Course Of Type 1 Diabetes Research Articles

7892 Longitudinal Changes in Bone Microarchitecture and Strength in Girls with Type 1 Diabetes

Abstract Disclosure: R. Dhaliwal: None. R.K. Saunders: None. M. Misra: None. M.L. Bouxsein: None. D.M. Mitchell: None. Introduction: Type 1 diabetes (T1D) confers an increased fracture risk, only partly explained by low areal bone mineral density (aBMD). We have previously shown in a cross-sectional study that bone microarchitecture is altered early in the course of T1D. The goal of this study is to evaluate how T1D influences longitudinal changes in volumetric BMD (vBMD) and microarchitecture. Methods: This is a 2-year prospective study of girls ages 10-16 years (62 with T1D and 59 controls). We used dual-energy x-ray absorptiometry (DXA) to measure aBMD, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius (7% site) and tibia (8% site) to measure vBMD and microarchitecture. We used linear mixed models to assess the effects of T1D on change in bone parameters over time, adjusting for bone age as an index of skeletal maturity, height, lean mass index (LMI), and fat mass index (FMI). Results: At baseline, mean duration of disease in T1D was 4.8 ± 3.2 years, and mean HbA1c was 8.6 ± 1.4%. The groups did not differ by age, bone age, and height, while T1D participants had higher LMI (p<0.001) and borderline higher FMI (p=0.107). Linear growth, weight gain, and changes in body composition over time did not differ between groups. Growth-mediated aBMD gains were observed in both groups at the subtotal body, total hip, femoral neck, and spine. While adjusted aBMD as well as trabecular bone score were lower in T1D, we did not observe between-group differences in changes in these endpoints over time. In both groups, at the distal radius, we observed significant increases over time in total and cortical vBMD, cortical thickness, trabecular (Tb) thickness, and estimated failure load, while cortical porosity decreased. While several microarchitectural parameters were altered in T1D participants, we did not observe significant between-group differences in changes in these measures over time. Of note, trabecular development was subtly altered, with T1D participants demonstrating a borderline significant decrease in Tb vBMD (-14.3 ± 9.0 mg HA/cm3, p=0.112) and Tb number (-0.14 ± 0.07 mm-[1], p=0.057), while control participants had no change in Tb vBMD or number, but a significant increase in Tb thickness (5.8 ± 2.5 µm, p=0.018). At the distal tibia, we observed similar overall detrimental effects of T1D at baseline. However, we did not observe between-group differences in microarchitectural change over time. Glycemic control as measured by HbA1c was not associated with changes in skeletal parameters among T1D participants. Conclusions: T1D leads to substantially altered areal and volumetric BMD as well as microarchitectural parameters in girls. While our data suggest that much of this deficit appears to occur early in the course of disease as prospective change is similar in T1D and controls, subtle changes in trabecular bone development at the radius may indicate ongoing impairment of bone accrual. Presentation: 6/3/2024

Exosomes; a Potential Source of Biomarkers, Therapy, and Cure for Type-1 Diabetes.

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their "origin", and (b) their "content", which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or β-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome "specificity" makes them suitable as biomarkers or predictors, and their "mobility" and "content" lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic β-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications.

1319-P: Vascular Multimorbidity in Danish Persons with Type 2 Diabetes Is Decreasing, Contributing to Mortality Decline

Background: Multimorbidity in persons with type 2 diabetes (T2D) has not been studied in population wide settings. We used a Danish nation-wide diabetes register to assess trends in incidence and prevalence of vascular multimorbidity. Methods: All Danish persons with T2D since 1996 were followed from diagnosis to death or 2020-12-31. Follow-up was classified by the number of vascular morbidities from: atrial fibrillation, heart failure, myocardial infarction, ischemic stroke, hemorragic stroke, transient cerebral ischemia, amputation, retinopathy and nephropathy. Persons could enter with any number of vascular morbidities. We analyzed mortality rates and rates of each additional morbidity, using age, calendar time and number of attained morbidities as predictors. Prevalence of morbidities at diagnosis and at calendar times was modeled by binomial regression. Results: 505,124 persons entered the study. Occurrence of first morbidity increased mortality by a factor 2. Further morbidities increased mortality by a factor of 1.5. Mortality decreased 4%/year regardless of morbidity status. Incidence of additional morbidities increased only for the first 2 acquired morbidities by factors 1.8 and 1.2 and decreased by 3%/year regardless of morbidity status. The prevalence of morbidities at date of T2D increased until 2015. The prevalence of 1+ morbidity in all persons with T2D increased till 2008 and remained stable at 40% for men and 25% for women at age 65, and for 2+ at 10 and 5%. Conclusion: The decrease in morbidity and mortality rates is an indication of successful treatment of Danish persons with diabetes with respect to adverse vascular outcomes. This could be the result of earlier diagnosis of T2D; including persons earlier in the course of T2D would result in a “healthier” population. The increase in prevalence of morbidities at T2D diagnosis and the constant prevalence over time among all T2D persons may be an indication that management of morbidities is improving. Disclosure B.Carstensen: Stock/Shareholder; Novo Nordisk. K.K.B.Clemmensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. V.Kosjerina: Research Support; Sanofi-Aventis Deutschland GmbH. F.Persson: Advisory Panel; AstraZeneca, Bayer Consumer Care AG, Boehringer-Ingelheim, Novo Nordisk A/S, Consultant; AstraZeneca, Boehringer-Ingelheim, Novo Nordisk A/S, Research Support; Boehringer-Ingelheim, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Bayer Consumer Care AG, Boehringer-Ingelheim, Novo Nordisk A/S, Sanofi.

Abstract #1405044: Prevalence and Pattern of Dyslipidemia within 6 months of Diagnosis of Type 1 Diabetes

Type 1 diabetes (T1D) is often synonymous with glycemic control with emphasis on maintaining and following up with glucose control. Most international guidelines recommended that screening for dyslipidemia as a cardiovascular risk factor should begin at around puberty. Over the last decade, there have been various studies in different regions of the world regarding the prevalence and pattern of dyslipidemia in T1D. Recent guidelines have recommended screening for dyslipidemia as early as 2 years’ age. However, data regarding dyslipidemia in Indians with T1D is scarce. We studied the prevalence and pattern of dyslipidemia soon after diagnosis of T1D in Indian population. This retrospective observational study using medical records (2008-2022) included patients (age >2 years) with T1D, who attended endocrine clinic at a tertiary care hospital. Patients with uncontrolled hypothyroidism, preexisting cardiovascular disease, familial hypercholesterolemia, or those already on statins were excluded. The information retrieved from the medical records included age at diagnosis of diabetes, family history of CAD or dyslipidemia, height, weight, BMI, blood pressure. The biochemical parameters were noted: fasting lipid profile in mg/dl (total cholesterol, triglycerides, LDL-cholesterol, non-HDL-cholesterol, HDL-cholesterol) done within six months of diagnosis of T1D, and Hba1c at that time. The cut offs for dyslipidemia were taken as per ISPAD and ADA guidelines. Lipid profile, soon after diagnosis of T1D, was available in 161 patients (93 males, 68 females). The mean age of the study population was 15.73 (±9.9) yrs, and mean BMI was 16.8 (±7.01) kg/m2. At least one abnormal lipid parameter was found in 67.7%, with elevated T.Chol in 11.8%, TG in 24.2%, LDLc in 36.6%, non-HDLc in 33.5% and low HDL in 14.9%. On stratifying according to age, 56.2% subjects <10yrs age (n=32) had at least one abnormal lipid with low HDLc being most common (28.1%), followed by raised TG (25%). In patients 10-19 yrs age group and those >19 yrs age, raised LDLc was most common (40.2% and 42.1% respectively), followed by low HDLc (31.9% and 38.6% respectively). Most patients with T1D (67.7%) had dyslipidemia within six months of diagnosis of T1D. Majority of children <10 yrs age also had abnormal lipids initially; most common being low HDLc and elevated TG. In patients >10yrs age, raised LDLc is most common. Dyslipidemia being an independent CV risk factor needs to be assessed for and addressed to, along with glycemic control, early in the course of T1D.

Selected Serum Markers Associated with Pathogenesis and Clinical Course of Type 1 Diabetes in Pediatric Patients-The Effect of Disease Duration.

Biochemical abnormalities in the course of type 1 diabetes (T1D) may cause the production/activation of various proteins and peptides influencing treatment and causing a risk of complications. The aim of this study was to assess concentrations of selected serum substances involved in the pathogenesis and course of T1D and to correlate their concentrations with the duration of T1D. The study included patients with T1D (n = 156) at the age of 3-17, who were divided according to the duration of the disease into those newly diagnosed (n = 30), diagnosed after 3-5 (n = 77), 6-7 (n = 25), and over 7 (n = 24) years from the onset of T1D, and age-matched healthy controls (n = 30). Concentrations of amylin (IAPP), proamylin (proIAPP), catestatin (CST), chromogranin A (ChgA), nerve growth factor (NFG), platelet-activating factor (PAF), uromodulin (UMOD), and intestinal fatty acid binding protein (I-FABP) were measured in sera using immunoenzymatic tests. There were significant differences in concentrations of all the substances except UMOD and NGF between T1D patients and healthy children. The duration of the disease affected concentrations of CST, ChgA, PAF, and NGF, i.e., proteins/peptides which could have an impact on the course of T1D and the development of complications. In long-term patients, a decrease in concentrations of CST and ChgA, and an increase in PAF concentrations were found. In the case of NGF, a decrease was observed after the initial high values, followed by an increase over 7 years after T1D diagnosis. Concluding, the results show that concentrations of selected serum indicators may change in the course of T1D. Further studies are needed to establish whether these indicators could be used in the context of predicting long-term complications.

Long-term Outcomes Among Young Adults With Type 2 Diabetes Based on Durability of Glycemic Control: Results From the TODAY Cohort Study.

To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes (T2D) and to assess the impact of fasting glucose (FG) variability on the clinical course of T2D. From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 457 participants (mean age, 14 years) with mean diabetes duration <2 years at entry and a minimum study follow-up of 10 years were included in these analyses. HbA1c, FG concentrations, and β-cell function estimates from oral glucose tolerance tests were measured longitudinally. Prevalence of comorbidities by glycemic control status after 10 years in the TODAY study was assessed. Higher baseline HbA1c concentration, lower β-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with T2D. Higher cumulative HbA1c concentration over 4 years and greater FG variability over a year within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in FG ≥8.3% predicted future loss of glycemic control and development of comorbidities. Higher baseline HbA1c concentration and FG variability during year 1 accurately predicted youth with T2D who will experience metabolic decompensation and comorbidities. These values may be useful tools for clinicians when considering early intensification of therapy.

Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience.

To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20-0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46-1.74 per SD [0.7%] increase in HbA1c). DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Trends in Glycemia between 2002 and 2016 among Incident Youth Cohorts Early in the Course of Type 1 Diabetes: The SEARCH for Diabetes in Youth Study.

Objective Hyperglycemia early in the course of type 1 diabetes (T1D) may increase the risk of cardiometabolic complications later in life. We tested the hypothesis that there were temporal trends in population-level glycemia and insulin pump use near T1D diagnosis among incident youth cohorts diagnosed between 2002 and 2016. Methods Weighted and adjusted regression models were applied to data from the SEARCH for Diabetes in Youth study to analyze trends in hemoglobin A1c (HbA1c), suboptimal glycemia (HbA1c > 9% or not), and insulin pump use among youth with T1D within 30 months of diagnosis. We tested the interaction of year with race and ethnicity, sex, and insulin regimen to assess potential disparities. Results Among the 3,956 youth with T1D, there was a small, clinically insignificant reduction in HbA1c between 2002 (7.9% ± 1.5) and 2016 (7.8% ± 2.4) (fully adjusted change by year (-0.013% [95% CI -0.026, -0.0008], p = 0.04). The proportion of youth with suboptimal glycemia increased with each year, but the adjusted odds did not change. Insulin pump use increased more than fivefold. Although interaction effects of time with race and ethnicity, sex, and insulin regimen were not detected, in 2016, suboptimal glycemia was 4.3 and 1.8 times more prevalent among Black and Hispanic than among non-Hispanic White youth, respectively. Conclusions There was not a clinically significant population-level improvement in glycemia across incident youth cohorts early in the course of T1D, despite severalfold increases in insulin pump use. Comprehensive clinical interventions to improve glycemia early in the T1D course and address disparities are urgently needed.

Preventing type 1 diabetes development and preserving beta-cell function.

Type 1 diabetes (T1D) is the most common chronic disease of childhood presenting a significant burden, both in terms of day-to-day medical management and lifelong care. Studies aligned with diverse strategies to prevent or modify the course of T1D are reviewed. The diagnosis of T1D precedes the classic clinical presentation when insulin dependence develops. With an increased understanding of the pathophysiology of the autoimmune process leading to T1D, treatment strategies to prevent the development of autoimmunity and/or modify the immune response have been trialed in persons at risk for developing the disease. Interventions prior to insulin dependence or very early after clinical diagnosis show some promise both in preventing disease onset and prolonging beta-cell insulin production. Significant progress has been made in the treatment of T1D. However, suboptimal glycemic control remains a challenge impacting overall health and quality of life for patients with this chronic disease. Although physicians and basic sciences investigators continue to pursue the prevention of the autoimmune process, the advent of disease-modifying agents is a promising strategy. Further studies are needed to ensure that insulin preservation can be achieved longer term.

Health Disparities Likely Emerge Early in the Course of Type-1 Diabetes in Youth.

Type-1 diabetes (T1D) management and glycemic control the year after diagnosis affects the long-term trajectory of T1D. Disparities in hemoglobin A1c (HbA1c) based on race, ethnicity, and socioeconomic status (SES) have been well-documented; however, there has been limited investigation into the timeline with which these disparities develop. This study aims to assess differences in HbA1c by race/ethnicity and SES among youth with T1D over 1 year post diagnosis. HbA1c at onset, and 3, 6, 9, and 12 months following diagnosis was collected from youth with T1D between 2016 and 2020. Mixed-effect models examined associations of HbA1c over time with race/ethnicity and SES. Of 758 patients, 71% identified as white. Mean (± SD) HbA1c was 11.4% ± 2.2% at diagnosis and 7.3% ± 1.2%, 7.3% ± 1.3%, 7.7% ± 1.4%, and 7.9% ± 1.4% at 3, 6, 9, and 12 months, respectively. HbA1c trajectories over time differed significantly by race (adjusting for sex and zip-code education and poverty levels) with Hispanic and black youth demonstrating higher HbA1c 1 year after diagnosis (8.7% vs 7.7%, p < .001) than white youth. These data revealed that youth did not meet glycemic targets at 1 year post diagnosis and that racial/ethnic minority youth had higher HbA1c 1 year post diagnosis, highlighting the need to optimize glycemic control and mitigate disparities early. Understanding the time course of these outcomes helps to inform the need for early interventions, particularly in disadvantaged patient populations, to lay the groundwork for improved control. Further research must also be done to better understand overlapping axes of disparities including race, ethnicity, and SES.

Type 2 Diabetes Remission with Significant Weight Loss: Definition and Evidence-Based Interventions.

Type 2 diabetes (T2D) has long been regarded as an incurable and chronic disease according to conventional management methods. Clinical and pathophysiological studies on the natural course of T2D have shown that blood glucose control worsens with an increase in the number of required anti-hyperglycemic agents, as β-cell function progressively declines over time. However, recent studies have shown remission of T2D after metabolic surgery, intensive lifestyle modification, or medications, raising the possibility that β-cell function may be preserved or the decline in β-cell function may even be reversible. The World Health Organization as well as the American Diabetes Association and the European Association for the Study of Diabetes recognize remission as an appropriate management aim. In the light of the state of evidence for T2D reversal, physicians need to be educated on treatment options to achieve T2D remission so that they can actively play a part in counseling patients who may wish to explore these approaches to their disease. This review will introduce each of these approaches, summarizing their beneficial effects, supporting evidence, degree of sustainability, and challenges to be addressed in the future.

Further RISE'ing to the Challenge of Type 2 Diabetes in Youth.

Despite three decades of increasing prevalence of type 2 diabetes (T2D) in adolescents (1), the diabetes community continues to grapple with the pathophysiology of youth-onset T2D. Accumulating evidence indicates that when compared with T2D in adults, T2D in youth follows a more aggressive course (2–4). Adolescents are therefore entering adulthood with an advanced and perhaps misunderstood disease that puts them at risk for morbidity from micro- and macrovascular complications. Moreover, as the susceptibility of individuals with diabetes to poor outcomes during the coronavirus pandemic became increasingly apparent (5), the urgency to address the health crisis of T2D in youth has been amplified. The Restoring Insulin Secretion (RISE) study, designed in 2014, tested interventions in both adolescents and adults to determine whether β-cell decline could be halted in people with prediabetes or early T2D (6). The primary analyses were overall disheartening regarding slowing the progression of T2D in youth (7–12). However, the RISE study provides the most direct opportunity yet to examine differences between T2D in youth and adults. In this issue of Diabetes Care , the RISE Consortium delivers three articles that offer mechanistic insights into the pathogenesis of T2D and potentially a path forward for the treatment of T2D in youth (13–15). A summary of these articles is presented in Table 1 and discussed in subsequent paragraphs. View this table: Table 1 Summary of RISE papers in this issue RISE was predicated on the critical role of progressive β-cell decline in the pathogenesis of T2D, where β-cell dysfunction results in excessive glucose and fatty acid exposure, termed glucolipotoxicity (6). Glucolipotoxicity coupled with insulin resistance compounds β-cell stress and contributes to β-cell failure. Previous data in adults suggest that early intensive intervention may delay β-cell dysfunction and slow the course of T2D (16–18). Prior to RISE, no …

Bone accrual in children and adolescents with type 1 diabetes: current knowledge and future directions.

Skeletal fragility is now recognized as a significant complication of type 1 diabetes (T1D). Many patients with T1D develop the disease in childhood and prior to the attainment of peak bone mass and strength. This manuscript will review recent studies investigating the effects of T1D on skeletal development. Mild-to-moderate deficits in bone density, structure, and mineral accrual were reported early in the course of T1D in some but not all studies. Childhood-onset disease was associated with a more severe skeletal phenotype in some adult studies. Lower than expected bone mass for muscle size was been described. Hemoglobin A1c was negatively associated with bone density and structure in several studies, though the mechanism was not clear. The use of advanced imaging techniques has shown that the adverse effects of T1D on the developing skeleton extend beyond bone density to include abnormalities in bone size, shape, microarchitecture, and strength. Despite these gains, a uniform understanding of the pathophysiology underlying skeletal fragility in this disorder remains elusive. Longitudinal studies, especially in association with interventions to reduce hyperglycemia or improve muscle strength, are needed to inform bone healthcare in T1D.

The evaluation of the role of BMI and insulin resistance on inflammatory markers, PAI-1 levels and arterial stiffness in newly diagnosed type 2 diabetes mellitus patients.

Increased cardiovascular risk, represented by endothelial inflammation, probably starts with the very first course of type-2 diabetes (T2DM). Almost 85.2% of all T2DM patients are overweight or obese. Thrombosis accounts 80% of all deaths in patients with diabetes. The thrombotic-fibrinolytic equilibrium shifts in favor of thrombosis by plasminogen activator inhibitor-1 (PAI-1). PAI-1 secretion is induced primarily by CRP. PAI-1 overexpression predisposes unstable plaque development. The contribution of obesity and diabetes to this process is not clearly understood. In this study, we aimed to investigate comparison of inflammatory markers, PAI-1 levels and arterial stiffness according to BMI and impaired glucose metabolism in patient with newly diagnosed T2DM. Newly diagnosed 60 T2DM patients were enrolled. Demographics and measurements were noted. Liver (AST, ALT), kidney (urea, creatinine, albumin/creatinine ratio), metabolic (fasting blood glucose, post-prandial blood glucose, insulin, c-peptide, HbA1c, total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglyceride) parameters, inflammatory markers [hsCRP, fibrinogen]), PAI-1 levels and pulse wave velocity was measured from all participants. The results were compared. Inflammatory markers and PAI-1 levels were significantly elevated in obese group compared to overweight participants. The correlation analysis showed that waist and hip circumferences, high-sensitive CRP, fibrinogen and PAI-1 levels were positively correlated with BMI but not with HbA1c levels. The results of our study showed that lipid levels, glycemic and blood pressure values of the obese and overweight patients were similar. BMI affects inflammatory markers and PAI-1 levels independent of glucose regulation and insulin resistance in newly diagnosed T2DM. According to the current study BMI is found to be more prominent in terms of inflammatory markers and PAI-1 levels compared to insulin resistance and impaired glucose metabolism in newly diagnosed T2DM.

1281-P: Pilot Study on the Feasibility of Weekly CGM Data Review in Youth with New-Onset Type 1 Diabetes

Despite advances in diabetes technology and treatment, many youth with type 1 diabetes (T1D) continue to have hemoglobin A1c (HbA1c) above target. Consistent use of continuous glucose monitors (CGM) improves HbA1c and time in range (TIR 70-180 mg/dl) glucose, while minimizing hypoglycemia in youth with T1D. A previous study suggested that long-term HbA1c outcomes may be determined early in the course of T1D. Thus, increased awareness of glucose trends and frequent insulin dose adjustments early in the course of T1D is hypothesized to improve long-term HbA1c and health outcomes. We have initiated CGM in the first month of T1D diagnosis. In March 2019, we added weekly remote review of CGM data by a pediatric endocrinologist or certified diabetes educator to provide dose adjustments. Data sharing is facilitated by using a custom platform including Apple HealthKit to transmit data from the Dexcom G6 mobile app to Epic MyChart. Inclusion criteria were diagnosis of T1D within the past 30 days and intention to follow in our clinic. During the initial 8 months of this study, we enrolled 43 youth (age at diagnosis 9.2±4.2 years, 57% male, 78% on private insurance, 42.5% non-Hispanic White, initial HbA1c 12.0±2.0%). Twenty-eight youth had at least 1 documented data review with an average of 15.8±8.1 reviews/patient and 5.4 dose adjustments/youth (∼1 dose adjustment every 3 weeks) via phone calls or secure MyChart messages. Based on CGM downloads, users had a high percentage of time of CGM wear (88±11% of time over 2-week periods), high percentage of TIR glucose (72.2±18.4%), and low incidence of hypoglycemia (32±54 min/day, 2.2±3.8%). This pilot study demonstrates that implementing routine data review as part of a new onset program increases the frequency of insulin dose adjustments. Tools should be developed to allow for efficient data review for population health management. Further follow up is needed to determine long-term outcomes, scalability, and sustainability of this new onset program. Disclosure M. Lee: None. J. Leverenz: None. B. Leverenz: None. N.M. Pageler: None. D. Scheinker: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. P. Prahalad: None. Funding Stanford Diabetes Research Center (P30DK116074)

OR08-06 Increased Carotid Intima Media Thickness in Pediatric Type 1 Diabetes Is Associated with Disease Duration

Background & ObjectivePatients with type-1-diabetes (T1D) are at risk of long-term micro and macrovascular complications causing significant morbidity and mortality. Overt complications are not common in childhood; however, subclinical impairments in endothelial function, may be found. Better understanding of the timeline for the appearance of diabetic complications and identifying individuals at increased risk is key for developing prevention strategies. We aimed to study endothelial function and it’s determinants in adolescents with T1D at different time points from diagnosis.MethodsForty adolescents 11-20 years of age with T1D followed at our pediatric diabetes clinic and 18 healthy control subjects were included. Two groups of patients were recruited based on time from T1D diagnosis; 20 individuals were diagnosed 2-4 months prior to the study visit and 20 at least 7 years prior to the visit. Investigations included: i) medical and demographic data ii) anthropometrics iii) fasting blood samples iv) EndoPAT testing of endothelial function and heart rate variability (Itamar Medical Ltd., Israel) v) Carotid intima media thickness (CIMT).ResultsMean age differed slightly between groups being 14.1±2.0years in individuals with recent-onset T1D, 16.2±2.5 in those with prolonged T1D, and 14.8±2.3 in the control group (p=0.02). There were no significant differences in pubertal stage or in BMI z-score between groups. Thirty-three (57%) females participated. No patient suffered from diabetic complications. Mean CIMT was significantly higher in individuals with prolonged T1D (0.49±0.07mm) compared to control subjects (0.43±0.05mm; p=0.013) and did not differ significantly between patients with recent-onset T1D (0.45±0.07mm) and controls. This difference remained significant when age and sex were included in the model. EndoPAT measures of endothelial function and heart rate variability did not differ significantly between groups. Mean HbA1c at the time of the visit differed between groups (6.7%±0.7, 9.6%±1.8, 5.4%±0.3, p<0.001). However, the average of HbA1c reflecting the 6-7 months prior to the visit did not differ significantly between subjects with recent onset T1D (9.8%±1.3) and those with prolonged T1D (9.5%±1.7). LDL was higher in subjects with prolonged T1D (114±28mg/dl) compared to either controls (93±26mg/dl) or recent onset T1D (88±19mg/dl),p=0.002. Diastolic blood pressure was higher in subjects with prolonged T1D (70±6mmHg) than in controls (61±6, p=0.007).ConclusionsOur results demonstrate disease duration to be an important factor in the development of subclinical arterial damage in the pediatric age group. Early in the course of T1D, CIMT results were similar in patients and control subjects, suggesting an important window for prevention. Larger studies could shed light on the precise timeline of endothelial impairment.

Mentalizing in mothers and children with type 1 diabetes.

Studies suggest that the relationship between psychosocial well-being and type 1 diabetes (T1D) is bidirectional, with T1D typically having a negative influence on psychological functioning, which in turn negatively affects the course of T1D. Here, we investigate the potential role of the capacity for mentalizing, or reflective functioning, in children and their mothers in diabetes control. We tested differences in mentalizing as assessed by the Reflective Functioning Scale in two groups of mother-son dyads with good (GDC) versus poor (PDC) diabetes control. Fifty-five boys (8-12 years old) and their mothers were recruited from the Juvenile Diabetes Foundation in Santiago, Chile. The mothers were interviewed with the Parental Development Interview and the children with the Child Attachment Interview, and both were scored for reflective functioning by using the Reflective Functioning Scale. Self-report measures of stress and diabetes outcomes were completed by the mothers and children, and levels of glycated hemoglobin (HbA1c) were assessed as an index of diabetes control. The results showed that both maternal and child reflective functioning were higher in the GDC than the PDC group and were negatively correlated with HbA1c in the total sample. Our findings suggest an important role for mentalizing in diabetes outcomes, but further prospective research is needed.

Serum complement C3 and islet β-cell function in patients with type 2 diabetes: A 4.6-year prospective follow-up study.

Serum complement C3 has been shown to contribute to the incidence of type 2 diabetes (T2D), but how serum complement C3 affects islet β-cell function throughout the course of T2D is unclear. This study explored whether serum complement C3 is independently associated with changes in islet β-cell function over time in patients with T2D. Serum complement C3 was measured, and endogenous β-cell function was evaluated by area under the C-peptide curve (AUCcp) during an oral glucose tolerance test (OGTT) in 411 patients with T2D at baseline from 2011 to 2015. Next, 347 of those patients with available data were pooled for a final follow-up analysis from 2014 to 2018. Changes in islet β-cell function at follow-up were evaluated by AUCcp percentage changes (ΔAUCcp%). In addition, other possible clinical risks for diabetes were also examined. The 347 patients included in the analysis had a diabetes duration of 4.84 ± 3.63 years at baseline. Baseline serum complement C3 (baseline C3) levels were positively correlated with baseline natural logarithm of AUCcp (lnAUCcp) (n = 347, r = 0.288, p < 0.001), and baseline C3 was independently associated with baseline lnAUCcp (β = 0.17, t = 3.52, p < 0.001) after adjustment for baseline glycemic status and other clinical confounders by multivariate liner regression analysis. Compared with the baseline values, complement C3 changes (ΔC3) and ΔAUCcp% was -0.15 ± 0.28 mg/ml and -17.2 ± 18.4%, respectively, at a follow-up visit 4.57 ± 0.78 years later. Moreover, ΔC3 was positively correlated with ΔAUCcp% (n = 347, r = 0.302, p < 0.001). Furthermore, each 0.1 mg/ml increase in ΔC3 was associated with a higher ΔAUCcp% (1.41% [95% CI, 0.82-2.00%]) after adjusting for changes in glycemic status and other clinical confounders at follow-up. In addition to serum complement C3 being independently associated with islet β-cell function at baseline, its changes were also independently associated with changes in islet β-cell function over time in patients with T2D.

Pancreatic Islets in Short Duration Type 2 Diabetes (T2D) Show Macrophage Infiltration and Increased Inflammatory Signaling

T2D is characterized by progressive pancreatic islet dysfunction; however, dissecting causes of this dysfunction in humans is challenging due to disease heterogeneity and the difficulty of obtaining relevant pancreatic samples. To address these challenges, we used an integrated approach to functionally and molecularly study the native pancreas and isolated islets from the same human T2D cadaveric donor. Using associated donor clinical information, we focused on donors with short disease duration (n=10, age 47-66 years, 2-7-year duration, oral medications). Compared to age-matched control islets, T2D islets had dysfunctional insulin (decreased) and glucagon (increased) secretion despite similar insulin and glucagon content. Tissue-section analysis of T2D pancreata showed no difference in relative endocrine (α, β and δ) cell composition. To assess for changes in the islet microenvironment, we analyzed macrophages by staining with Iba1 and endothelial cells with Caveolin-1 and found a 2-fold increase in intraislet macrophages (T2D vs. control: 3.01% vs. 1.45% by area) but no change in intraislet endothelial cell area (T2D vs. control: 8.97% vs. 8.21% by area). Interestingly, costaining with Iba1 and thioflavin S demonstrated that T2D islets with amyloid did not have increased macrophage infiltration compared to T2D islets without amyloid although a close spatial association of macrophages and amyloid deposits was noted. RNA-sequencing analysis of FACS-purified α and β cells from T2D islets showed increased inflammatory signaling pathways in both cell types. Specifically, transcripts for cytokine receptors such as IL6R, IL1R1, and IFNGR1 as well as downstream regulators including NFKB1 and NFKB2 were elevated in T2D α and/or β cells. Together, these data suggest that early in the course of T2D, increased macrophages in the islet microenvironment may lead to elevated α and β cell inflammatory signaling and contribute to human α and β cell dysfunction. Disclosure J.T. Walker: None. S. Shrestha: None. N. Prasad: None. T. Richardson: None. R. Aramandla: None. G. Poffenberger: None. R. Bottino: None. M. Brissova: None. A.C. Powers: None.

Targeting beta-cell preservation in the management of type 2 diabetes

Type 2 diabetes (T2D) is widely considered a chronic and progressive disease without cure. As beta-cell function progressively declines over time, blood glucose rises. Current management of T2D involves incremental introduction of dietary and drug therapies to achieve normoglycaemia. However, recent studies have demonstrated remission of T2D following bariatric surgery, very low calorie diet or intensive insulin therapy, raising the possibility that the declining beta-cell function in T2D may be arrested or even reversed. The point at which such interventions are introduced in the course of T2D is key for clinical benefit. Future treatment strategies should be revised to target early beta-cell preservation and thus disease remission. This article reviews the pathogenesis of beta-cell dysfunction and evidence for the clinical benefit of preserving beta-cell function in T2D, and discusses the evidence for beta-cell preservation of current glucose-lowering therapies with particular reference to their effect when initiated at the time of diagnosis of T2D.