No description available.

Many adolescents with type 1 diabetes (T1DM) have suboptimal glycaemic control, increasing the risk of diabetic complications. This thesis explores some of the causes, consequences and therapeutic options for adolescents with T1DM and poor glycaemic control. Insulin resistance occurs in T1DM and normal puberty and contributes to poor glycaemic control. The effect of rosiglitazone, an insulin sensitizer, in addition to insulin on the glycaemic control of adolescents with T1DM was tested using a randomized, double blind placebo controlled trial. Treatment with rosiglitazone did not improve HbA1c, however there was a significant reduction in insulin dose and adiponectin, suggesting improved in insulin sensitivity. Insulin sensitivity by euglycaemic hyperinsulinaemic clamp varied widely between individuals and there was no consistent pattern with rosiglitazone. Potential markers of insulin resistance in T1DM were examined. Total and high molecular weight (HMW) adiponectin levels were lower in children and adolescents with T1DM than controls. HMW adiponectin was significantly associated with other markers of insulin resistance, such as insulin dose, body mass index standard deviation score (BMI-SDS), age, pubertal stage and duration of diabetes. There is increasing evidence that insulin resistance may play a role in T1DM complications. The natural history and risk factors for the development of microalbuminuria was described using a retrospective cohort study of 972 children and adolescents. Most cases of microalbuminuria were transient. Apart from baseline albumin excretion rate, HbA1c and age at diagnosis, other predictors of subsequently developing persistent microalbuminuria included several markers of insulin resistance (higher cholesterol, BMI-SDS, and insulin dose). In addition to insulin resistance, there are many other factors that contribute to glycaemic control. The role of the variability in carbohydrate intake was assessed using questionnaires and food diaries. Although carbohydrate consumption varied by approximately 45grams each day, it had no significant correlation with HbA1c. The impact of socioeconomic status, quality of life and health care delivery is discussed by comparing glycaemic control of children with T1DM in three diabetes centres. A model for the factors associated with poor glycaemic control in adolescents with T1DM is proposed, and the challenges of research and clinical practice in this population are discussed.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Includes bibliographical references.

Type 1 Diabetes (T1D) is an autoimmune disease affecting around 0.1-0.8% of the population worldwide and is characterized by a progressive destruction of insulin-producing beta cells. Pro-inflammatory cytokines released by immune cells around the islets contribute for the “first wave” of beta cell apoptosis. Cytokine-mediated activation of the transcription factor nuclear factor kappa (NF-κB) contributes to beta cell demise in T1D. This is unusual, since NF-κB has anti-apoptotic effects in other cells. NF-κB is activated in most cells via the canonical pathway, while its activation via the non-canonical NF-κB pathway is restricted to few cell types, such as maturing/differentiating immune cell and osteoclasts. We have now observed that IL-1β+IFN-γ induces an atypical activation of the non-canonical NF-κB pathway in beta cells. This activation depends on different crosstalk mechanisms between the canonical and non-canonical NF-κB pathways, including the down-regulation of the E3 ligase Fbw7, which targets the p100 for proteasomal degradation, and up-regulation of another E3 ligase, βTrCP, which in turn induces cleavage of p100 to p52, a hallmark step in the non-canonical NF-κB activation. Importantly, cytokine-mediated activation of the non-canonical pathway regulates the expression of late NF-κB dependent genes, such as Ccl5, Ccl19, Ccl12, Fas that regulate both pro-inflammatory and pro-apoptotic responses and are implicated in beta cell loss in T1D. This atypical activation of the non-canonical NF-κB pathway by pro-inflammatory cytokines in beta cells constitutes a novel “feed-forward” mechanism that may explain the particular pro-apoptotic effect of this transcription factor in beta cells. Besides regulation of pro-death responses, NF-κB activation in beta cells triggers the expression of the ubiquitin-editing protein A20, encoded by TNFAIP3. A20 restricts NF-κB signalling and possess anti-apoptotic activities in beta cells. Importantly, genome-wide association studies have identified TNFAIP3 as a candidate gene for T1D. We presently demonstrated that A20 effects in beta cells are not restricted to inhibition of NF-κB. Thus, A20 also suppresses the pro-apoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), and activates the survival signaling mediated via the v-akt murine thymoma viral oncogene homolog (Akt), thus inhibiting the intrinsic pathway of apoptosis. Finally, a cohort study of T1D children indicated that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predict lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating that this candidate gene contributes for reduced residual beta-cell function and impaired glycemic control in early T1D. In conclusion, our results indicate a critical role for A20 in the regulation of beta cell survival and unveil novel mechanisms by which A20 controls beta-cell fate. Moreover, we identified the single nucleotide polymorphism rs2327832 of TNFAIP3 as a prognostic marker for diabetes outcome in children with T1D.We have also observed that A20 protects beta cells against the pro-apoptotic effects of cytokines by preventing the degradation of the anti-apoptotic protein Mcl-1. Mcl-1 belongs to the Bcl-2 family of proteins that regulate the intrinsic apoptotic pathway. It was previously shown that Mcl-1 depletion contributes to apoptosis in rat beta cells and that its expression is downregulated in islets from T1D individuals infected by enteroviruses. We have now confirmed in human beta cells that decreased Mcl-1 expression contributes to cytokine-mediated beta cell death. We generated a beta cell specific Mcl-1 knockout mouse line (βMcl-1 KO) and observed that islets derived from these mice were more susceptible to pro-apoptotic stimuli exposure ex vivo. Of note, βMcl-1 KO mice were more vulnerable to multiple low dose streptozotocin-induced diabetes than their wild type littermates. One of the mechanisms by which cytokines mediate Mcl-1 degradation is via its phosphorylation by GSK3β. Overexpression of A20 increased AKT phosphorylation, providing a negative feedback on GSK3β activity and preventing Mcl-1 degradation. Cytokines also increase Mcl-1 ubiquitination, a process regulated by the E3 ligases Mule and βTrCP and the deubiquitinase USP9X. The present findings indicate that pro-inflammatory cytokines trigger post-translational modifications of Mcl-1 leading to its degradation. This contributes to exacerbation of pro-death responses and beta cell demise in T1D, but it can be prevented, at least in part, by A20. As a whole, our data unveil novel post-translational mechanisms and different ubiquitin editing proteins that regulate beta cell fate in T1D and are modulated by pro-inflammatory cytokines. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

This study examined how children and adolescents with type 1 diabetes mellitus' (T1DM) glucose levels during and prior to academic performance impact the outcome on a variety of reading, writing, and mathematics tasks. The study sample was selected from a larger study. Participants wore a continuous glucose monitor for approximately six days and complete a neurobehavioral evaluation that consisted of a variety of tasks including tasks that assessed basic reading skills, reading fluency, reading comprehension, math fact fluency, math calculation, math problem solving, spelling, and writing fluency. Results indicated that individuals who experience extreme glucose levels (e.g. hyperglycemia or hypoglycemia) perform worse on spelling accuracy tasks. Additionally, when an individual is hyperglycemic his or her reading and writing fluency skills decrease. Moreover, poor glucose control prior to academic performance increased individual's risk for exhibiting impaired performance on reading and mathematics tasks. Overall, the study results suggest that one's glucose levels prior to and during academic performance potentially impact overall execution of reading, writing, and mathematics abilities. Therefore, these findings support the need to move beyond consideration of only overall glucose levels and review temporal influence of glucose levels on academic performance to track fluctuations on academic performance and determine necessary accommodations to buffer glycemic dysregulation effects. In particular, individuals whose glucose levels are frequently within the hyperglycemic range are at greatest risk for performing below their optimal level.

Background and Objective: Type 1 diabetes mellitus (T1DM) is one of the most common pediatric chronic illnesses. Youth with T1DM have been shown to be at risk for internalizing problems and obtaining insufficient sleep. An emerging body of literature has demonstrated the feasibility and potential benefit of increasing sleep duration as a strategy to improve psychological outcomes in nondiabetic school age populations. The current study seeks to investigate the relationship between sleep and internalizing symptoms and empirically examine the effect of a sleep extension intervention on internalizing symptoms in youth with T1DM. Methods: The sample consisted of 106 youth with T1DM (mean age = 13.5 ± 2.1 years) who were part of a larger study recruited over a three-year period. Participants were 52.8% male and 50.9% identified as non-white. The primary outcome measure was the Behavior Assessment System for Children, Second Edition (BASC-2), both parent and self-report. Other behavioral and sleep measures included actigraphy, sleep diary, the School Sleep Habits Survey (SSHS), Pediatric Symptoms Checklist (PSC), and the Child Sleep Habits Questionnaire (CSHQ). Participants were randomly assigned to either the Sleep Extension condition (n = 50), in which they were asked to extend their sleep duration, or the Fixed Sleep Duration condition (n = 56), in which they were asked to maintain the same amount of sleep as their baseline. Results: Average sleep durations varied across measures, with all values falling in the lower range or below national recommendations. More than a third (34.5%) of the sample had elevated scores for internalizing problems based on parent report, and 17.7% were elevated based on self-report. Pearson correlations indicated that parent reported sleep duration was negatively related to self-reported anxiety, r(106) = -0.237, p = 0.018, as well as parent-reported depression, r(106) = -0.218, p = 0.028, and emotional self-control, r(106) = -0.232, p = 0.018. No other measure of sleep duration was significantly correlated with internalizing symptoms. Secondary analyses of measures of sleep quality including sleep efficiency (SE), wake after sleep onset (WASO), and sleepiness, were significantly related to internalizing problems based on both parent and self-report (all p < 0.05), whereas more variability in sleep duration (CV) was related to higher self-reported depression, r(106) = 0.210, p = 0.033. Following the sleep intervention, participants in the Sleep Extension condition increased their average sleep duration by 26.71 minutes based on actigraphy, while participants in the Fixed Sleep duration decreased by 0.14 minutes from pre- to post-intervention. Participants in the Sleep Extension condition had significantly lower scores on the BASC-2 Internalizing Problems Composite than participants in the Fixed Sleep Duration condition following the intervention, after controlling for sex and baseline internalizing symptoms, F(1, 98) = 4.18, p = 0.044. On average, the Internalizing Problems Composite score of participants in the Sleep Extension condition decreased by almost half a standard deviation (4.65 ± 6.41 points), compared to a decrease of 2.31 ± 6.59 points for participants in the Fixed Sleep Duration condition. There were no significant effects for self-report. Conclusions: Youth with T1DM obtained insufficient sleep and experienced high rates of internalizing symptoms. The results also suggest that relations between sleep and internalizing symptoms exist; however, these associations may be more driven by other aspects of sleep rather than actual sleep loss, such as nighttime sleep disturbance, daytime sleepiness, and variability of the sleep schedule. The findings further indicated that a sleep extension intervention was effective in increasing sleep duration, as well as reducing parent-reported internalizing symptoms in a sample of children and adolescents with T1DM. This intervention has the potential to be utilized as a cost effective, and relatively easy to implement method for reducing internalizing symptoms in youth with T1DM.

Type 1 diabetes (T1D) is an autoimmune disorder, targeting the β-cells of the pancreas. Processes occurring in the gut and pancreas are inferred to be involved. The pre-diabetic expression signature in these tissues is largely uncharacterized. HYPOTHESIS: Spontaneous models of T1D, the LEW.1AR1/Ztm-iddm rat (LEW-DP) and BioBreeding diabetes-prone rat (BBdp) exhibit a distinct transcriptional signature prior to T1D onset. Transcriptional profiling was used to elucidate the expression signatures of the LEW-DP gut and BBdp pancreas. The LEW-DP gut displayed decreased expression of markers of anti-inflammatory M2 macrophages. The LEW-DP rats showed an upregulation of markers of pro-inflammatory signaling when fed a diabetes-promoting cereal diet compared with LEW-DP rats fed a protective hydrolyzed casein diet. Prospective pancreatectomy was used to analyze T1D development in the BBdp rat. Significant upregulation of β-cell markers Reg3α, Reg3β, and Trim26 was observed in pre-diabetic rats. Thus, it was shown that environment modifies the transcriptional program and the transcriptional profile is programmed early to affect T1D development.

Magister Chirurgiae Dentium (MChD) / Chronic inflammation of the periodontium is known as periodontal disease. The inflammation can be contained only within gingival connective tissue or can progress, leading to the loss of gingival connective tissue and alveolar bone. Lately, periodontal disease is considered as a co-morbidity of diabetes mellitus (Polak, Sanui et al., 2020). Though studies that have assessed the relationship of periodontal status with the glycemic control in type 1 diabetes mellitus adolescents, such studies have not been conducted in South Africa.

Thesis advisor: Judith A. Vessey / Significance of Problem: Emerging adults (ages 18-30) with type 1 diabetes (T1D) are a specific group that experiences worse glycemic control, more frequent severe hypoglycemia and more frequent diabetic ketoacidosis (DKA) than any other age group. The multiple transitions and stressors associated with the developmental stage of emerging adulthood can magnify and exacerbate the diabetes specific emotional burden of living with T1D, resulting in increased diabetes distress (DD). However, there is no measure of DD specific to the developmental stage of emerging adulthood. Purpose: The purpose of this program of research is to explicate the need for a developmental stage-specific measure of DD, as well as to develop, refine and psychometrically validate a new measure of DD in emerging adults. Method: This multi-phase study employed methods grounded in both item response theory (Rasch analysis) and classical test theory to reduce, refine and validate a new measure of DD in emerging adulthood, entitled the Problem Areas in Diabetes-Emerging Adult version (PAID-EA). In phase 1, data were collected from emerging adults with T1D using a cross-sectional online survey strategy. Rasch methodology was used to reduce and refine the PAID-EA. In phase 2, an additional cross-sectional online survey was conducted using the refined PAID-EA. Classical test theory-based approaches were employed to examine the psychometric properties of the refined measure. Finally, the relationships between scores on the PAID-EA and related constructs and clinical variables were explored. Conclusions: Collectively, this work advances the science by providing insight into how the challenges of emerging adulthood impact life with T1D during this developmental stage and providing a new measure to accurately and validly capture this experience for both clinical and research purposes. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

No description available.