Meghan E. Pauley

Introduction: Type 1 diabetes (T1D) is associated with increased risk of dementias and other neurodegenerative diseases. Plasma biomarkers of neurodegeneration and neuroinflammation hold utility in risk prediction and diagnosis of neurodegenerative disease and other neuropathology, but there remains a paucity of data in the T1D population. This study quantified plasma levels of biomarkers of neurodegeneration and neuroinflammation [phosphorylated tau-181 (pTau-181), total tau (Tau), amyloid beta 42/amyloid beta 40 (Aβ42/40), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)], and tested associations with T1D and related characteristics. Methods: This cross-sectional analysis of a subset of participants from the Coronary Artery Calcification in Type 1 Diabetes study included adults with and without T1D. Biomarker levels were quantified using Quanterix Simoa, then log-transformed and analyzed using linear regression models adjusted for age, body mass index (BMI), race and ethnicity, smoking status, and estimated glomerular filtration rate (eGFR). A subsequent sensitivity analysis included diabetic retinopathy (DR). Results: 136 adults with T1D (n=90, age 52 years, 58% female, average HbA1c 7.7%) and without T1D (n=46, age 53 years, 57% female, average HbA1c 5.4%) were included. In fully adjusted models, T1D was associated with higher pTau-181 [estimate (pg/mL) 1.221, (95% confidence interval 1.003, 1.486) p=0.046], GFAP [1.296 (1.129, 1.489), p<0.001], and NfL [1.355 (1.162, 1.579), p<0.001], relative to adults without T1D. In the sensitivity analysis, relative to adults without T1D, T1D with moderate/severe DR was associated with higher pTau-181 [1.330 (1.063, 1.663), p=0.013], GFAP [1.369 (1.653, 1.608), p<0.001], and NfL [1.495 (1.252, 1.786), p<0.001], and T1D with none/mild DR was associated with higher GFAP [1.228 (1.046, 1.442), p=0.013] and NfL [1.235 (1.037, 1.470), p=0.018]. As compared to T1D with none/mild DR, T1D with moderate/severe DR was associated with higher NfL [1.211 (1.011, 1.451), p=0.038]. Across both models, eGFR was inversely associated with pTau-181, NfL, and Tau (p<0.05 for all). Discussion: T1D is associated with a greater burden of plasma biomarkers of neurodegeneration and neuroinflammation, and microvascular complications such as DR and impaired kidney function may contribute to this burden. Further study is needed to fully characterize the interplay between these biomarkers and neuropathology in T1D.

Neurobiological frameworks of obesity in youth have focused largely on non-homeostatic systems (reward, salience, executive control), while the homeostatic system-particularly the hypothalamus-is comparatively understudied. A clearer picture of how these systems interact in adolescents with severe obesity is needed to inform treatment. This study sought to test whether adolescents with severe obesity exhibit altered hypothalamic functional connectivity, relative to healthy-weight peers, across fasting and fed states. We analyzed data from the Food and Adolescent Brain Study, a single-blinded randomized cross-over trial (NCT04208256) of 13-18-year-old adolescents with severe obesity (SO; body mass index [BMI] >99th %ile; n = 30; mean [SD] age 14.6 years [1.5]) and with healthy weight (HW; BMI <85th %ile; n = 26; 15.5 years [1.6]). Participants completed resting-state functional magnetic resonance scans during fasting and after ingesting a 75-gram glucose drink (1 255.8 kJ [300 kcal]) to induce a fed state. Multivariate general linear models were run in seed-to-voxel analyses to estimate functional connectivity, setting the hypothalamus as the seed region. All models were adjusted for sex and household income with significance determined via cluster-forming voxel-level p < 0.005 and false discovery rate-corrected cluster-level p < 0.05. In adolescents with SO, during fasting, hypothalamic connectivity was weaker to the bilateral cerebellum and left(L) middle occipital gyrus, and stronger to the right(R) postcentral/supramarginal gyri, compared to the HW group. During the fed state, hypothalamic connectivity increased to the bilateral middle frontal gyri and R putamen and decreased to the R caudate and L superior frontal gyrus in adolescents with SO, relative to the HW group. Severe obesity in adolescence is associated with altered communication between homeostatic (hypothalamus) and non-homeostatic brain structures, evident across fasting and fed states. Findings underscore the need to incorporate homeostatic circuitry into pediatric obesity frameworks.

Context: Over half of all new cases of type 1 diabetes (T1D) are diagnosed in adults, yet the natural history of adult-onset T1D, particularly in nonfamilial populations, is not fully understood. Objective: This study measured the prevalence of islet autoantibodies (IA) in adults without known diabetes and irrespective of T1D family history from Colorado (USA). Methods: The Autoimmunity Screening for Kids study screened for IAs to insulin, glutamic acid decarboxylase (GADA), islet antigen-2, and zinc transporter 8 in 1087 adults without known diabetes [mean age 40.7 years with range 19.6-63.9 years, 63% non-Hispanic White (NHW), 10% with family history of T1D in a first-degree relative, and 78% female] from Colorado. IAs were measured using radiobinding assay and electrochemiluminescence detection methods. Results: In total, 3.86% of adults screened positive for any IA, 0.55% screened positive for multiple IAs, and 1.75% were positive for a single IA by both detection methods. Compared to NHW, those with Hispanic race/ethnicity were more likely to screen positive for a single IA (relative risk 2.32, 95% confidence interval 1.40, 3.84, P = .001), but there was no difference in the risk of screening positive for multiple IAs when comparing across race/ethnicity. GADA was the most prevalent IA, found in 2.67% of adults. Conclusion: IA prevalence was high in this sample of adults without known diabetes from Colorado. Further study is needed to fully characterize the risk of progression to clinical diabetes among adults who screen positive for IAs, particularly in nonfamilial populations.

Adult-onset diabetes increases one’s risk of neurodegenerative disease including Alzheimer’s disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aβ40, Aβ42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aβ40, Aβ42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Purpose of Review The incidence of type 1 diabetes (T1D) is rising in all age groups. T1D is associated with chronic microvascular and macrovascular complications but improving glycemic trends can delay the onset and slow the progression of these complications. Utilization of technological devices for diabetes management, such as continuous glucose monitors (CGM) and insulin pumps, is increasing, and these devices are associated with improvements in glycemic trends. Thus, device use may be associated with long-term prevention of T1D complications, yet few studies have investigated the direct impacts of devices on chronic complications in T1D. This review will describe common diabetes devices and combination systems, as well as review relationships between device use and cardiovascular outcomes in T1D. Recent Findings Findings from existing cohort and national registry studies suggest that pump use may aid in improving cardiovascular risk factors such as hypertension and dyslipidemia. Furthermore, pump users have been shown to have lower arterial stiffness and better measures of myocardial function. In registry and case–control longitudinal data, pump use has been associated with fewer cardiovascular events and reduction of cardiovascular disease (CVD) and all-cause mortality. Summary CVD is the leading cause of morbidity and mortality in T1D. Consistent use of diabetes devices may protect against the development and progression of macrovascular complications such as CVD through improvement in glycemic trends. Existing literature is limited, but findings suggest that pump use may reduce acute cardiovascular risk factors as well as chronic cardiovascular complications and overall mortality in T1D.

Meghan E. Pauley, Suyuan Tan, Gita Sikand, Erin C. Cobry; Severe, Refractory Insulin Edema With Cardiopulmonary Congestion Requiring Multiple Treatment Modaliti

Diabetes-related technology has undergone great advancement in recent years. These technological devices are more commonly utilized in the type 1 diabetes population, which requires insulin as the primary treatment modality. Available devices include insulin pumps, continuous glucose monitors, and hybrid systems referred to as automated insulin delivery systems or hybrid closed-loop systems, which combine those two devices along with software algorithms to achieve advanced therapeutic capabilities, including automatic modulation of insulin delivery based on sensor-derived glucose levels to minimize abnormal glucose trends. Use of diabetes technology is associated with significant positive health and psychosocial outcomes, yet utilization rates are generally lacking across both adult and pediatric type 1 diabetes populations in the United States and other countries. There are consistent themes in existing barriers to technology uptake reported by individuals with type 1 diabetes or parents of children with type 1 diabetes, including physical burdens associated with wearing the devices, concerns in navigating the technology and the devices’ abilities to meet user expectations, high cost, inadequate resources within the healthcare team to support device use, disparities in technology access, and psychosocial barriers. It is important to understand the common barriers to uptake of not only the automated insulin delivery systems but also their component devices (insulin pumps and continuous glucose monitors) to fully support individuals in utilizing these devices and optimizing health benefits. The purpose of this article is to summarize the current automated insulin delivery devices that are available for use in management of type 1 diabetes, review common barriers to uptake of those systems and their component devices, and provide expert opinion on existing and future solutions to identified barriers.