Major cardiovascular events and death in parents of children with type 1 diabetes: a register-based matched cohort study in Sweden.

AIMS/HYPOTHESIS: Parenting a child with type 1 diabetes has been associated with stress-related symptoms. This study aimed to elucidate the potential impact on parental risk of major cardiovascular events (MCE) and death. METHODS: In this register-based study, we included the parents of 18,871 children, born 1987-2020 and diagnosed with type 1 diabetes in Sweden at <18 years. The median parental age at the child's diagnosis was 39.0 and 41.0 years for mothers and fathers, respectively. The cohort also encompassed 714,970 population-based matched parental control participants and 12,497 parental siblings. Cox proportional hazard regression models were employed to investigate the associations between having a child with type 1 diabetes and incident MCE and all-cause death, and, as secondary outcomes, acute coronary syndrome and ischaemic heart disease (IHD). We adjusted for potential confounders including parental type 1 diabetes and country of birth. RESULTS: During follow-up (median 12 years, range 0-35), we detected no associations between parenting a child with type 1 diabetes and MCE in mothers (adjusted HR [aHR] 1.02; 95% CI 0.90, 1.15) or in fathers (aHR 1.01; 95% CI 0.94, 1.08). We noted an increased hazard of IHD in exposed mothers (aHR 1.21; 95% CI 1.05, 1.41) with no corresponding signal in fathers (aHR 0.97; 95% CI 0.89, 1.05). Parental sibling analysis did not confirm the association in exposed mothers (aHR 1.01; 95% CI 0.73, 1.41). We further observed a slightly increased hazard of all-cause death in exposed fathers (aHR 1.09; 95% CI 1.01, 1.18), with a similar but non-significant estimate noted in exposed mothers (aHR 1.07; 95% CI 0.96, 1.20). The estimates from the sibling analyses of all-cause death in fathers and mothers were 1.12 (95% CI 0.90, 1.38) and 0.73 (95% CI 0.55, 0.96), respectively. CONCLUSIONS/INTERPRETATION: Having a child diagnosed with type 1 diabetes in Sweden was not associated with MCE, but possibly with all-cause mortality. Further studies are needed to disentangle potential underlying mechanisms, and to investigate parental health outcomes across the full lifespan.

Predictive biomarkers of rapidly developing insulin deficiency in children with type 1 diabetes.

INTRODUCTION: The rate of progression to complete insulin deficiency varies greatly in type 1 diabetes. This constitutes a challenge, especially when randomizing patients in intervention trials aiming to preserve beta cell function. This study aimed to identify biomarkers predictive of either a rapid or slow disease progression in children with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: A retrospective, longitudinal cohort study of children (<18 years) with type 1 diabetes (N=46) was included at diagnosis and followed until complete insulinopenia (C-peptide <0.03 nmol/L). Children were grouped into rapid progressors (n=20, loss within 30 months) and slow progressors (n=26). A sex-matched control group of healthy children (N=45) of similar age was included for comparison. Multiple biomarkers were assessed by proximity extension assay (PEA) at baseline and follow-up. RESULTS: At baseline, rapid progressors had lower C-peptide and higher autoantibody levels than slow. Three biomarkers were higher in the rapid group: carbonic anhydrase 9, corticosteroid 11-beta-dehydrogenase isozyme 1, and tumor necrosis factor receptor superfamily member 21. In a linear mixed model, 25 proteins changed over time, irrespective of group. One protein, a coxsackievirus B-adenovirus receptor (CAR) increased over time in rapid progressors. Eighty-one proteins differed between type 1 diabetes and healthy controls. Principal component analysis could not distinguish between rapid, slow, and healthy controls. CONCLUSIONS: Despite differences in individual proteins, the combination of multiple biomarkers analyzed by PEA could not distinguish the rate of progression in children with new-onset type 1 diabetes. Only one marker was altered significantly when considering both time and group effects, namely CAR, which increased significantly over time in the rapid group. Nevertheless, we did find some markers that may be useful in predicting the decline of the C-peptide. Moreover, these could potentially be important for understanding type 1 diabetes pathogenesis.

Higher risk of severe hypoglycemia in children and adolescents with a rapid loss of C-peptide during the first 6 years after type 1 diabetes diagnosis.

INTRODUCTION: The progression to insulin deficiency in type 1 diabetes is heterogenous. This study aimed to identify early characteristics associated with rapid or slow decline of beta-cell function and how it affects the clinical course. RESEARCH DESIGN AND METHODS: Stimulated C-peptide was assessed by mixed meal tolerance test in 50 children (<18 years) during 2004-2017, at regular intervals for 6 years from type 1 diabetes diagnosis. 40% of the children had a rapid decline of stimulated C-peptide defined as no measurable C-peptide (<0.03 nmol/L) 30 months after diagnosis. RESULTS: At diagnosis, higher frequencies of detectable glutamic acid decarboxylase antibodies (GADA) and IA-2A (p=0.027) were associated with rapid loss of beta-cell function. C-peptide was predicted positively by age at 18 months (p=0.017) and 30 months duration (p=0.038). BMI SD scores (BMISDS) at diagnosis predicted higher C-peptide at diagnosis (p=0.006), 3 months (p=0.002), 9 months (p=0.005), 30 months (p=0.022), 3 years (p=0.009), 4 years (p=0.016) and 6 years (p=0.026), whereas high HbA1c and blood glucose at diagnosis predicted a lower C-peptide at diagnosis (p=<0.001) for both comparisons. Both GADA and IA-2A were negative predictors of C-peptide at 9 months (p=0.011), 18 months (p=0.008) and 30 months (p<0.001). Ten children had 22 events of severe hypoglycemia, and they had lower mean C-peptide at 18 months (p=0.025), 30 months (p=0.008) and 6 years (p=0.018) compared with others. Seven of them had a rapid decline of C-peptide (p=0.030), and the odds to experience a severe hypoglycemia were nearly fivefold increased (OR=4.846, p=0.04). CONCLUSIONS: Low age and presence of multiple autoantibodies at diagnosis predicts a rapid loss of beta-cell function in children with type 1 diabetes. Low C-peptide is associated with an increased risk of severe hypoglycemia and higher Hemoglobin A1C. A high BMISDS at diagnosis is predictive of remaining beta-cell function during the 6 years of follow-up.

Good glycemic control without exceeding the BMI trajectory during the first 5 years of treatment in children and adolescents with type 1 diabetes.

OBJECTIVE: To study BMI changes and glycemic control in children and adolescents during the first 5 years following diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: The 295 children and adolescents (<18 years) diagnosed with type 1 diabetes started on multiple injection treatment and were followed during the first 5 years of treatment with respect to glycemic control and weight change. Growth curves preceding the onset of diabetes were obtained from the school health services and child care centers. BMI was recalculated into BMI SD scores (BMISDS). RESULTS: Prior to the onset of diabetes, the BMISDS was 0.46 ± 1.24 (mean ± SD), which decreased to -0.61 ± 1.36 (p < 0.001) at presentation. At 1 year, BMISDS was 0.59 ± 0.99 (p > 0.05) and increased to 0.80 ± 1.03 at 5 years; 0.97 ± 0.93 in females versus 0.68 ± 1.08 in males (p < 0.001). BMISDS at 1 year and 5 years were directly proportional to and highly predicted by BMISDS prior to the onset of type 1 diabetes, (r = 0.76; p < 0.001) vs. (r = 0.58; p < 0.001). HbA1c at 1 year was 50 ± 10 mmol/mol, which increased to 58 ± 12 mmol/mol (p < 0.001) at 5 years; females had HbA1c 60 ± 14 mmol/mol versus males 56 ± 11 mmol/mol (r = 0.35, p < 0.001). There was a correlation, irrespective of gender, between HbA1c and BMISDS at 1 year (r = 0.18, p < 0.003), but not at 5 years (r = 0.036, (p > 0.5). CONCLUSION: During the first 5 years of treatment of type 1 diabetes in children and adolescents it is possible to achieve good glycemic control without excess weight gain.

Better HbA1c during the first years after diagnosis of type 1 diabetes is associated with residual C peptide 10 years later.

OBJECTIVE: To identify the factors associated with residual C peptide production at least 10 years after diagnosis in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: 73 children and adolescents (<25 years), born in 1988-2005, diagnosed with type 1 diabetes were included during the 4-year study period (2013-2016). At least 10 years after diagnosis, we measured any remaining C peptide concentration using an ultrasensitive C peptide ELISA (≥1.17 pmol/L). The average hemoglobin A1c (HbA1c) was calculated during each of the 10 years after diagnosis and further grand average was calculated for the entire study period. RESULTS: C peptide was detectable in 38% of participants. The C peptide concentration was 4.3±5.3 pmol/L. At onset of type 1 diabetes, participants were on average approximately 5 years of age, and their average HbA1c was 9.4% (79 mmol/mol). During the first 3 years after diagnosis, HbA1c was lower in the group with detectable C peptide at follow-up ≥10 years later. Moreover, detectable C peptide was more common among female participants. Body mass index SD scores had not increased since the 1-year follow-up, but were higher in patients with measurable C peptide. Nine participants (12%) had been diagnosed with celiac disease and two (3%) with hypothyreosis. Eighteen (25%) participants had retinopathy. CONCLUSIONS: Children and adolescents with detectable C peptide after more than 10 years of diabetes duration were predominantly female and had better HbA1c than others during the first 3 years after diagnosis.

Recovery of premorbid BMI trajectory without overshoot during the first year of treatment of children with type 1 diabetes.

OBJECTIVE: To study body mass index (BMI) changes and metabolic control in children and adolescents during the first year following the diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: 200 children and adolescents (<18 years) diagnosed with type 1 diabetes, started on multiple injection treatment and followed up for 1 year were studied with respect to metabolic control and weight change. Growth curves preceding the onset of diabetes were procured from the school health services. BMI was recalculated into BMI SD scores (BMISDS). RESULTS: Glycated hemoglobin (HbA1c) at 1 year was 6.7±1.3% (50±10 mmol/mol). HbA1c was positively correlated with daily insulin dose (R(2)=0.13; p<0.001), negatively correlated with age (R(2)=0.03; p<0.05) but not related to gender, BMISDS at 1 year, HbA1c at presentation, or ketoacidosis at presentation. Prior to the onset of diabetes, BMISDS was 0.41±1.20 and decreased to -0.63±1.25 at presentation. BMISDS at 1 year was 0.54±0.97 and not different from the premorbid value (p>0.05). In a multiple regression analysis, BMISDS at 1 year was directly proportional to and highly predicted by BMISDS prior to onset of diabetes (R(2)=0.57; p<0.001). BMISDS at 1 year was also inversely correlated with age (R(2)=0.03; p<0.001) but could not be predicted by gender, daily insulin dose, HbA1c at 1 year, HbA1c at presentation, or by ketoacidosis at presentation. CONCLUSIONS: During the first year of treatment of type 1 diabetes in children and adolescents, it is possible to achieve good metabolic control without excess weight gain.