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Objectives To determine trajectories of glycemic control and body mass index (BMI) z‐score in a large pediatric sample with type 1 diabetes (T1D) over a 38‐year period, and to evaluate sex differences and temporal changes in the prevalence of these trajectories. Methods We conducted a longitudinal, retrospective study of 7002 2 to 18 year olds with T1D followed between 1978 and 2016 at a single center. Group‐based modeling was used to identify trajectories for hemoglobin A1c (HbA1c) and BMI z‐score. Multinomial logistic regression identified predictors of membership to less favorable glycemic trajectories. Results Group‐based modeling yielded 5 HbA1c trajectories. A total of 86% of the sample fell within 3 trajectories that were largely stable across childhood and adolescence, and 14% fell within 2 trajectories characterized by marked deterioration beginning in pre‐adolescence. Girls were more likely to be in the HbA1c trajectory with the highest starting HbA1c and significant deterioration during adolescence, and in the highest two BMI z‐score trajectories. Patients with non‐white race had the highest odds of belonging to a less favorable HbA1c trajectory. Prevalence of the high stable HbA1c trajectory decreased and prevalence of the low stable HbA1c trajectory increased over the study period. Conclusions A minority of youth with T1D experienced deterioration of glycemic control during adolescence. Girls were more likely to belong to the worst HbA1c trajectory and to BMI z‐score trajectories in the overweight/obese range, which may increase cardiometabolic risk. Addressing racial/ethnic disparities in glycemic control should remain a priority. Advances in T1D management correlated with favorable shifts in HbA1c trajectory prevalence.

Identification of individuals who are at risk of suffering from acute coronary syndromes (ACS) may allow to introduce preventative measures. We aimed to identify ACS-related urinary peptides, that combined as a pattern can be used as prognostic biomarker. Proteomic data of 252 individuals enrolled in four prospective studies from Australia, Europe and North America were analyzed. 126 of these had suffered from ACS within a period of up to 5 years post urine sampling (cases). Proteomic analysis of 84 cases and 84 matched controls resulted in the discovery of 75 ACS-related urinary peptides. Combining these to a peptide pattern, we established a prognostic biomarker named Acute Coronary Syndrome Predictor 75 (ACSP75). ACSP75 demonstrated reasonable prognostic discrimination (c-statistic = 0.664), which was similar to Framingham risk scoring (c-statistics = 0.644) in a validation cohort of 42 cases and 42 controls. However, generating by a composite algorithm named Acute Coronary Syndrome Composite Predictor (ACSCP), combining the biomarker pattern ACSP75 with the previously established urinary proteomic biomarker CAD238 characterizing coronary artery disease as the underlying aetiology, and age as a risk factor, further improved discrimination (c-statistic = 0.751) resulting in an added prognostic value over Framingham risk scoring expressed by an integrated discrimination improvement of 0.273 ± 0.048 (P < 0.0001) and net reclassification improvement of 0.405 ± 0.113 (P = 0.0007). In conclusion, we demonstrate that urinary peptide biomarkers have the potential to predict future ACS events in asymptomatic patients. Further large scale studies are warranted to determine the role of urinary biomarkers in clinical practice.

Compromised bone structural and mechanical properties are implicated in the increased fracture risk in type 1 diabetes (T1D). We investigated bone structure and turnover by histomorphometry in postmenopausal women with T1D and controls without diabetes using tetracycline double‐labeled transiliac bone biopsy. After in vivo tetracycline double labeling, postmenopausal women with T1D of at least 10 years and without diabetes underwent transiliac bone biopsy. An expert blinded to the study group performed histomorphometry. Static and dynamic histomorphometry measurements were performed and compared between the two groups. The analysis included 9 postmenopausal women with T1D (mean age 58.4 ± 7.1 years with 37.9 ± 10.9 years of diabetes and HbA1c 7.1% ± 0.4%) and 7 postmenopausal women without diabetes (mean age 60.9 ± 3.3 years and HbA1c 5.4% ± 0.2%). There were no significant differences in serum PTH (38.6 ± 8.1 versus 51.9 ± 23.9 pg/mL), CTX (0.4 ± 0.2 versus 0.51 ± 0.34 ng/mL), or P1NP (64.5 ± 26.2 versus 87.3 ± 45.3 ng/mL). Serum 25‐hydroxyvitamin D levels were higher in T1D than in controls (53.1 ± 20.8 versus 30.9 ± 8.2 ng/mL, p < 0.05). Bone structure metrics (bone volume, trabecular thickness, trabecular number, and cortical thickness) were similar between the groups. Indices of bone formation (osteoid volume, osteoid surface, and bone formation rate) were 40% lower in T1D and associated with lower activation frequency. However, the differences in bone formation were not statistically significant. Long‐standing T1D may affect bone turnover, mainly bone formation, without significantly affecting bone structure. Further research is needed to understand bone turnover and factors affecting bone turnover in people with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. Bone Turnover in Postmenopausal women with T1D.

BACKGROUNDElevated circulating branched chain amino acids (BCAAs), measured at a single time point in middle life, are strongly associated with an increased risk of developing type 2 diabetes mellitus (DM). However, the longitudinal patterns of change in BCAAs through young adulthood and their association with DM in later life are unknown.METHODSWe serially measured BCAAs over 28 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of apparently healthy Black and White young adults at baseline. Trajectories of circulating BCAA concentrations from years 2-30 (for prevalent DM) or years 2-20 (for incident DM) were determined by latent class modeling.RESULTSAmong 3,081 apparently healthy young adults, trajectory analysis from years 2-30 revealed 3 distinct BCAA trajectory groups: low-stable (n = 1,427), moderate-stable (n = 1,384), and high-increasing (n = 270) groups. Male sex, higher body mass index, and higher atherogenic lipid fractions were more common in the moderate-stable and high-increasing groups. Higher risk of prevalent DM was associated with the moderate-stable (OR = 2.59, 95% CI: 1.90-3.55) and high-increasing (OR = 6.03, 95% CI: 3.86-9.43) BCAA trajectory groups in adjusted models. A separate trajectory group analysis from years 2-20 for incident DM after year 20 showed that moderate-stable and high-increasing trajectory groups were also significantly associated with higher risk of incident DM, after adjustment for clinical variables and glucose levels.CONCLUSIONBCAA levels track over a 28-year span in most young adults, but serial clinical metabolomic measurements identify subpopulations with rising levels associated with high risk of DM in later life.FUNDINGThis research was supported by the NIH, under grants R01 HL146844 (JTW) and T32 HL069771 (MRC). The CARDIA study is conducted and supported by the NIH National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I).

To examine whether continuous glucose monitoring (CGM) with remote monitoring by followers (family/friends) changes glucose management, follower interventions, and health outcomes compared to CGM alone in pregnant women with diabetes. We prospectively stratified first trimester pregnant women with Type 1 Diabetes to CGM Share (remote monitoring) or CGM Alone. We enrolled a main follower per woman. We retrospectively acquired data for pregnant women who did not use CGM (no CGM). We compared hemoglobin A1c (HbA1c) between groups. We compared sensor glucose, follower interventions, and gestational outcomes between CGM Alone and CGM Share. Longitudinal mixed effects models were used for analyses of changes in outcomes over time. HbA1c decreased in all groups throughout pregnancy and was significantly lower over time in women using CGM Share (n = 15) compared to CGM Alone (n = 13) or no CGM (n = 8) (p = 0.0042). CGM Share users had lower median sensor glucose levels (p = 0.0331) and percent time spent >180 mg/dL (p = 0.0228) across pregnancy. There were no significant differences in maternal and fetal outcomes between groups. CGM Share followers had more alerts for hypoglycemia, but did fewer interventions. In this small pilot study, use of CGM with remote monitoring improved some glycemic metrics in pregnant women with diabetes.

To evaluate the associations of ultra-processed food (UPF) consumption and obesity indicators among individuals with and without type 1 diabetes mellitus (T1DM) from the Coronary Artery Calcification in Type 1 Diabetes cohort study. A secondary analysis. The consumption of UPF was assessed using the dietary data collected with the Harvard FFQ, and each food item was categorised according to the NOVA food processing classification. Height, weight and waist circumference were measured at baseline and after a mean of 14·6-year follow-up. Generalised estimating equations stratified by diabetes status were used to assess the associations between UPF intake and obesity indicators over 14 years of follow-up. USA. A total of 600 adults (256 T1DM and 344 non-diabetic controls) aged 39 ± 9·1 years at baseline and followed up for over 14 years were included. Participants with T1DM consumed significantly more UPF than non-diabetic controls at baseline: 7·6 ± 3·8 . 6·6 ± 3·4 servings per day of UPF, respectively ( < 0·01). Participants with T1DM and with the highest UPF intake had the highest weight ( = 3·07) and BMI ( = 1·02, all < 0·05) compared with those with the lowest UPF intake. Similar positive associations were observed in non-diabetic controls. Individuals with T1DM may consume more UPF than non-diabetic controls. Positive associations between UPF consumption and obesity indicators suggest that limiting UPF can be recommended for obesity prevention and management. Further research is needed to confirm these findings.

Background Dietary fiber has been recommended for glucose control, and typically low intakes are observed in the general population. The role of fiber in glycemic control in reported literature is inconsistent and few reports are available in populations with type 1 diabetes (T1D). Methods Using data from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study [ n  = 1257; T1D: n  = 568; non-diabetic controls: n  = 689] collected between March 2000 and April 2002, we examined cross-sectional (baseline) and longitudinal (six-year follow-up in 2006–2008) associations of dietary fiber and HbA1c. Participants completed a validated food frequency questionnaire, and a physical examination and fasting biochemical analyses (12 h fast) at baseline visit and at the year 6 visit. We used a linear regression model stratified by diabetes status, and adjusted for age, sex and total calories, and diabetes duration in the T1D group. We also examined correlations of dietary fiber with HbA1c. Results Baseline dietary fiber intake and serum HbA1c in the T1D group were 16 g [median (IQ): 11–22 g) and 7.9 ± 1.3% mean (SD), respectively, and in the non-diabetic controls were 15 g [median (IQ): 11–21 g) and 5.4 ± 0.4%, respectively. Pearson partial correlation coefficients revealed a significant but weak inverse association of total dietary fiber with HbA1c when adjusted for age, sex, diabetes status and total calories (r = − 0.07, p  = 0.01). In the adjusted linear regression model at baseline, total dietary fiber revealed a significant inverse association with HbA1c in the T1D group [β ± SE = − 0.32 ± 0.15, p  = 0.034], as well as in the non-diabetic controls [− 0.10 ± 0.04, p  = 0.009]. However, these results were attenuated after adjustment for dietary carbohydrates, fats and proteins, or for cholesterol and triglycerides. No such significance was observed at the year 6 follow-up, and with the HbA1c changes over 6 years. Conclusion Thus, at observed levels of intake, total dietary fiber reveals modest inverse associations with poor glycemic control. Future studies must further investigate the role of overall dietary quality adjusting for fiber-rich foods in T1D management.

Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9–23) mimotopes engineered to bind the mouse MHCII molecule, IA ᵍ⁷, in an unfavorable position or register. Because of the similarities between IA ᵍ⁷ and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9–23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9–23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset. Significance Certain class II major histocompatibility alleles confer disease risk for type 1 diabetes (T1D). Insulin-specific and other autoantibodies often precede T1D development, but major efforts at disease prevention using insulin preparations (subcutaneous, oral, and intranasal) to induce tolerance have not been effective. Measuring insulin-specific T-cell responses from the peripheral blood has been a challenging feat but would allow for assessment of therapeutic response in these trials. In our study, we report CD4 T-cell responses to a mutated insulin B-chain peptide in new-onset and established T1D as well as control subjects dependent on HLA-DQ genotype. Our results have important implications for the application and monitoring of insulin-specific therapies to prevent diabetes onset.

Type 1 diabetes (T1D) has been associated with increased risks of atherosclerotic cardiovascular disease, and poor glycemic control and oxidative stress play a major role in its pathology. There is a lack of data on the role of dietary antioxidant micronutrients, including vitamins and trace elements, in glycemic control in T1D. The aim of this study is to examine associations of dietary intakes of micronutrients with glycemic status. We report data from a cross-sectional analysis from the coronary artery calcification in type 1 diabetes (CACTI) study (n=1257; T1D: n=568; nondiabetic controls: n=689) collected between the years 2000 and 2002. Participants completed a validated food frequency questionnaire, a physical examination, and biochemical analyses. Linear regression was used to examine the associations of dietary antioxidant micronutrients with HbA1c and estimated insulin sensitivity (eIS) in models adjusted for relevant covariates and stratified by diabetes status. In adults with T1D, we observed higher dietary manganese intake associated with higher eIS in the model adjusted for age, sex, diabetes duration, and total calories. In nondiabetic controls, higher intake of manganese associated with lower HbA1c and higher eIS values that persisted in models adjusted for all relevant covariates. On the other hand, dietary copper revealed a positive association with HbA1c in models adjusted for all covariates, except BMI and plasma lipids. No associations were noted for vitamins C and E and dietary carotenoids in either group. These findings reveal dietary antioxidant micronutrients, especially trace elements such as copper and manganese deserve special attention in glycemic control in adults with T1D as well as in nondiabetic controls.This trial is register with NCT00005754.

Type 1 diabetes (T1D) increases fracture risk across the lifespan. The low bone turnover associated with T1D is thought to be related to glycemic control, but it is unclear whether peripheral hyperinsulinemia due to dependence on exogenous insulin has an independent effect on suppressing bone turnover. The purpose of this study was to test the bone turnover marker (BTM) response to acute hyperinsulinemia. Fifty‐eight adults aged 18 to 65 years with T1D over 2 years were enrolled at seven T1D Exchange Clinic Network sites. Participants had T1D diagnosis between age 6 months to 45 years. Participants were stratified based on their residual endogenous insulin secretion measured as peak C‐peptide response to a mixed meal tolerance test. BTMs (CTX, P1NP, sclerostin [SCL], osteonectin [ON], alkaline phosphatase [ALP], osteocalcin [OCN], osteoprotegerin [OPG], osteopontin [OPN], and IGF‐1) were assessed before and at the end of a 2‐hour hyperinsulinemic‐euglycemic clamp (HEC). Baseline ON (r = −0.30, p = .022) and OCN (r = −0.41, p = .002) were negatively correlated with age at T1D diagnosis, but baseline BTMs were not associated with HbA1c. During the HEC, P1NP decreased significantly (−14.5 ± 44.3%; p = .020) from baseline. OCN, ON, and IGF‐1 all significantly increased (16.0 ± 13.1%, 29.7 ± 31.7%, 34.1 ± 71.2%, respectively; all p < .001) during the clamp. The increase in SCL was not significant (7.3 ± 32.9%, p = .098), but the decrease in CTX (−12.4 ± 48.9, p = .058) neared significance. ALP and OPG were not changed from baseline (p = .23 and p = .77, respectively). Baseline ON and SCL were higher in men, but OPG was higher in women (all p ≤ .029). SCL was the only BTM that changed differently in women than men. There were no differences in baseline BTMs or change in BTMs between C‐peptide groups. Exogenous hyperinsulinemia acutely alters bone turnover, suggesting a need to determine whether strategies to promote healthy remodeling may protect bone quality in T1D. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.