Social self-efficacy associated with HbA1c through physical activity and diabetes quality of life: A serial mediation study.

OBJECTIVE: Type 1 diabetes (T1D) is one of the most common pediatric chronic illnesses and increasing worldwide in prevalence. Physical activity has been positively linked with better glycemic control in youth with T1D. Although not yet studied, children's social self-efficacy may be a parameter related to physical activity in youth with diabetes. The current study investigated associations among social self-efficacy, physical activity, diabetes quality of life, and hemoglobin A1c (HbA1c) among youth with T1D utilizing mediation and serial mediation models. RESEARCH DESIGN AND METHODS: Participants were 144 youth (M age = 14.95) with T1D (53.5% girls) and their caregivers. Youth completed the PedsQL Diabetes Module, the Physical Activity Questionnaire for Older Children and Adolescents and the Self-Efficacy Questionnaire for Social Skills for Children. Youths' HbA1c values were also measured. RESULTS: Physical activity significantly mediated the relationship between greater youth social self-efficacy and better diabetes quality of life. Diabetes quality of life mediated the relationship between greater physical activity and lower HbA1c. The serial mediation model demonstrated greater social self-efficacy is related to greater physical activity, which in turn is related to better diabetes quality of life and ultimately resulting in lower HbA1c. CONCLUSIONS: Physical activity, social self-efficacy, and diabetes-related quality of life may be modifiable factors related to HbA1c for youth with T1D. Findings indicate a need for healthcare providers to consider youth physical activity, quality of life, and social self-efficacy when evaluating and intervening in youth diabetes treatment adherence.

Impact of insulin reduction on glycemic control in children attending a residential diabetes camp.

BACKGROUND/OBJECTIVES: Children attending diabetes camp are more active, increasing the risk of hypoglycemia. Decreasing initial insulin doses may reduce this risk. The objectives of our study were to compare glycemic control between campers receiving multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII), and analyze the impact of decreasing basal insulin by 10%. METHODS: We analyzed 849 camp sessions (599 children, 5-19 years old) from Camp Sweeney's 2016/2017 summers. Campers were separated into groups by year and insulin route (MDI_2016, MDI_2017, CSII_2016, and CSII_2017). The MDI_2016 group had initial basal insulin decreased 10%, while CSII_2016, MDI_2017, and CSII_2017 did not. Time spent in blood glucose ranges and area under the curve (AUC) were compared by year and insulin route using ANOVA. We also performed repeated measures ANOVA using campers who attended both years. RESULTS: No significant differences in time spent in any glucose range could be attributed to the initial 10% basal decrease, including on paired analysis. MDI_2017 had more decreases to basal insulin than the other groups. CSII campers had higher AUC and more hyperglycemia than MDI campers. CONCLUSIONS: Campers on MDI may benefit from decreasing basal insulin, either at the beginning of camp or during the first week. Future research is needed to optimize glycemic control in the camp setting.

Diazoxide for the Treatment of Hypoglycemia Resulting From Dumping Syndrome in a Child.

Dumping syndrome-associated hypoglycemia is caused by an exaggerated hyperinsulinemic response to glucose absorption in the small intestine. Diazoxide acts on the ATP-sensitive potassium channels and prevents insulin secretion and, thus, should be beneficial for the treatment of hypoglycemia secondary to dumping syndrome. We report on the efficacy of diazoxide in a pediatric patient with dumping syndrome. A 6-year-old girl born at 32 weeks' gestation age with resultant short gut syndrome and liver failure, who had undergone liver, small bowel, and pancreas transplantation at 1 year of age, developed late dumping-like symptoms with postprandial hypoglycemia, headaches, tremors, and irritability. She experienced relief of symptoms with oral intake. An oral glucose tolerance test showed a fasting and 2-hour blood glucose of 3.9 and 2.8 mmol/L, respectively. A gastric emptying study confirmed the diagnosis of dumping. A diet with 2 g of fiber and cornstarch and antimotility medications failed to improve the dumping symptoms. Diazoxide was started orally at a dose of 3 mg/kg/d and was increased to 5 mg/kg/d, divided every 8 hours, after 1 month, with improvement of postprandial blood glucose values (3.6 to 5.0 mmol/L). No hypertrichosis, fluid retention, respiratory concerns, or other side effects were noted. Several duodenal dilations were performed, with resultant improvement of gastric emptying. She was eventually weaned from diazoxide, and no further episodes of substantial hypoglycemia occurred. In conclusion, diazoxide was efficacious and safe for the treatment of hypoglycemia secondary to dumping syndrome in children. It could be of particular use as a bridging therapy for children awaiting more definitive surgical interventions.

PedsQL 3.2 Diabetes Module for Children, Adolescents, and Young Adults: Reliability and Validity in Type 1 Diabetes.

OBJECTIVE: The objective of the study was to report on the measurement properties of the revised and updated Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for children, adolescents, and young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: The 33-item PedsQL 3.2 Diabetes Module and PedsQL Generic Core Scales were completed in a 10-site national field test study by 656 families of patients ages 2-25 years with type 1 diabetes. RESULTS: The 15-item Diabetes Symptoms Summary Score and 18-item Diabetes Management Summary Score were derived from the factor analysis of the items. The Diabetes Symptoms and Diabetes Management Summary Scores evidenced excellent reliability (patient self-report α = 0.88-0.90; parent proxy report α = 0.89-0.90). The Diabetes Symptoms and Diabetes Management Summary Scores demonstrated construct validity through medium to large effect size correlations with the Generic Core Scales Total Scale Score (r = 0.43-0.67, P < 0.001). HbA1c was significantly correlated with the Diabetes Symptoms and Diabetes Management Summary Scores (r = -0.21 to -0.29, P < 0.001). Minimal clinically important difference scores ranged from 5.05 to 5.55. CONCLUSIONS: The PedsQL 3.2 Diabetes Module Diabetes Symptoms and Diabetes Management Summary Scores demonstrated excellent measurement properties and may be useful as standardized patient-reported outcomes of diabetes symptoms and diabetes management in clinical research, clinical trials, and practice in children, adolescents, and young adults with type 1 diabetes.

Diabetes management mediating effects between diabetes symptoms and health-related quality of life in adolescents and young adults with type 1 diabetes.

OBJECTIVES: The primary objective was to investigate the mediating effects of diabetes management in the relationship between diabetes symptoms and generic health-related quality of life (HRQOL) in adolescents and young adults (AYAs) with type 1 diabetes. The secondary objective explored patient health communication and perceived treatment adherence barriers as mediators in a serial multiple mediator model. METHODS: The PedsQL 3.2 Diabetes Module 15-item diabetes symptoms summary score, 18-item diabetes management summary score, and PedsQL 4.0 generic core scales were completed in a 10-site national field test study by 418 AYA aged 13 to 25 years with type 1 diabetes. Diabetes symptoms and diabetes management were tested for bivariate and multivariate linear associations with overall generic HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of diabetes management as an intervening variable between diabetes symptoms and generic HRQOL. RESULTS: The predictive effects of diabetes symptoms on HRQOL were mediated in part by diabetes management. In predictive analytics models utilizing multiple regression analyses, demographic and clinical covariates, diabetes symptoms, and diabetes management significantly accounted for 53% of the variance in generic HRQOL (P < 0.001), demonstrating a large effect size. Patient health communication and perceived treatment adherence barriers were significant mediators in an exploratory serial multiple mediator model. CONCLUSIONS: Diabetes management explains in part the effects of diabetes symptoms on HRQOL in AYA with type 1 diabetes. Patient health communication to healthcare providers and perceived treatment adherence barriers further explain the mechanism in the relationship between diabetes symptoms and overall HRQOL.

Diabetes symptoms predictors of health-related quality of life in adolescents and young adults with type 1 or type 2 diabetes.

OBJECTIVES: The objective was to investigate the patient-reported diabetes symptoms predictors of generic health-related quality of life (HRQOL) in adolescents and young adults (AYA) with type 1 or type 2 diabetes. METHODS: The 15-item PedsQL™ 3.2 Diabetes Module Diabetes Symptoms Summary Score and PedsQL™ 4.0 Generic Core Scales were completed in a 10-site national field test study by 513 AYA ages 13-25 years with type 1 (n = 424) or type 2 (n = 89) diabetes. Diabetes symptoms were tested for bivariate and multivariate linear associations with generic HRQOL. RESULTS: Diabetes symptoms were associated with decreased HRQOL in bivariate analyses. In predictive analytics models utilizing hierarchical multiple regression analyses controlling for relevant demographic and clinical covariates, diabetes symptoms accounted for 38 and 39% of the variance in patient-reported generic HRQOL for type 1 and type 2 diabetes, respectively, reflecting large effect sizes. The diabetes symptoms facets hyperglycemia symptoms, hypoglycemia symptoms, and nonspecific diabetes symptoms individually accounted for a significant percentage of the variance in separate exploratory predictive analytics models after controlling for demographic and clinical covariates, with small-to-large effect sizes. CONCLUSIONS: Diabetes symptoms are potentially modifiable predictors of generic HRQOL in AYA with diabetes. Identifying specific diabetes symptoms or symptoms facets that are the most important predictors from the patient perspective facilitates a patient-centered approach in clinical research, clinical trials, and practice designed to enhance overall generic HRQOL in AYA with diabetes.

A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus.

BACKGROUND: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1ß (IL-1ß) represent potential therapeutic targets for disease modifying therapy. OBJECTIVE: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. SUBJECTS AND METHODS: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. RESULTS: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged "possibly related" to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P = .01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P = .05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in "remission," defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. CONCLUSIONS: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

Gene expression changes in human islets exposed to type 1 diabetic serum.

A major obstacle to the success of islet cell transplantation as a standard treatment for labile type 1 diabetes mellitus is the immediate loss of up to 70% of the transplanted islet mass. Activation of the complement cascade and coagulation factors has been implicated in initiating the destruction of the islet graft. In this study, we analyzed the gene expression changes in islet cells following exposure to type 1 diabetes mellitus serum (T1DM). Isolated human pancreatic islet cells were cultured for 2 d to stabilize islet cell gene expression. Cultured islets were divided into three groups for treatment as follows: group 1 was treated with autologous donor serum, while groups two and three were treated with sera from ABO-matched allogeneic donors or autoantibody positive type 1 diabetic patient, respectively. Complement was detected using anti-C3 FITC and CH50 assay. Islet gene expression was analyzed using Illumina micro-array technology. Results were confirmed using real-time PCR. Immunofluorescent imaging demonstrated complement deposition only in the T1DM condition. Gene array and class prediction analysis generated a list of 50 genes that were able to predict the effect of T1DM serum on islets. Quantitative PCR corroborated microarray results. Both techniques demonstrated upregulation of MMP9 (243%), IL-1ß (255%), IL-11 (220%), IL-12A (132%), RAD (343%) and a concomitant downregulation of IL-1RN (64%) in islets treated with T1DM serum. Islets treated with T1DM serum overexpressed genes associated with angiogenesis while decreasing transcription of genes that protect islets from inflammatory cytokines and reactive oxygen species.

Toll-like receptors, the NLRP3 inflammasome, and interleukin-1ß in the development and progression of type 1 diabetes.

Traditionally, type 1 diabetes (T1D) has been thought of as a disease of cellular immunity, but there is increasing evidence that components of the innate immune system, controlled largely by Toll-like receptors (TLRs), play a significant role in T1D development. TLRs are pattern-recognition molecules on immune cells that recognize pathogens, leading to the production of cytokines such as interleukin-1ß (IL1ß, encoded by the IL1B gene). IL1ß is increased in patients with newly diagnosed T1D and likely acts as an early inflammatory signal in T1D development. Because hyperglycemia is a hallmark of T1D, the effects of hyperglycemia on IL1ß expression in peripheral blood mononuclear cells (PBMCs) and islet cells have been examined, but with inconsistent results, and the mechanisms leading to this increase remain unknown. Fatty acids stimulate IL1ß expression and may promote inflammation, causing hyperglycemia and insulin resistance. The mechanisms by which IL1ß is involved in T1D pathogenesis are controversial. Overall, studies in pancreatic ß-cells suggest that IL1ß-mediated damage to islet cells involves multiple downstream targets. Potential therapies to decrease the progression of T1D based on IL1ß biology include pioglitazone, glyburide, IL1 receptor antagonists, and agents that remove IL1ß from the circulation.

Preliminary studies related to anti-interleukin-1ß therapy in children with newly diagnosed type 1 diabetes.

BACKGROUND: Interleukin-1ß (IL-1ß) may play a role in the pathogenesis of type 1 diabetes, but there are no data regarding the efficacy of agents antagonizing IL-1ß in patients with this disorder. We characterized the effects of IL-1ß on gene expression in peripheral blood mononuclear cells (PBMC) and the clinical and gene expression effects of a short course of recombinant IL-1 receptor antagonist protein, anakinra, on children with newly diagnosed diabetes. METHODS: PBMC from healthy adult volunteers were exposed to IL-1ß for 24 h in vitro. Gene expression was analyzed via microarray. Fifteen children within 1 wk of diagnosis of type 1 diabetes received daily anakinra for 28 d and were followed for 6 months. Blood was drawn for microarray analysis before and after anakinra treatment. Insulin secretory capacity was assessed by mixed-meal tolerance testing (MMTT) at 3-4 wk and 7 months after diagnosis. Hemoglobin A1c (HbA1c) and insulin doses were periodically recorded. Data were compared with two historical control groups of children with newly diagnosed diabetes. RESULTS: Although in vitro exposure to IL-1ß caused many changes in PBMC gene expression, gene expression did not change significantly after anakinra therapy in diabetes patients. Anakinra-treated patients had similar HbA1c and MMTT responses, but lower insulin requirements 1 and 4 months after diagnosis compared to controls, and lower insulin-dose-adjusted A1c 1 month after diagnosis. CONCLUSIONS: Anakinra therapy is well tolerated in children with newly diagnosed type 1 diabetes. Further studies are needed to demonstrate biological effects.