Diabetes Australia

Aging is accompanied by chronic low-grade inflammation (inflammaging), driving age-related diseases. Urolithin A (UA), a gut microbial metabolite, possesses anti-inflammatory properties, yet its mechanism in hepatic aging remains unclear. This study investigated UA's effects on aging-associated inflammation and the involvement of Nur77 in D-galactose-induced macrophage senescence and mouse liver aging models using molecular docking, Western blotting, and immunoprecipitation. UA alleviated cellular senescence markers (p53, p21), suppressed pro-inflammatory factors (IL-6, IL-1β), and elevated anti-inflammatory IL-10. Mechanistically, UA enhanced Nur77 protein stability by inhibiting MDM2-mediated ubiquitination and degradation, thereby restoring inflammatory homeostasis. In vivo, UA ameliorated D-gal-induced liver injury and modulated the hepatic Nur77-MDM2 axis. Conclusion: UA stabilizes Nur77 by inhibiting its ubiquitination, alleviating hepatic aging-associated inflammation. This study identifies the MDM2-Nur77 axis as a potential therapeutic target for hepatic aging.

Risk differences allow decision makers to easily estimate the excess safety risk associated with a medical product relative to the potential benefits. However, in post-market observational surveillance studies that actively monitor (e.g., sequentially over time) for safety risk of new medical products, available methods target a relative measure (e.g., odds ratio and relative risk), which can be especially unstable in the rare event setting. These studies are typically conducted within distributed healthcare networks (e.g., Food and Drug Administration [FDA] Sentinel and Centers for Disease Control [CDC] Vaccine Safety Datalink) with patient-level data protected behind firewalls, but sharing of aggregate, deidentified data for centralized analyses. We propose an inverse probability of treatment weighting (IPTW) method that uses site-specific propensity scores to estimate site-specific risk differences that are combined to create an overall stratified risk difference estimate. This method is tailored to the rare event setting and requires minimal data sharing. The stratified IPTW approach is then extended to the active post-market surveillance setting by incorporating group sequential monitoring boundaries using a novel permutation approach. A simulation study is conducted to evaluate the performance of the new methods relative to two centralized analysis approaches, and the methods are applied to a safety surveillance study comparing the risk of febrile seizure between two vaccines using FDA Sentinel Data from three healthcare organizations.

To identify meaningful clusters of participants with shared baseline characteristics (demographic, clinical, and psychological) from a sample of adults with type 1 diabetes (T1D) completing dose adjustment for normal eating (DAFNE) structured T1D education, or the updated DAFNEplus programme. Further, to determine whether those clusters respond differently, at 6- and 12 months, to DAFNE and DAFNEplus on core outcomes: HbA1c and diabetes-specific quality of life (QoL). Latent profile analysis was conducted on the DAFNEplus randomised control trial dataset using relevant indicator variables (age; HbA1c; hypoglycaemia awareness; diabetes-specific QoL, distress, and positive well-being; fear of hypoglycaemia; satisfaction with diabetes management). Model fit indices were used to select the optimal number of clusters and multilevel linear regression models to estimate the effect of DAFNEplus (compared with DAFNE) on HbA1c and diabetes-specific QoL in each cluster. A total of n = 363 participants were included in the analysis (n = 147, 40% randomised to DAFNEplus). The final model included two clusters: the first was consistently worse off on clinical and psychological indicator variables. The multilevel analysis showed a significant adjusted mean difference, at 12 months (first cluster only), between DAFNE and DAFNEplus in diabetes-specific QoL (0.81; 95% CI: 0.19-1.43; p = 0.01), but not at other time points or in HbA1c. This study suggests that DAFNEplus has significant added benefits in reducing the negative impact of diabetes on QoL for a subgroup of adults with T1D, but not for their HbA1c. This provides important insights for the future real-world implementation of the DAFNEplus programme.

Background/Objectives: Gonadotroph adenomas (GA), classically known as poorly differentiated tumors that secrete hormones inefficiently, are often misdiagnosed as nonfunctioning macroadenomas (NFA) 1 .Our series aims to challenge conventional views on GA as uniformly silent by demonstrating these tumors can exhibit subtle to overt hormonal and structural activity with significant clinical consequences.This series serves as a resource to general endocrinologists with an approach that enables early functional GA (FGA) recognition and treatment.Case Series: A premenopausal woman with recurrent resistant FGA and ovarian hyperstimulation syndrome (OHSS) was managed over ten years with multiple surgeries and medical therapies.Two men presented with visual decline and abnormal gonadotropin biochemical testing.Discussion: Despite most being clinically silent, GA variably express gonadotropin hormones by immunohistochemistry (IHC).A clinically significant subset presents with increased serum gonadotropins which can lead to infertility, OHSS, and testicular enlargement.The pathogenesis is not well established, but it has been shown that gonadotropin releasing hormone receptor (GnRHR) gene expression is enriched in FGA compared to non-functioning GA.Resection is the standard upfront treatment with medical therapy and consideration of radiation therapy in recurrent/refractory cases. Conclusion:FGA exists in a functional spectrum rather than as uniformly silent tumors.Transsphenoidal surgery (TSS) remains the mainstay of therapy.Medical management may provide periods of short-term control.This study aims to increase awareness of the not-so-silent and not-so-rare presentations of GA and describe management strategies.

Aims/hypothesis Subcutaneous insulin delivery in individuals with insulin-deficient type 1 diabetes bypasses the portal circulation, disrupting the physiological porto-systemic insulin gradient and affecting postprandial hepatic glucose regulation. However, direct, non-invasive measurement of these liver-specific dynamics and their deviation from normal physiology in individuals with type 1 diabetes is challenging. To address this, we integrated metabolic imaging with whole-body tracer dilution to map postprandial glucose metabolism in both the liver and systemically in adults with type 1 diabetes and healthy control individuals.Methods In this cross-sectional study, ten adults with type 1 diabetes and ten healthy control individuals with similar age, BMI and gender distributions were enrolled. After an overnight fast, participants ingested 60 g [6,6'-2H2]-glucose (D-Glc); subcutaneous insulin was administered to type 1 diabetes participants according to their carbohydrate-to-insulin ratio. Interleaved deuterium metabolic imaging (DMI) and 13C-magnetic resonance spectroscopy (13C-MRS) at 7 T were performed from pre-ingestion to 150 min post-ingestion to quantify hepatic D-Glc and glycogen concentrations. Blood samples were collected to measure plasma glucose, insulin and glucagon. Postprandial glucose-insulin dynamics were quantified using the single tracer oral minimal model, accounting for non-steady-state insulin exposure.Results At baseline, individuals with type 1 diabetes had significantly higher plasma glucose concentrations than control individuals (10.7±2.3 and 5.2±0.4 mmol/l, respectively; p<0.001), while preprandial glycogen levels did not differ significantly. Following D-Glc administration, hepatic D-Glc increased more markedly in the individuals with type 1 diabetes compared with the control group (peak values 4.7±2.0 and 3.0±0.8 mmol/l, respectively; p=0.02). In the postprandial period, glycogen levels did not significantly rise at 150 min in type 1 diabetes, whereas a clear increase was observed in control individuals (iAUC0-180=2.4 mol/l × min). Despite similar systemic insulin exposure and no significant differences in postprandial glucagon concentrations between groups, individuals with type 1 diabetes demonstrated significantly reduced suppression of endogenous glucose production (p=0.001) but similar insulin-dependent glucose disposal. Hierarchical clustering identified two distinct type 1 diabetes subgroups: Subgroup 1 exhibited a steeper increase in both hepatic and systemic D-Glc profiles, while subgroup 2 showed a divergent D-Glc trajectory and net glycogen depletion relative to accumulation in subgroup 1 (iAUC0-180=-3.0 vs 2.5 mol/l × min, p=0.04), despite no overt clinical differences between subgroups.Conclusions/interpretation By integrating DMI/13C-MRS liver imaging with systemic stable-isotope modelling, this comparative study demonstrates significantly altered hepatic glucose metabolism in adults with well-managed type 1 diabetes vs control individuals, together with substantial phenotypic heterogeneity within the type 1 diabetes cohort. These findings highlight the potential of non-invasive metabolic phenotyping to resolve metabolic alterations and inter-individual variation in type 1 diabetes, which are essential steps towards the provision of precision medicine.

Background/Objectives: A stem cell therapy for type 1 diabetes (T1D) is experimentally available but only to those few humans in whom the use of systemic immunosuppression can be justified. For others with T1D, a means to deliver the islets needs to be perfected. We have previously bioengineered a removable device for this purpose and now wish to test the effect of adding extracellular matrix (ECM) derived from decellularised human pancreas to it. Methods: The complete device consists of encapsulated pluripotent stem cell differentiated islets seeded into tubular scaffolds of polycaprolactone made by melt electrospin writing and to which ECM was added. The seeded device was implanted either subcutaneously (SC) or intraperitoneally (IP) into streptozotocin diabetic immunodeficient mice. The outcome over the next few months was compared with that achieved in diabetic mice implanted IP with encapsulated islets alone. Results: The device seeded with encapsulated islets but not containing ECM functioned less well than encapsulated islets implanted alone, with lower human C-peptide production. However, when ECM was added to the seeded device and whether implanted SC or IP, islets functioned as efficiently as those implanted without use of a scaffold. Conclusions: These data provide optimism for the use of seeded scaffolds in diabetic humans in whom a single scaffold seeded with multiple encapsulated islets can more readily be removed if needed for safety reasons than can multiple encapsulated islets not seeded into a scaffold.