Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.

Context: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis. Objective: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States. Methods: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions. Results: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes. Conclusion: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.

ROUTE-T1D: A behavioral intervention to promote optimal continuous glucose monitor use among racially minoritized youth with type 1 diabetes: Design and development.

BACKGROUND: Type 1 diabetes management is often challenging during adolescence, and many youth with type 1 diabetes struggle with sustained and optimal continuous glucose monitor (CGM) use. Due to racial oppression and racially discriminatory policies leading to inequitable access to quality healthcare and life necessities, racially minoritized youth are significantly less likely to use CGM. METHODS: ROUTE-T1D: Research on Optimizing the Use of Technology with Education is a pilot behavioral intervention designed to promote optimal CGM use among racially minoritized youth with type 1 diabetes. Intervention strategies include problem solving CGM challenges and promoting positive caregiver-youth communication related to CGM data. RESULTS: This randomized waitlist intervention provides participants with access to three telemedicine sessions with a Certified Diabetes Care and Education Specialist. Caregiver participants are also connected with a peer-parent coach. CONCLUSION: Hypothesized findings and anticipated challenges are discussed. Future directions regarding sustaining and optimizing the use of diabetes technology among racially minoritized pediatric populations are reviewed.

Social Determinants of Health Screening in Type 1 Diabetes Management.

Type 1 diabetes management is intricately influenced by social determinants of health. Economic status impacts access to vital resources like insulin and diabetes technology. Racism, social injustice, and implicit biases affect equitable delivery of care. Education levels affect understanding of self-care, leading to disparities in glycemic outcomes. Geographic location can limit access to health care facilities. Stressors from discrimination or financial strain can disrupt disease management. Addressing these social factors is crucial for equitable diabetes care, emphasizing the need for comprehensive strategies that go beyond medical interventions to ensure optimal health outcomes for all individuals with type 1 diabetes.

Young Adults with Type 1 Diabetes.

Young adults experience multiple developmental transitions across social, educational, vocational, residential, and financial life domains. These transitions are potential competing priorities to managing a chronic condition such as type 1 diabetes and can contribute to poor psychosocial and medical outcomes. In this narrative review, we describe population outcomes of young adult populations and the unique considerations associated with managing type 1 diabetes in young adulthood. We provide an overview of the current evidence-based strategies to improve care for young adults with type 1 diabetes and recommendations for future directions in the field.

Increasing Continuous Glucose Monitoring Use for Non-Hispanic Black and Hispanic People With Type 1 Diabetes: Results From the T1D Exchange Quality Improvement Collaborative Equity Study.

Despite the benefits of continuous glucose monitoring (CGM), there is lower use of this technology among non-Hispanic Black and Hispanic people with type 1 diabetes compared with their non-Hispanic White counterparts. The T1D Exchange Quality Improvement Collaborative recruited five endocrinology centers to pilot an equity-focused quality improvement (QI) study to reduce racial inequities in CGM use. The centers used rapid QI cycles to test and expand interventions such as provider bias training, translation of CGM materials, provision of CGM education in multiple languages, screening for social determinants of health, and shared decision-making. After implementation of these interventions, median CGM use increased by 7% in non-Hispanic White, 12% in non-Hispanic Black, and 15% in Hispanic people with type 1 diabetes. The gap between non-Hispanic White and non-Hispanic Black patients decreased by 5%, and the gap between non-Hispanic White and Hispanic patients decreased by 8%.

Association between insulin and Nrf2 signalling pathway in Alzheimer's disease: A molecular landscape.

Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD.

The Ndc80-Cdt1-Ska1 complex is a central processive kinetochore-microtubule coupling unit.

It is known that microtubule-binding proteins including the Ska1 complex and the DNA replication licensing factor, Cdt1, enable the kinetochore-localized Ndc80 complex to form robust kinetochore-microtubule attachments. However, it is not clear how the Ndc80 complex is stably coupled to dynamic spindle microtubule plus-ends. Here, we have developed a conditional auxin-inducible degron approach to reveal a function for Cdt1 in chromosome segregation and kinetochore-microtubule interactions that is separable from its role in DNA replication licensing. Further, we demonstrate that a direct interaction between Cdt1 and Ska1 is required for recruiting Cdt1 to kinetochores and spindle microtubules. Cdt1 phosphorylation by Cdk1 kinase is critical for Ska1 binding, kinetochore-microtubule attachments, and mitotic progression. Furthermore, we show that Cdt1 synergizes with Ndc80 and Ska1 for microtubule binding, including forming a diffusive, tripartite Ndc80-Cdt1-Ska1 complex that can processively track dynamic microtubule plus-ends in vitro. Taken together, our data identify the Ndc80-Cdt1-Ska1 complex as a central molecular unit that can promote processive bidirectional tip-tracking of microtubules by kinetochores.

The role of structural racism and geographical inequity in diabetes outcomes.

Diabetes is pervasive, exponentially growing in prevalence, and outpacing most diseases globally. In this Series paper, we use new theoretical frameworks and a narrative review of existing literature to show how structural inequity (structural racism and geographical inequity) has accelerated rates of diabetes disease, morbidity, and mortality globally. We discuss how structural inequity leads to large, fixed differences in key, upstream social determinants of health, which influence downstream social determinants of health and resultant diabetes outcomes in a cascade of widening inequity. We review categories of social determinants of health with known effects on diabetes outcomes, including public awareness and policy, economic development, access to high-quality care, innovations in diabetes management, and sociocultural norms. We also provide regional perspectives, grounded in our theoretical framework, to highlight prominent, real-world challenges.

Interventions to address global inequity in diabetes: international progress.

Diabetes is a serious chronic disease with high associated burden and disproportionate costs to communities based on socioeconomic, gender, racial, and ethnic status. Addressing the complex challenges of global inequity in diabetes will require intentional efforts to focus on broader social contexts and systems that supersede individual-level interventions. We codify and highlight best practice approaches to achieve equity in diabetes care and outcomes on a global scale. We outline action plans to target diabetes equity on the basis of the recommendations established by The Lancet Commission on Diabetes, organising interventions by their effect on changing the ecosystem, building capacity, or improving the clinical practice environment. We present international examples of how to address diabetes inequity in the real world to show that approaches addressing the individual within a larger social context, in addition to addressing structural inequity, hold the greatest promise for creating sustainable and equitable change that curbs the global diabetes crisis.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits ß-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

Ferroptosis: the vulnerability within a cancer monster.

Treatment-resistant cancer, such as neuroendocrine prostate cancer (NEPC), is a lethal disease with limited therapeutic options. RB1 is a tumor suppressor gene that is lost in a majority of NEPC tumors. In this issue of the JCI, Wang and colleagues examined how RB1 loss may sensitize cancer cells to ferroptosis inducers through elevation of ACSL4, a key enzyme that promotes lipid peroxidation and triggers ferroptosis. We discuss a high potential of RB1-deficient cells to undergo ferroptosis due to the elevation of ACSL4. This is normally kept in check by abundant expression of GPX4, an antioxidant enzyme, in cancer cells. This balance, however, is tilted by GPX4 inhibitors, leading to massive ferroptosis. We highlight possible therapeutic strategies that exploit this inherent vulnerability for targeting RB1-deficient, treatment-resistant cancer.

Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer.

The hormonal transcription factor androgen receptor (AR) is a master regulator of prostate cancer (PCa). Protein palmitoylation, which attaches a palmitate fatty acid to a substrate protein, is mediated by a class of 23 ZDHHC (Zinc-Finger DHHC motif)-family palmitoyltransferases. Although palmitoylation has been shown to modify many proteins and regulate diverse cellular processes, little is known about ZDHHC genes in cancer. Here we examined ZDHHC family gene expression in human tissue panels and identified ZDHHC7 as a PCa-relevant member. RNA-seq analyses of PCa cells with ZDHHC7 de-regulation revealed global alterations in androgen response and cell cycle pathways. Mechanistically, ZDHHC7 inhibits AR gene transcription and therefore reduces AR protein levels and abolishes AR signaling in PCa cells. Accordingly, ZDHHC7 depletion increased the oncogenic properties of PCa cells, whereas restoring ZDHHC7 is sufficient to suppress PCa cell proliferation and invasion in vitro and mitigate xenograft tumor growth in vivo. Lastly, we demonstrated that ZDHHC7 is downregulated in human PCa compared to benign-adjacent tissues, and its loss is associated with worse clinical outcomes. In summary, our study reveals a global role of ZDHHC7 in inhibiting androgen response and suppressing PCa progression and identifies ZDHHC7 loss as a biomarker for aggressive PCa and a target for therapeutic intervention.

Glycemic Risk Index Profiles and Predictors Among Diverse Adults With Type 1 Diabetes.

BACKGROUND: The Glycemia Risk Index (GRI) was introduced as a single value derived from the ambulatory glucose profile that identifies patients who need attention. This study describes participants in each of the five GRI zones and examines the percentage of variation in GRI scores that is explained by sociodemographic and clinical variables among diverse adults with type 1 diabetes. METHODS: A total of 159 participants provided blinded continuous glucose monitoring (CGM) data over 14 days (mean age [SD] = 41.4 [14.5] years; female = 54.1%, Hispanic = 41.5%). Glycemia Risk Index zones were compared on CGM, sociodemographic, and clinical variables. Shapley value analysis examined the percentage of variation in GRI scores explained by different variables. Receiver operating characteristic curves examined GRI cutoffs for those more likely to have experienced ketoacidosis or severe hypoglycemia. RESULTS: Mean glucose and variability, time in range, and percentage of time in high, and very high, glucose ranges differed across the five GRI zones (P values < .001). Multiple sociodemographic indices also differed across zones, including education level, race/ethnicity, age, and insurance status. Sociodemographic and clinical variables collectively explained 62.2% of variance in GRI scores. A GRI score ≥84.5 reflected greater likelihood of ketoacidosis (area under the curve [AUC] = 0.848), and scores ≥58.2 reflected greater likelihood of severe hypoglycemia (AUC = 0.729) over the previous six months. CONCLUSIONS: Results support the use of the GRI, with GRI zones identifying those in need of clinical attention. Findings highlight the need to address health inequities. Treatment differences associated with the GRI also suggest behavioral and clinical interventions including starting individuals on CGM or automated insulin delivery systems.

Clinical and Social Outcomes of Cochlear Implantation in Older Prelinguals.

BACKGROUND AND OBJECTIVES: Cochlear implantation in late implanted prelinguals necessitates a complex decision-making process for clinicians and patients due to the uncertainty of achieving adequate benefit in auditory and speech perception. This study longitudinally evaluated clinical and social outcomes of prelingually deaf children with implantation in their late childhood. Subjects and. METHODS: A total of 113 (49 females and 64 males) participants, with an age range of 5-15 years, were assessed for the pre-implant parameters such as hearing loss etiology, aided responses, anatomical aspects, and psychological evaluation. The Category of Auditory Performance, Speech Awareness Threshold, Speech Reception Threshold, and Speech Discrimination Score were administered to assess the patient's auditory skills. Further, the Speech Intelligibility Rating scale was administered to evaluate the patient's speech intelligibility at 3, 6, 9, 12, 18, and 24 months post-surgery. Subjectively perceived benefits were evaluated using the satisfaction rating scale and a questionnaire. RESULTS: The statistical results showed a significant impact of cochlear implantation in all domains. Positive impact and improvement post-implantation were noted in all the spheres, including auditory, linguistic, social, and educational. CONCLUSIONS: The study highlighted that the outcomes of a cochlear implant at a later age might not parallel with the implantation at a younger age. However, this still provides measurable benefits even after a longer period of auditory deprivation.

XPS Investigation on Improving Hydrogen Sorption Kinetics of the KSiH3 System by Using Zr-Based Catalysts.

The superior hydrogen storage properties makes the KSiH3 system a potential hydrogen storage material for practical applications. A theoretical capacity of 4.3 wt% bring this material to the front line of all the available hydrogen storage materials; however, the activation barrier of the reaction restricts the system to absorb and desorb hydrogen reversibly at elevated temperatures even if the thermodynamics suggest its room temperature operation. Several catalysts have already been tested to enhance its kinetic properties. In this work, the efforts were made to reduce the activation energy by using Zr-based catalysts to the KSi/KSiH3 system. The value of activation energy was found to be lowest (i.e., 87 kJ mol-1) for the ZrH2-added KSiH3 system. The mechanism of this improvement was investigated by using X-ray photoelectron spectroscopy (XPS).