Factors Affecting Quality of Life in Adolescents Living With Type 2 Diabetes: A Substudy of the Improving Renal Complications in Adolescents With Type 2 Diabetes Through REsearch (iCARE) Cohort.

OBJECTIVES: Type 2 diabetes (T2D) disproportionately impacts adolescents living in challenging socioeconomic conditions. However, the impacts of T2D on quality of life (QOL) in this context are unknown. Our aim in this study was to evaluate QOL and identify its biological, psychological, and social determinants among adolescents living with and without T2D from similar sociodemographic backgrounds. Relationships between glycemic stability, early complications, and treatments of T2D and QOL were also examined. METHODS: Ninety-two adolescents with T2D and 59 at-risk controls were included from the Improving Renal Complications in Adolescents With Type 2 Diabetes Through Research (iCARE) cohort. The main outcome was QOL (Pediatric QOL Inventory [PedsQL]). Biological covariates included age, sex, body mass index z score, glycated hemoglobin, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. Psychological factors included perceived stress (14-item Perceived Stress Scale) and mental distress (6-item Kessler scale). Social factors included food security (Household Food Security Survey Module) and income quintile. Multivariate linear regression analyses were used to identify factors associated with QOL between adolescents with and without T2D, and within the T2D cohort. RESULTS: Mean total QOL scores among adolescents with T2D were lower than in controls (67.0±14.8 vs 71.7±16.2, p=0.04). Age, sex, and percent Indigenous ethnicity were not significantly different between groups. Mean duration of T2D was 2.3±2.0 years. In the multivariate analysis, QOL was not associated with diabetes status, but negative associations were seen between mental distress (ß=-1.46, p<0.001) and food insecurity QOL (ß=-6.26, p=0.037). No differences were seen between biological factors and QOL in either analysis. CONCLUSIONS: Significant factors associated with decreased QOL in adolescents living with T2D include mental distress and food insecurity, indicating areas for targeted intervention.

Walking in two worlds with type 2 diabetes: a scoping review of prevention and management practices incorporating traditional indigenous approaches.

Type 2 diabetes is a complex chronic disease rapidly increasing among young people and disproportionately impacting Indigenous youth. Treatment programs are often inadequate for this population as they lack cultural relevance. A scoping review was conducted to explore traditional Indigenous approaches for diabetes prevention and management, to inform a program aimed at supporting Indigenous youth and families with type 2 diabetes. We seek to answer the following question: "Which traditional medicines and practices have been incorporated into intervention or prevention strategies for Indigenous people living with diabetes?" Search was done June 2021 using Ovid Medline, ESBCO and ProQuest databases. Terms included wellbeing, intervention, diabetes, and traditional approaches. Of the 2138 titles screened, 34 met inclusion criteria. Three studies integrated traditional Indigenous approaches into Western-based intervention programming. Content included traditional food and nutrition programs, gardening programs, Elder knowledge sharing, story telling, talking circles, feasting, prayer, traditional dancing, hunting, and school-based wellness curricula. Many were wholistic, co-created with community, Indigenous-led and held in accessible community spaces. The heterogeneity in approaches reflects the diversity of Indigenous nations and communities. This review identifies important elements to include in culturally relevant programs to address diabetes-related wellness.

Impact of COVID-19 Pandemic on Adolescents and Young Adults Living With Type 2 Diabetes.

OBJECTIVES: The aim of this study was to assess the impacts of the COVID-19 pandemic on adolescents and young adults living with type 2 diabetes (T2D) involved in the national Improving Renal Complications in Adolescents with T2D through REsearch (iCARE) study. METHODS: The Environmental influences on Child Health Outcomes (ECHO) COVID-19 Questionnaire developed by the National Institutes of Health ECHO COVID-19 Task Force was administered to participants (n=85) from the iCARE study between June 2020 and October 2020. Children 12 years old (via parent report) and adolescents and young adults ≥13 years old (via self-report) participated. The questionnaire assessed the impact of the pandemic on health-care appointments, lifestyle, internet use, social connections and mental health. RESULTS: Participants were 17.0±3.1 (range, 12 to 27) years of age and predominantly female (61.3%). During the pandemic, 69.4% were able to attend their health-care appointments by telephone or virtual platforms, 31.7% ate more, 45.1% slept more and 29.3% spent less time on physical activities. There was an increase in internet use for both educational (42.0%) and noneducational purposes (54.9%). Participants felt less socially connected (64.6%). Participants also felt sometimes (59.2%), often (19.7%) and very often (6.7%) satisfied with their lives. DISCUSSION: Our study revealed that the COVID-19 pandemic has had various impacts on the daily lives of adolescents and young adults living with T2D. Future research should include longitudinal studies of the health burden of the COVID-19 pandemic on this population, with a more in-depth evaluation of mental health outcomes and clinical outcomes.

Poor Sleep, Increased Stress and Metabolic Comorbidity in Adolescents and Youth With Type 2 Diabetes.

OBJECTIVES: The impacts of stress and disrupted sleep on type 2 diabetes management and related comorbidities in adolescents and youth remain unknown. In this study, we examine sleep in adolescents and youth living with type 2 diabetes and matched controls and its association with stress, glycemic management, albuminuria and hypertension. METHODS: A cross-sectional analysis was conducted to assess the relationship between sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and stress (Perceived Stress Scale-14 [PSS-14] and Kessler Psychological Distress Scale [K6]) with metabolic control within a cohort of male and female adolescents and youth (10 to 23 years old) with type 2 diabetes and weight- and ethnicity-matched controls. RESULTS: One hundred eighty-one adolescents and youth with type 2 diabetes (15.0±2.44 years of age, body mass index z score [BMIz] 1.85±0.60, 62.5% female) and 52 controls (16±2.9 years, BMIz 1.99±0.58, 61.5% female) were included in the investigation. Participants slept for an average of 8.38 hours per night, and 49% of individuals with type 2 diabetes and 46% of controls rated their sleep quality as "poor." No sex differences were seen for sleep scores (p=0.13), but females reported higher stress (p=0.001) and distress (p=0.03). No differences in glycated hemoglobin (p=0.11), BMIz (p=0.28), hypertension (p=0.24) or albuminuria (p=0.79) were seen in individuals reporting good vs poor sleep. Regression analysis showed that poor sleep was associated with higher glycated hemoglobin (p=0.029). CONCLUSIONS: Many adolescents and youth reported poor sleep, which was associated with stress, distress and worse glycemic management. Differences were observed between sexes. The long-term effects of poor sleep and psychological distress warrant further study.

Physical activity and cardiometabolic health in adolescents with type 2 diabetes: a cross-sectional study.

INTRODUCTION: Youth living with type 2 diabetes display increased risk of cardiovascular disease (CVD). It is unclear if regular physical activity (PA) modifies this risk. RESEARCH DESIGN AND METHODS: We compared CVD risk factors in a cross-sectional study of 164 youth with type 2 diabetes stratified according to weekly vigorous-intensity PA. Outcomes were hemoglobin A1c (HbA1c), ambulatory blood pressure (BP; ambulatory 24-hour readings), plasma lipoproteins, and albuminuria. The main exposure, vigorous-intensity PA, was quantified with the Adolescent Physical Activity Recall Questionnaire. RESULTS: Youth were 15±3 years, and 78% lived rurally and 68% were female, with a mean body mass index (BMI) Z-score of 2.4±1.1 and a mean HbA1c of 9.6% ±2.6%. Youth who participated in regular vigorous-intensity PA (40%; n=67) achieved nearly twice the dose of PA than peers who did not (62 vs 34 metabolic equivalent score-hour/week, p=0.001). After adjusting for duration of diabetes, BMI Z-score, sex, and smoking, youth who engaged in vigorous-intensity PA displayed lower HbA1c (9.1% vs 9.9%, p=0.052), diastolic BP (70 mm Hg vs 73 mm Hg, p=0.002), diastolic load (20% vs 26%, p=0.023), and mean arterial pressure (87.3 mm Hg vs 90.3 mm Hg, p<0.01), compared with youth who did not. Compared with youth who did not participate in regular vigorous-intensity PA, those who did also displayed lower odds of albuminuria after adjusting for duration of diabetes, sex, smoking, rural residence, and BMI Z-score (adjusted OR: 0.40, 95% CI 0.19 to 0.84). CONCLUSIONS: Among youth with type 2 diabetes, participation in vigorous-intensity PA is associated with lower CVD risk.

Comparison of Clinical and Social Characteristics of Canadian Youth Living With Type 1 and Type 2 Diabetes.

OBJECTIVES: Our aim in this study was to describe the clinical and social characteristics of 2 Canadian cohorts of adolescents with diabetes. METHODS: Participants from the Improving renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) study (n=322) and the Early Determinants of Cardio-Renal Disease in Youth With Type 1 Diabetes (n=199) study were compared. RESULTS: Adolescents were 10 to 18 years of age (mean ± standard deviation: 14.8±2.4 years). The T2DM cohort had a shorter duration of diabetes. Both groups had glycated hemoglobin levels above target. The type 2 diabetes (T2D) cohort was comprised of predominantly Indigenous youth. The type 1 diabetes (T1D) cohort was 58.3% European/Caucasian, with a high proportion (41.7%) of visible minority groups (Afro-Caribbean, Asian/Pacific Islander, Hispanic). The prevalence of obesity, hypertension, left ventricular hypertrophy, albuminuria and hyperfiltration was higher in the T2D cohort. The T1D cohort was more socially and economically advantaged in all 4 dimensions of health inequality. CONCLUSIONS: There are significant differences in clinical and social characteristics of adolescents with T2D and T1D in Canada. Both have inadequate glycemic control with evidence of onset and progression of diabetes-related complications.

Time Course and Sex Effects of α-Linolenic Acid-Rich and DHA-Rich Supplements on Human Plasma Oxylipins: A Randomized Double-Blind Crossover Trial.

BACKGROUND: Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins. OBJECTIVES: Time course and sex differences of plasma oxylipins in response to ALA- compared with DHA-rich supplements were examined. METHODS: Healthy men and women, aged 19-34 y and BMI 18-28 kg/m2, were provided with capsules containing ∼4 g/d of ALA or DHA in a randomized double-blind crossover study with >6-wk wash-in and wash-out phases. Plasma PUFA and oxylipin (primary outcome) concentrations at days 0, 1, 3, 7, 14, and 28 of supplementation were analyzed by GC and HPLC-MS/MS, respectively. Sex differences, supplementation and time effects, and days to plateau were analyzed. RESULTS: ALA supplementation doubled ALA concentrations, but had no effects on ALA oxylipins after 28 d, whereas DHA supplementation tripled both DHA and its oxylipins. Increases in DHA oxylipins were detected as early as day 1, and a plateau was reached by days 5-7 for 11 of 12 individual DHA oxylipins and for total DHA oxylipins. Nine individual DHA oxylipins reached a plateau in females with DHA supplementation, compared with only 4 in males. A similar time course and sex difference pattern occurred with EPA and its oxylipins with DHA supplementation. DHA compared with ALA supplementation also resulted in higher concentrations of 4 individual arachidonic acids, 1 linoleic acid, and 1 dihomo-γ-linolenic acid oxylipin, despite not increasing the concentrations of these fatty acids, further demonstrating that oxylipins do not always reflect their precursor PUFA. CONCLUSIONS: DHA compared with a similar dose of ALA has greater effects on both n-3 and n-6 oxylipins in young, healthy adults, with differences in response to DHA supplementation occurring earlier and being greater in females. These findings can help explain differences in dietary effects of ALA and DHA.This study was registered at clinicaltrials.gov as NCT02317588.

Distinct effects of dietary flax compared to fish oil, soy protein compared to casein, and sex on the renal oxylipin profile in models of polycystic kidney disease.

Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFA) that are important regulators of kidney function and health. Targeted lipidomic analyses of renal oxylipins from four studies of rodent models of renal disease were performed to investigate the differential effects of dietary flax compared to fish oil, soy protein compared to casein, and sex. Across all studies, dietary fish oil was more effective than flax oil in reducing n-6 PUFA derived oxylipins and elevating eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins, whereas dietary flax oil resulted in higher α-linolenic acid (ALA) oxylipins. Dietary soy protein compared to casein resulted in higher linoleic acid (LA) derived oxylipins. Kidneys from females had higher levels of arachidonic acid (AA) oxylipins, but similar or lower levels of oxylipins from other PUFA. Modulation of the oxylipin profile by diet and sex may help elucidate their effects on renal physiology and health.

Distinct oxylipin alterations in diverse models of cystic kidney diseases.

Cystic kidney diseases are characterized by multiple renal cysts and are the leading cause of inherited renal disease. Oxylipins are bioactive lipids derived from fatty acids formed via cyclooxygenase, lipoxygenase and cytochrome P450 activity, and are important regulators of renal health and disease. Oxylipins are altered in nephronophthisis, a type of cystic kidney disease. To further investigate and to determine whether other cystic renal diseases share these abnormalities, a targeted lipidomic analysis of renal oxylipins was performed in orthologous models of autosomal dominant polycystic kidney disease 1 (Mx1Cre+Pkd1flox/flox mouse) and 2 (Pkd2ws25/- mouse), autosomal recessive polycystic kidney disease (PCK rat) and nephronophthisis (jck/jck mouse). Kidney cyclooxygenase oxylipins were consistently higher in all diseased kidneys, even in very early stage disease. On the other hand, cytochrome P450 epoxygenase derived oxylipins were lower only in the autosomal recessive polycystic kidney disease and nephronophthisis models, while lipoxygenase and cytochrome P450 hydroxylase derived oxylipins were lower only in nephronophthisis. Sex effects on renal oxylipin alterations were observed but they did not always coincide with sex effects on disease. For oxylipins with sex effects, arachidonic acid derived oxylipins formed via cyclooxygenases and lipoxygenases were higher in females, while oxylipins from other fatty acids and via cytochrome P450 enzymes were higher in males. The consistent and unique patterns of oxylipin alterations in the different models indicates the importance of these bioactive lipids in cystic renal diseases, suggesting that pharmacological agents (e.g. cyclooxygenase inhibitors) may be useful in treating these disorders, for which effective treatment remains elusive.

Omega-3 Polyunsaturated Fatty Acids and Oxylipins in Neuroinflammation and Management of Alzheimer Disease.

Alzheimer disease (AD) is becoming one of the most prevalent neurodegenerative conditions worldwide. Although the disease progression is becoming better understood, current medical interventions can only ameliorate some of the symptoms but cannot slow disease progression. Neuroinflammation plays an important role in the advancement of this disorder, and n-3 (ω-3) polyunsaturated fatty acids (PUFAs) are involved in both the reduction in and resolution of inflammation. These effects may be mediated by the anti-inflammatory and proresolving effects of bioactive lipid mediators (oxylipins) derived from n-3 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in fish oil. Although interventions have generally used fish oil containing both EPA and DHA, several studies that used either EPA or DHA alone or specific oxylipins derived from these fatty acids indicate that they have distinct effects. Both DHA and EPA can reduce neuroinflammation and cognitive decline, but EPA positively influences mood disorders, whereas DHA maintains normal brain structure. Fewer studies with a plant-derived n-3 PUFA, α-linolenic acid, suggest that other n-3 PUFAs and their oxylipins also may positively affect AD. Further research identifying the unique anti-inflammatory and proresolving properties of oxylipins from individual n-3 PUFAs will enable the discovery of novel disease-management strategies in AD.

Lack of Benefit of Early Intervention with Dietary Flax and Fish Oil and Soy Protein in Orthologous Rodent Models of Human Hereditary Polycystic Kidney Disease.

Rationale for dietary advice in polycystic kidney disease (PKD) is based in part on animal studies that have examined non-orthologous models with progressive development of cystic disease. Since no model completely mimics human PKD, the purpose of the current studies was to examine the effects of dietary soy protein (compared to casein) or oils enriched in omega-3 fatty acids (fish or flax oil compared to soy oil) on early disease progression in two orthologous models of PKD. The models studied were Pkd2WS25/- mice as a model of autosomal dominant PKD, and PCK rats as a model of autosomal recessive PKD. After 13 weeks of feeding, dietary fish (but not flax) oil resulted in larger kidneys and greater kidney water content in female Pkd2WS25/- compared to control mice. After 12 weeks of feeding male PCK compared to control rats, both fish and flax compared to soy oil resulted in enlarged kidneys and livers, greater kidney water content and higher kidney cyst area in diseased rats. Dietary soy protein compared to casein had no effects in Pkd2WS25/- compared to control mice. In PCK rats, kidney and liver histology were not improved, but lower proteinuria and higher urine pH suggest that soy protein could be beneficial in the long term. Therefore, in contrast to studies in non-orthologous models during the progressive development phase, these studies in orthologous PKD models do not support dietary advice to increase soy protein or oils enriched in omega-3 oils in early PKD.

Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs.

Oxylipins formed from polyunsaturated fatty acids (PUFAs) are the main mediators of PUFA effects in the body. They are formed via cyclooxygenase, lipoxygenase, and cytochrome P450 pathways, resulting in the formation of prostaglandins, thromboxanes, mono-, di-, and tri-hydroxy fatty acids (FAs), epoxy FAs, lipoxins, eoxins, hepoxilins, resolvins, protectins (also called neuroprotectins in the brain), and maresins. In addition to the well-known eicosanoids derived from arachidonic acid, recent developments in lipidomic methodologies have raised awareness of and interest in the large number of oxylipins formed from other PUFAs, including those from the essential FAs and the longer-chain n-3 (ω-3) PUFAs. Oxylipins have essential roles in normal physiology and function, but can also have detrimental effects. Compared with the oxylipins derived from n-3 PUFAs, oxylipins from n-6 PUFAs generally have greater activity and more inflammatory, vasoconstrictory, and proliferative effects, although there are notable exceptions. Because PUFA composition does not necessarily reflect oxylipin composition, comprehensive analysis of the oxylipin profile is necessary to understand the overall physiologic effects of PUFAs mediated through their oxylipins. These analyses should include oxylipins derived from linoleic and α-linolenic acids, because these largely unexplored bioactive oxylipins constitute more than one-half of oxylipins present in tissues. Because collated information on oxylipins formed from different PUFAs is currently unavailable, this review provides a detailed compilation of the main oxylipins formed from PUFAs and describes their functions. Much remains to be elucidated in this emerging field, including the discovery of more oxylipins, and the understanding of the differing biological potencies, kinetics, and isomer-specific activities of these novel PUFA metabolites.

Dietary flax oil rich in α-linolenic acid reduces renal disease and oxylipin abnormalities, including formation of docosahexaenoic acid derived oxylipins in the CD1-pcy/pcy mouse model of nephronophthisis.

The CD1-pcy/pcy mouse model of nephronophthisis displays reduced renal docosahexaenoic acid (DHA) levels and alterations in renal cyclooxygenase and lipoxygenase oxylipins derived from n-6 fatty acids. Since dietary flax oil ameliorates disease progression, its effect on renal fatty acids and oxylipins was examined. Sixteen weeks of feeding resulted in reduced disease progression and enrichment of renal phospholipid α-linolenic acid (ALA) and eicosapentaenoic acid, reduction in arachidonic acid (AA), but no change in linoleic acid (LA) or DHA. In diseased kidneys, flax oil feeding mitigated the elevated levels of renal cyclooxygenase derived oxylipins formed from AA and the lowered lipoxygenase and cytochrome P450 derived oxylipins formed from ALA and DHA. Increased DHA oxylipins occurred with flax feeding despite not altering DHA levels. Dietary flax oil may therefore reduce disease progression via mitigation of oxylipin abnormalities. This study also provides evidence of in vivo ALA conversion to DHA in amounts necessary to restore DHA oxylipin levels.