Laura Pyle

Objective: Compare continuous glucose monitoring (CGM) and other metabolic markers in progression to stage 3 type 1 diabetes (T1D) in early-stage T1D and evaluate CGM time above 140 mg/dL (TA140) across different stages. Methods: In a combined dataset from three prospective studies, 152 early-stage T1D individuals had baseline CGM, oral glucose tolerance test (OGTT) and HbA1c with 54 (36%) progressing to stage 3. ROC curves were generated to compare the areas under the curve (AUC) for stage 3 prediction. Risk of progression was estimated by Accelerated Failure Time (AFT) and Kaplan–Meier analyses. Results: TA140 > 10% and 2-hour glucose > 140 mg/dL had the exact same specificity (83%), negative predictive value (88%), and sensitivity (55%) for stage 3 prediction at 2 years. In univariable AFT, the HRs for stage 3 at 5 years were significant for all CGM metrics tested (all P ≤ .008), while significant OGTT metrics included 2-hour glucose, AUC_glucose, AUC_C-peptide, and peak_C-peptide (all P ≤ .021). In multivariable AFT, younger age, male sex, HbA1c ≥ 5.7%, TA140 > 15%, and 2-hour glucose > 140 mg/dL were strong predictors of accelerated progression to stage 3. Cumulative incidence curves for stage 3 were similar for TA140 > 15%, HbA1c ≥ 5.7% and 2-hour glucose > 140 mg/dL. Among 406 longitudinal CGMs, participants at stage 3 had higher median TA140 (17.2%, IQR 7.9-33.2) compared to stage 2 (8.6%, IQR 3.8-15.2) and stage 1 (3.2%, IQR 1.3-7.7) (all pairwise P ≤ .024). Conclusion: In this largest dataset of individuals at early-stage T1D, we define CGM-derived TA140 criteria for the various stages. Furthermore, we show that TA140 has similar performance to a 2-hour OGTT value for predicting stage 3.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.

Youth-onset type 2 diabetes (T2D) is characterized by accelerated β-cell decline and early treatment failure, and there is an urgent need to improve the understanding of molecular drivers of loss of glycemic control (LOGC). To identify multiprotein signatures associated with loss of glycemic control (LOGC) in youth-onset T2D. Longitudinal observational study with a mean follow-up of 10.8 ± 3.8 years using data from the TODAY study, with external validation in three youth cohorts and one adult-onset T2D cohort. Multicenter clinical research study. Participants from the TODAY study (N = 374; age 14 ± 2 years; 37% male), of whom 72% experienced LOGC over 10.8 ± 3.8 years. None. LOGC, defined as HbA1c ≥ 8% for ≥6 months or inability to discontinue insulin after acute metabolic decompensation. Plasma proteomics quantified 7604 aptamers representing 6596 proteins using the SomaScan 7 K platform. Sixty-seven proteins were associated with LOGC after false discovery rate correction and multivariable adjustment. Key proteins included plexin-B2 (HR: 1.46 [95% CI: 1.29-1.66]) and semaphorin-6A (HR: 1.31 [1.18-1.47]), which were also associated with glycemic outcomes in independent youth and adult cohorts. Enrichment analyses implicated pathways related to axon guidance, immune response, inflammation, and metabolism. Novel proteins involved in axon guidance, immune response, inflammation, and metabolism associated with LOGC in youth-onset T2D with proteins demonstrating consistent associations across the lifespan and proteomic platforms.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants with AKI and CKD enrolled within the Kidney Precision Medicine Project (KPMP) and did so at the patient participant level. Using an unsupervised approach, we identified two multi-cellular programs associated with clinical and histopathological features of acute injury and chronic damage, respectively. We found that these programs are expressed across patients with AKI and CKD, supporting shared, rather than distinct, underlying molecular mechanisms. These programs capture tissue-level compositional changes towards adaptive and failed-repair states in tubular epithelial cells, as well as intra-cellular molecular changes characteristic of stress in all cell types. We identified subunits of the NFkB and AP-1 complexes, as well as members of the STAT family, as putative upstream regulators of the acute and chronic programs. We were able to map these continuous molecular measures of acute injury and chronic damage to urine and plasma protein profiles obtained at time of biopsy. These non-invasive protein signatures were predictive of renal outcomes in an independent cohort of 44 thousand participants from the UK biobank. In summary, unbiased identification of cellular programs in kidney disease biopsies defined molecular programs of injury cutting across conventional disease categorization and established a non-invasive molecular link to long term patient outcomes. Graphical

OBJECTIVE: In this post hoc analysis, we used the data from the Adjunct Semaglutide Treatment in Type 1 Diabetes (ADJUST-T1D) trial, a double-blind, multicenter, randomized, placebo-controlled trial of semaglutide 1 mg/week in adults with type 1 diabetes (T1D) and obesity, to evaluate the relationship between insulin dose reduction and weight loss. RESEARCH DESIGN AND METHODS: Changes between semaglutide and placebo groups over 26 weeks in total daily insulin dose (TDD), basal and bolus insulin doses, carbohydrate intake, and user-initiated bolus counts were analyzed using linear mixed models. Mediation analysis was used to attribute direct effects of semaglutide versus weight loss on insulin dose reduction. RESULTS: From baseline to week 26, there was a significant 22.6% reduction in TDD (95% CI −28.3 to −17.0), which was driven by greater reductions in bolus insulin (−30.5%; 95% CI −39.5 to −21.5) than basal insulin (−15.6%; 95% CI −21.5 to −9.7). The basal-to-TDD ratio increased from 0.56 to 0.62 (P < 0.001) and insulin dose (in units/kg/day) decreased from 0.72 to 0.60 (P < 0.001) in the semaglutide group. At week 4, an 83% (−11.1 units/day) reduction in TDD was due to a direct drug effect, and 17% (−2.3 units/day) was attributed to weight loss, whereas at week 26, the difference was split evenly between direct effect (−11.4 units/day; 52%) and weight loss (−10.5 units/day; 48%). Daily carbohydrate intake decreased from 137 g (95% CI 107–167) at baseline to 107 g (95% CI 76–137) at 26 weeks. CONCLUSIONS: Semaglutide produced rapid, sustained, and primarily bolus-driven insulin dose reductions, with early effects being largely independent of weight loss in adults with T1D and obesity.

Purpose: Women are generally protected against insulin resistance and related comorbidities when compared with men, potentially due to the role of sex hormones. While epidemiological and animal studies suggest that sex hormones may impact insulin sensitivity, studies in humans on the effects of estradiol and testosterone treatment on insulin sensitivity assessed by gold-standard measures remain limited. The molecular mechanisms involved are also not well understood. Therefore, we aimed to investigate changes in insulin sensitivity and associated change in plasma proteome following 3 months of sex hormone therapy. Methods: This prospective, observational study included 29 individuals initiating feminizing (estradiol with GnRH analogue; n = 16) or masculinizing (testosterone; n = 13) therapy. Measurements at baseline and after 3 months included insulin sensitivity, assessed via hyperinsulinemic-euglycemic clamp (M-value: adjusted for lean body mass and M/I ratio: M-value adjusted for plasma insulin concentrations), along with plasma proteomics. Results: During feminizing hormone therapy, insulin sensitivity increased (M-value: + 23.3%, M/I ratio: + 20.2%; P < .05), whereas during masculinizing hormone therapy, no changes were observed. Of the differentially expressed plasma proteins (49 during feminizing and 356 during masculinizing hormone therapy), 16 correlated with changes in insulin sensitivity. Several were involved in immunoregulation and inflammation (vascular endothelial growth factor D, 5′-nucleotidase), iron homeostasis and erythropoiesis (hepcidin, transferrin receptor protein 1:cytoplasmic domain), and oxidative stress (superoxide dismutase 3). Conclusion: Feminizing hormone therapy, characterized by high serum estradiol and low serum testosterone concentrations, enhanced insulin sensitivity. These findings highlight the impact of sex hormones on insulin sensitivity and may inform sex-specific precision medicine.

Background: Engaging patients, care partners, and others in research planning and conduct is increasingly valued. However, identifying the most effective ways to do so remains a challenge. Objective: This study aimed to evaluate participation and participant experience using 3 engagement methods with the Low-Grade Glioma (LGG) Registry’s Optimizing Engagement in Discovery of Molecular Evolution of Low-Grade Glioma (OPTIMUM) project, part of the National Cancer Institute’s Participant Engagement and Cancer Genome Sequencing Network. Methods: We evaluated LGG Registry research advisory council (RAC) meetings, Twitter (now known as X), and Facebook discussions across 4 engagement activities with each group. Researchers recorded discussions and performed qualitative content analysis to evaluate differences in the nature of interactions and recommendations for promoting trust and participation in LGG Registry research. Participants completed experience surveys after engagements 1 and 4 (Public and Patient Engagement Evaluation Tool, Research Engagement Survey Tool, Trust in Medical Researchers Scale, and Patient Engagement in Research Scale). Results: RAC engagements involved 25 unique participants representing diverse backgrounds; tweet chats and Facebook discussions had 197 and 133 participants, respectively. Qualitative findings highlighted differences in the nature of interactions (eg, communication styles and types of information shared) across groups, but there was general agreement around recommendations for promoting participation in genomic research. Postengagement surveys (n=52 in ipostengagement activity 1; n=40 in postengagement activity 4) showed patterns suggesting a more positive experience overall for the RAC. Conclusions: Advisory councils and social media engagement methods have advantages and disadvantages. Advisory councils provide consistent interactions with the same individuals and clear procedures. Despite theoretically broader reach, social media engagement may yield less diverse perspectives. The LGG Registry aims to use RAC and social media engagement methods to promote diverse perspectives and maintain consistent interactions.

BACKGROUND: Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored. METHODS: This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n = 23) or masculinizing (testosterone; n = 21) therapy. Baseline and 3-month assessments included mGFR (iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics. RESULTS: During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; P < 0.05) without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, epidermal growth factor (EGF), monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (–53%, –42%, –45%, and –58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma tumor necrosis factor receptor 1 (TNFR-1) increased (+134% and +8%, respectively; P < 0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin). CONCLUSION: Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine. TRIAL REGISTRATION: Dutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).

Sexual dimorphism plays an important role in the pathogenesis and progression of CKD. Men with CKD often exhibit faster kidney function decline, leading to higher rates of kidney failure and mortality compared with women. Studies suggest that sex hormones may influence this apparent dimorphism, although the mechanisms underlying these influences remain poorly understood. In this review, we first summarize recent findings on sex differences in the prevalence and progression of CKD. Subsequently, we will focus on ( 1 ) the role of sex hormones in these sex differences, ( 2 ) kidney structural and hemodynamic differences between men and women, ( 3 ) the influence of sex hormones on pathophysiological processes leading to kidney disease, including glomerular hyperfiltration and key pathways involved in kidney inflammation and fibrosis, and finally, focus on the consequences of the underrepresentation of women in clinical trials. Understanding these sex differences is critical for advancing precision medicine and improving outcomes for both men and women with CKD.