Type 1 Diabetes (T1D) is a complex autoimmune disorder in which T cells destroy the pancreatic islets, leading to a loss of insulin production and hyperglycemia. The disease incidence has increased globally over the last decades, primarily in individuals with low to moderate genetic risk. There is evidence that environmental factors play a role alongside genetic risk to trigger the disease. An environmental factor that has global influence is adoption of the Western diet, characterized by increased consumption of n-6 fatty acids, including linoleic acid (LA), and decreased consumption of n-3 fatty acids. Increased n-6/n-3 ratios are associated with enhanced susceptibility to autoimmune diseases. We sought to understand how linoleic acid affects the survival and function of T cells from the non-obese diabetic (NOD) mouse, a model for T1D. We found that linoleic acid's presence during in vitro activation of T cells led to an increased expansion of the cells in culture. Additionally, CD4+ and CD8+ T cells activated in linoleic acid's presence produced increased levels of pro-diabetogenic cytokines, including Interleukin-21 (IL-21) and Interferon-gamma (IFN-γ). In contrast, linoleic acid reduced IL-10-producing CD4+ T cells, which are protective in T1D, significantly changing the balance between pro-and anti-inflammatory T cell subsets. Gene expression analysis of T cells exposed to linoleic acid during in vitro activation revealed decreased gene expression of lipid-regulated transcription factors, peroxisome proliferator-activated receptors (PPAR), PPARα and PPARγ. These data suggest a role for these transcription factors and their associated pathways in linoleic acid-mediated T cell functions. Finally, we tested whether the T cell fatty acid response is regulated by the cytokine IL-7, which modulates T cell immunometabolism. However, our data did not reveal a prominent role for IL-7 in regulating the T cell response to linoleic acid. Together, these studies add to evidence that fatty acids present in the microenvironment can directly alter T cell functions and that changes in dietary components may contribute to enhanced T1D susceptibility.

Abstract: Purpose: Effective interventions are needed to help adolescents with T1D develop independent self-management skills to prevent commonly observed deterioration of disease self-management resulting in poor health outcomes. Using a prospective RCT design, we assessed the impact of a nurse-led education program based on motivational interviewing (MI) in youth with Type 1 diabetes (T1D). Design and methods: After parental consent and youth assent, we prospectively randomized 66 adolescents 13-18 years old with T1D to either usual care (every 3 months visit with pediatric endocrinologist) or usual care supplemented by 2 in-person and 4 follow-up phone calls with a nurse educator in a pediatric endocrinology clinic of the University Hospital Farhat Hached, Sousse, Tunisia. We used MI sessions to support youth general and disease specific self-management skills. Outcomes were change, between baseline and 6 months, in TRAQ (a validated measure of youth self-management) scores and HbA1c values. Results: Mean TRAQ scores (based on a 5-point Likert scale) increased by 1.44 points (s.d. = 0.56) in the Intervention Group versus 0.26 points (s.d.= 0.34) in the control group (p < 0.001). The mean HbA1C value decreased in the intervention group by 0.95 units versus a decrease of 0.12 units in the control group (p=0.047). Conclusion: We found that a brief, nurse-led MI-based educational intervention, integrated into specialty pediatric care, resulted in a significant improvement in both self-reported self-management skills and in HbA1c values. Trial registration: Registered in ClinicalTrials.gov Identifier: NCT04798937

Indiana University-Purdue University Indianapolis (IUPUI) / Type 1 diabetes (T1D) is a multifactorial disease involving genetic and environmental factors. One of the factors implicated in disease pathogenesis is early life viral infection. A typical immune response to viral infection includes production of type 1 interferons (IFN), such as IFN-α, which can induce stress in the pancreatic β-cells. Reactive oxygen species (ROS) accumulation occurs after exposure to other inflammatory cytokines, causing oxidative stress that may be linked to T1D pathogenesis. Therefore, we hypothesized that IFN-α may also elicit β-cell ROS accumulation. Our in vivo and in vitro experiments with human islets showed rapid and heterogenous ROS accumulation with IFN-α. Although T1D is characterized by autoimmune destruction of β-cells, some cells survive this persistent attack. We hypothesized that survival/ death of β-cells could be attributed to the ability to effectively mitigate ROS accumulation. One mechanism to mitigate ROS is autophagy, which degrades and recycles cellular components to promote cellular homeostasis. We observed an impairment in autophagy in β-cells of donors with T1D as well as in islets of diabetic non-obese diabetic (NOD) mouse model of autoimmune diabetes. Autophagic flux was also impaired in diabetic NOD mouse islets, further confirming impairment of autophagy. Interestingly, we observed an induction of autophagy after acute treatment with IFN-α both in vitro and in vivo, suggesting compensatory upregulation of autophagy to restore homeostasis. Similarly, we observed an increase in autophagosomes and telolysosomes in β-cells of normoglycemic autoantibody positive organ donors compared to nondiabetic organ donors. Together, these data implicate a defect in the final degradation step of autophagy involving lysosomes. Therefore, we analyzed the activity and expression of lysosomal cysteine protease Cathepsin H (CTSH, a T1D susceptibility locus), and found both to be increased in islets of pre-diabetic NOD mice. Together, these data support compensatory hyperactivation of lysosomal enzymes prior to overt diabetes, potentially to rid the cell of ROS and degradation-resistant oxidized proteins and lipids. We also observed that C57Bl/6J mice lacking a key autophagy enzyme, ATG7, in their β-cells, spontaneously developed hyperglycemia. Collectively, these data highlight the importance of -phagic degradation process in the pathogenesis of T1D. / 2022-12-28

No description available.

Type 1 diabetes mellitus (T1DM), a common, chronic disease, affects the patient as well as the family. It requires daily vigilance in blood sugar monitoring, dietary management and insulin administration. Research has examined the impact of T1DM on family adaptation and relationships. However, few current data describes parents' perceptions of challenges. The purpose of this study was to identify challenges and impact on the family perceived by parents raising children with T1DM. Using a qualitative descriptive design, 21 parents raising children with T1DM participated in audio-recorded focus groups. At the time of the interviews the children ranged in age from 2 to 17 years, with duration of diagnosis ranging from six months to 10 years. Seven major themes were identified, including issues regarding (a) children's behavior and development, (b) physical management of diabetes, (c) parenting challenges, (d) siblings and extended family, (e) friends and community, (f) school, and (g) health care system and diabetes organizations. Within each theme, numerous sub-themes were identified. The identification of challenges and unmet needs of families raising children with T1DM suggests health care and schools systems improve the services and support provided. Mental health issues should be managed. A follow-up plan should be in place at the time of hospital discharge, to include provider initiated contact as well as contact by another parent raising a child with T1DM.

The purpose of this study was to evaluate the effectiveness of a workshop/support group for parents raising children with type 1 diabetes mellitus (T1DM). Diagnosis of a chronic disease in a child generally arouses acute anxiety and stress in parents. Parental stress when raising a child with type 1 diabetes is often centered on worry about their child's health and parents' ability to maintain the care activities needed by these children. Parents are the primary caregivers of children with Type 1 diabetes, and the effect of stress on parents can impact the health of both children and parents. The present study examined parents of children with type 1 diabetes who attended four separate two hour support groups/workshops. The Pediatric Inventory for Parents (Streisand, 2001) measured parenting stress. The parents completed the Pediatric Inventory for Parents, at the beginning of the first workshop and again at the end of all the workshops. Parents also completed an open ended questionnaire at the end of each workshop. Parents responded positively to the workshops. Parents stated that hearing how others worked through difficult situations while raising their child with type 1 diabetes was helpful. In quantitative analyses, parents had lower mean scores, post- vs. pre- test on measures of stress related to emotional functioning, communication, medical care, and role function. Research shows that support groups that involve the entire family are most beneficial (McBroom & Enriquez, 2009). Nurse practitioners should consider sponsoring or becoming involved in workshops for parents raising children with type 1 diabetes.

Type 1 diabetes [T1D] is an autoimmune illness that results in insulin deficiency. Managing this illness during childhood requires maintaining blood glucose within a healthy range and is a constant challenge. This can result in increased stress for children and their caregivers. School attendance is one factor that may result in stress. Studies have highlighted the fact that teachers of students with T1D may receive little education regarding management of the disease and may be required to make accommodations which can result in confusion, miscommunication, and increased psychosocial stress. The goal of this research was to learn about the experiences of teachers of students with T1D, what is expected of them, what resources they have, and factors which they perceive as barriers or facilitators to education for students with T1D. Semi-structured interviews were conducted with two high school teachers in East Tennessee who had experience teaching students with T1D. The results of the interviews showed that teachers receive limited education regarding T1D, that they are expected to make accommodations such as having snacks on hand and allowing extra access to phones, and that there are perceived barriers to education of individuals with T1D due to the possibility of life-threatening events. The teachers reported that school nurses are involved in the care of students with T1D. Limitations of this study include that only two teachers were interviewed, and while the results are important to take into consideration, saturation was not reached. Future research could include more in-depth interviews or surveys with teachers, coaches, and school nurses.

No description available.

Levels of circulating large extracellular vesicles (L-EVs) are increased in individuals with type 1 diabetes mellitus (T1DM) and associated with increased cardiovascular risk. T1DM in pregnancy induces vascular injury leading to adverse maternal and neonatal outcomes. Conversely, exercise has been shown to improve cardiovascular and metabolic health in pregnancy and may represent a non-pharmacological approach to improving pregnancy outcomes. Assessment of vascular health may aid in the identification of individuals at risk of complications and allow for intervention with strategies to improve the maternal vasculature. Unfortunately, there is a paucity of strategies for assessing vascular health in pregnant women. L-EVs are membrane-encapsulated particles released from stressed/injured cells. They are emerging biomarkers of vascular health. The purpose of this thesis was to assess the impact of T1DM and pregnancy on L-EV levels and protein composition, the relationship between L-EVs and pregnancy outcomes and the effect of exercise on L-EV levels. In aim #1, I observed that high levels of L-EVs are predictive of adverse pregnancy outcomes. In aim # 2, I examined the protein composition of circulating L-EVs in hypertensive, diabetic and healthy mice models. Diabetes-enriched proteins were involved in inflammation, SNARE signaling and NAD+ biogenesis. The changes were found in L-EV protein content were consistent with proteins associated with inflammation, cytoskeletal organization, and angiogenesis. Finally, in aim #3, I examined the changes in plasma L-EVs after an acute bout of moderate-intensity aerobic exercise in healthy pregnant and non-pregnant women. I observed that circulating L-EVs significantly decreased after the acute exercise only in non-pregnant individuals. Taken together, my thesis work advances knowledge on L-EVs in T1DM, pregnancy, and hypertension and sets the stage for future work on L-EVs as predictive biomarkers, for molecular profiling, and for monitoring of vascular health interventions in pregnancy.

The objective of this thesis was to examine muscle function and myofiber physiology in skeletal muscles in those with type 1 diabetes (T1D) by investigating the effects of diabetic myopathy on these metrics of muscle health under various conditions: at rest, after exercise and with increasing age. These works recruited adults from surrounding communities with T1D and non-diabetic counterparts (i.e. controls) matched for age, sex, body mass index, and self-reported physical activity levels. We hypothesized that adults with T1D would exhibit decreased muscle function (i.e. lower maximal strength) and altered myofiber physiology in each of these conditions. At rest, we observed that those with T1D exhibited more fast-twitch fibers and fewer satellite cells. After exercise, T1D muscles recovered less strength, showed higher amounts of myofiber damage, and delayed satellite cell proliferation. With increasing age, adults with T1D exhibited exaggerated signs of muscular aging compared to age-matched controls in the form of more abundant hybrid fibers and type 1 fiber grouping. Finally, individuals with T1D exhibited higher baseline expression of myostatin, a negative muscle growth regulator, compared to controls. Overall, our work provides the first evidence in muscle dysfunction from humans with T1D at various ages and after damaging exercise. Our findings provide novel insights on muscle health and its contribution to overall health during this lifelong, debilitating disease. Our work aims to guide future clinical & exercise guidelines with the ultimate purpose of improving the lives of millions of individuals living with T1D. / Thesis / Doctor of Philosophy (PhD) / Type 1 diabetes (T1D) is a disease that affects millions of adults worldwide by harming their ability to manage blood sugar levels. Insulin therapy has allowed for longer and healthier lives but requires constant attention manage blood sugar levels. Over time, the quality of life declines because of complications from T1D. Muscle is able to control blood sugar levels through exercise, but little is known about muscle in those with T1D. Therefore, the purpose of this work was to examine skeletal muscle health in people with T1D who do not have other complications. We found that adults with T1D exhibit signs of aging in their muscles earlier than non-diabetic people. Also, we observed that muscle from young adults with T1D recovered slower from exercise. Finally, we learned that people with T1D have more of a muscle-shrinking protein. This is the first evidence of dysfunctional muscle fibers at rest, after exercise, and with age in adults with T1D. This work aims to improve future guidelines for millions of adults with T1D.