS hybrid closed-loop system in adults with type 1 diabetes.
Gawrecki, A, Zozulinska-Ziolkiewicz, D, Michalak, MA, Adamska, A, Michalak, M, Frackowiak, U, Flotynska, J, Pietrzak, M, Czapla, S, Gehr, B, et al
PloS one. 2021;(4):e0248965
Abstract
BACKGROUND The aim of the study was to assess the safety and glycemic outcomes with the use of a Do-It-Yourself (DIY) Hybrid Closed-Loop (HCL) system based on the AndroidAPS application in type 1 diabetes (T1D). METHODS Single-center clinical trial, with 3-week run-in and 12-week study period. DIY HCL system consisted of the Dana Diabecare RS insulin pump, Dexcom G5 continuous glucose monitoring system and AndroidAPS application. Primary outcome was safety: incidences of severe hypoglycemia, diabetic ketoacidosis, time spent in glycemia <54 mg/dl. Secondary endpoints included percentage of time in range (TIR) 70-180 mg/dl, time below 70 mg/dl, HbA1c, insulin requirements, and body weight. RESULTS In total 12 subjects (5 men, 7 women) were enrolled, mean age 31.3±6.7, 95%CI(27.7-34.9) years, mean diabetes duration 16.1±5.7, 95%CI(13.0-19.2) years. No episodes of severe hypoglycemia or ketoacidosis were observed. Percentage of time spent in glycemia below 54mg/dl was not increased. Average sensor glycemia was lower in the study period than baseline (141.1 ± 8.4, 95%CI(136.3-145.9) vs. 153.3 ± 17.9, 95%CI(143.2-163.4), mg/dl p<0.001). TIR 70-180 mg/dl was improved by 11.3%, 95%CI(2.8%-19.8%) (from 68.0 ± 12.7 to 79.3 ± 6.4%, p<0.001), without increasing hypoglycemia time. The HbA1c level decreased by -0.5%, 95%CI(-0.9%--0.1%) (from 6.8 ± 0.5 to 6.3 ± 0.4%, p<0.001). Additionally, in the last 4 weeks of the study period participants significantly improved and showed TIR 70-180 mg/dl 82.1 ± 5.6%, 95%CI(78.9-85.3), time <54 mg/dl 0.30 (0.20-0.55)%, median 95%CI(0.1-0.7) and <70 mg/dl 1.90 (1.10-3.05)%, median 95%CI(0.7-3.2). The insulin requirement and body weight did not change in the study. CONCLUSIONS The study revealed safety of the Do-It-Yourself HCL system AndroidAPS in adults with T1D, limited to well-controlled, highly selected and closely monitored patients. The use of AndroidAPS significantly improved HbA1c, time in range and average sensor glycemia without increasing hypoglycemia. As both patients and their medical team are gaining experience using the system over time, they improve glycemic control. TRIAL REGISTRATION German Clinical Trials Register: no. DRKS00015439; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015439.
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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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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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Long-term (52-week) efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: An uncontrolled, open-label extension of a phase III study.
Kaku, K, Isaka, H, Sakatani, T, Toyoshima, J
Journal of diabetes investigation. 2020;(3):662-671
Abstract
INTRODUCTION The aim of the present study was to assess the long-term (52-week) efficacy and safety of ipragliflozin in insulin-treated Japanese patients with type 1 diabetes mellitus and inadequate glycemic control. MATERIALS AND METHODS In this 28-week, open-label extension of a multicenter, randomized, placebo-controlled, 24-week phase III study, ipragliflozin recipients continued treatment (50 mg, once daily), and placebo recipients were switched to once-daily 50 mg ipragliflozin at the start of the extension period. The ipragliflozin dose could be increased to 100 mg if warranted. The primary end-point was change in glycated hemoglobin; secondary end-points were change in insulin dose and bodyweight. Safety outcomes were monitored as treatment-emergent adverse events. RESULTS A total of 53 (placebo switched to ipragliflozin) and 108 (ipragliflozin) patients completed the open-label extension (treatment period 2), with 24 and 44 patients, respectively, receiving dose increases. From baseline to end of treatment, the overall mean change (standard deviation [SD]) in glycated hemoglobin was -0.33% (0.72; -3.7 mmol/mol [7.9]), with changes in basal, bolus and total insulin doses of -3.76 IU (SD 3.85 IU), -2.51 IU (SD 7.08 IU) and -6.27 IU (SD 8.16 IU), respectively. No serious drug-related treatment-emergent adverse events or deaths were reported. Treatment-emergent adverse events leading to study discontinuation occurred in zero and three (2.6%) patients in the placebo switched to ipragliflozin and ipragliflozin groups, respectively; all were considered drug-related. There were no cases of severe hypoglycemia or diabetic ketoacidosis, and no safety concerns related to dose increase. CONCLUSIONS The efficacy and safety of 50 mg, once-daily ipragliflozin in insulin-treated type 1 diabetes mellitus patients were confirmed in this long-term, open-label extension study. No safety concerns were attributed to a dose increase to 100 mg.
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Collagen methionine sulfoxide and glucuronidine/LW-1 are markers of coronary artery disease in long-term survivors with type 1 diabetes. The Dialong study.
Holte, KB, Svanteson, M, Hanssen, KF, Sveen, KA, Seljeflot, I, Solheim, S, Sell, DR, Monnier, VM, Berg, TJ
PloS one. 2020;(5):e0233174
Abstract
OBJECTIVES Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes. METHODS In this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA. RESULTS In the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27-0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16-3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23-0.28, p<0.05), while pentosidine correlated with soft/mixed plaque volume (r = 0.29, p = 0.008), also in the adjusted analysis. CONCLUSIONS Low levels of collagen-bound methionine sulfoxide were associated with normal coronary arteries while glucuronidine/LW-1 was positively associated with established CHD in long-term type 1 diabetes, suggesting a role for metabolic and oxidative stress in the formation of atherosclerosis in diabetes.
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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.
Kaku, K, Isaka, H, Toyoshima, J, Sakatani, T
Diabetes, obesity & metabolism. 2019;(6):1445-1454
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AIM: To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium-glucose co-transporter-2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS We conducted a multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive 25, 50, or 100 mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration-time curve 24 hours postdose (AUC24h ), maximum plasma concentration (Cmax ), and renal clearance. Key pharmacodynamic endpoints included 24-hour urinary glucose excretion, mean plasma glucose AUC0-24h , and mean renal glucose clearance. Changes in total, basal, and bolus insulin dosages were recorded. Adverse events (AEs) were monitored for safety. RESULTS Dose-dependent increases were observed in AUC24h and Cmax on days 1 and 14 for 25-, 50-, and 100-mg ipragliflozin. The mean plasma glucose AUC0-24h was lower than that of placebo and the mean renal glucose clearance increased in a dose-dependent manner from baseline, but remained unchanged in the placebo group. The mean (standard deviation) change from baseline in total daily insulin dose was greater in the ipragliflozin 25-, 50-, and 100-mg groups (-14.77 ± 14.04%, -18.40 ± 12.49% and -19.25 ± 16.77%, respectively), than placebo (-4.51 ± 16.28%). Most AEs were mild in severity; no patients discontinued the study because of treatment-emergent AEs. CONCLUSIONS The pharmacokinetic and pharmacodynamic properties of ipragliflozin in Japanese patients with type 1 diabetes mellitus were confirmed. Increases in urinary glucose excretion lead to dose-dependent decreases in plasma glucose. Concomitant insulin dose decreased with ipragliflozin treatment. No clinically relevant safety concerns were identified.
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Efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: A randomized, double-blind, phase 3 trial.
Kaku, K, Isaka, H, Sakatani, T, Toyoshima, J
Diabetes, obesity & metabolism. 2019;(10):2284-2293
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AIM: To assess the efficacy and safety of once-daily ipragliflozin 50 mg versus placebo in Japanese people with type 1 diabetes mellitus (T1DM) inadequately controlled with insulin. MATERIALS AND METHODS We conducted a multicentre, double-blind, parallel-group, placebo-controlled phase 3 study. Participants (N = 175) were randomized (2:1) to receive once-daily ipragliflozin 50 mg (n = 115) or placebo (n = 60), combined with insulin, for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c); key secondary endpoints included change in insulin dose and body weight. Treatment-emergent adverse events (TEAEs) were evaluated. RESULTS The ipragliflozin group demonstrated a significant decrease in HbA1c from baseline to end of treatment versus the placebo group: adjusted mean difference (AMD) -3.8 mmol/mol (95% confidence interval [CI] -6.2, -1.5) or - 0.36% (95% CI -0.57, -0.14; P = 0.001). Significant reductions in total daily insulin dose (AMD -7.35 IU [95% CI -9.09, -5.61]; P < 0.001) and body weight (AMD -2.87 kg [95% CI -3.58, -2.16]; P < 0.001) were observed for the ipragliflozin group versus placebo. Two serious TEAEs occurred (major hypoglycaemia and abdominal abscess); both were in the placebo group. All other TEAEs were mild or moderate in severity. Four cases of study discontinuation occurred; three in the placebo group and one in the ipragliflozin group. No diabetic ketoacidosis was reported for any participant in this study. CONCLUSIONS Daily ipragliflozin 50 mg in combination with insulin significantly reduced HbA1c, daily insulin dose and body weight versus placebo in people with T1DM. No safety concerns were identified after 24 weeks of treatment. Overall, once-daily ipragliflozin 50 mg was both efficacious and well tolerated.
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Soluble CD163 correlates with lipid metabolic adaptations in type 1 diabetes patients during ketoacidosis.
Svart, M, Rittig, N, Møller, N, Møller, HJ, Gronbaek, H
Journal of diabetes investigation. 2019;(1):67-72
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INTRODUCTION Diabetic ketoacidosis (DKA) is associated with inflammation and increased lipolysis. The macrophage activation marker, soluble CD163 (sCD163), is associated with obesity, non-alcoholic fatty liver disease and type 2 diabetes. We aimed to investigate whether sCD163 correlates with key elements of lipolysis in type 1 diabetes patients during mild DKA. MATERIALS AND METHODS We investigated nine patients with type 1 diabetes twice during: (i) euglycemic control conditions and a bolus of saline; and (ii) hyperglycemic ketotic conditions induced by lipopolysaccharide administration combined with insulin deprivation. Blood samples, indirect calorimetry, palmitate tracer and adipose tissue biopsies were used to investigate lipid metabolism. RESULTS We observed a significant increase in plasma sCD163 levels after lipopolysaccharide exposure (P < 0.001). Concentrations of sCD163 were positively correlated with plasma concentrations of free fatty acids, palmitate rate of appearance and lipid oxidation rates, and negatively correlated to the expression of G0/G1 switch 2 gene messenger ribonucleic acid content in adipose tissue (P < 0.01 for all). Furthermore, sCD163 levels correlated positively with plasma peak concentrations of cortisol, glucagon, tumor necrosis factor-α, interleukin-6 and interleukin-10 (P < 0.01 for all). Data on lipolysis and inflammation have previously been published. CONCLUSIONS Macrophage activation assessed by sCD163 might play an important role in DKA, as it correlates strongly with important components of lipid metabolism including free fatty acids, palmitate, lipid oxidation, G0/G1 switch 2 gene and pro-inflammatory cytokines during initial steps of DKA. These results are novel and add important knowledge to the field of DKA.
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Dietary intake and eating patterns of young children with type 1 diabetes achieving glycemic targets.
Seckold, R, Howley, P, King, BR, Bell, K, Smith, A, Smart, CE
BMJ open diabetes research & care. 2019;(1):e000663
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INTRODUCTION Young children with type 1 diabetes (T1D) consume more saturated fat and less fruit and vegetables than recommended. A common challenge in this age group is unpredictable appetite potentially impacting the way parents manage diabetes cares at mealtimes. This small study aimed to assess nutritional intake and mealtime routines of young children with T1D in a clinic where the majority of children were achieving glycemic targets. A secondary aim was to explore association of eating pattern with HbA1c. METHODS A retrospective, cross-sectional review of children aged less than 7.0 years with T1D attending a pediatric diabetes service in Australia was performed (n=24). Baseline characteristics, glycated hemoglobin (HbA1c), a 3-day weighed food diary and a mealtime management survey were collected. RESULTS Twenty-two children (55% male) were included aged 4.9±1.3 years (mean±SD), HbA1c 47±10 mmol/mol (6.4%±0.9%), body mass index Z-score 0.8±0.9 and diabetes duration 1.7±1.1 years. Preprandial insulin use was reported in 95% of children. Macronutrient distribution (% energy intake) was carbohydrate (48%±4%), protein (16%±2%) and fat (33%±5%) with saturated fat (15%±3%). The majority of children did not meet vegetable and lean meat/protein intake recommendations (0% and 28%, respectively). HbA1c was not correlated with daily total carbohydrate, protein or fat intake (p>0.05). HbA1c was significantly higher in children offered food in a grazing pattern compared with those offered regular meals (mean 61 mmol/mol vs 43 mmol/mol (7.7% vs 6.1%), p=0.01). CONCLUSIONS Dietary quality is a concern in young children with T1D with excessive saturated fat and inadequate vegetable intake. Our results suggest that young children meeting glycemic targets give insulin before meals and follow a routine eating pattern.