Hypoglycaemia remains a barrier to optimal diabetes management, with few tools for capturing real-time person-reported hypoglycaemia (PRH). This study evaluated the Hypo-METRICS app, originally developed for a multinational 10-week prospective study of hypoglycaemia. It enables real-time reporting of hypoglycaemic episodes and their impact on daily functioning using Ecological Momentary Assessment (EMA), thereby overcoming limitations of retrospective self reports.

After completing the Hypo-METRICS study, 120 participants with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) from Austria, Denmark, the Netherlands, and the United Kingdom were invited to complete a web-based questionnaire assessing app content, functionality, intervention effects, user engagement and the influence of the Covid-19 pandemic.

Ninety-six participants (80%; 29 T1D, 67 T2D) completed the questionnaire (40% women; mean age 57.2 ± 16.1 years; 26% impaired hypoglycaemia awareness; HbA1c 60 ± 13 mmol/mol (7.6 ± 1.1%); diabetes duration 20.4 ± 11.3 years). App content and functionality were rated highly (>8/10 and >7/10, respectively). Some reported declining engagement, likely due to study length. COVID-19 had a minimal impact on app use.

The Hypo-METRICS app was well accepted, with strong ratings for usability and functionality. Given its unique strengths, the app has the potential to become an essential instrument for researchers aiming to capture the real-world burden and impact of hypoglycaemia.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction, posing a substantial global health challenge. This review systematically summarizes the therapeutic potential of berberine, a natural isoquinoline alkaloid, in the management of T2DM. Berberine's pharmacological activities are discussed from multiple perspectives, including enhancing insulin sensitivity and regulating glucose metabolism-encompassing glycogen synthesis, gluconeogenesis, and glucose transport. The review also highlights berberine's anti-inflammatory, antioxidant, and epigenetic enzyme-targeting actions and its involvement in key T2DM-related signaling pathways such as AKT, AMPK, and GLUTs. These findings collectively elucidate the multi-targeted and multi-pathway molecular mechanisms underlying berberine's efficacy against T2DM. Additionally, the review covers the pharmacological activities and molecular mechanisms of berberine in treating T2DM complications-including diabetic nephropathy, retinopathy, cardiomyopathy, neuropathy, and diabetic foot ulcers-as well as its clinical and preclinical applications and the synergistic benefits of combination therapy with agents such as metformin, ginsenoside Rb1, and probiotics. By systematically reviewing the literature retrieved from PubMed and Web of Science up to 2025, this article provides a comprehensive summary of current research, offering a theoretical foundation for the clinical use of berberine in T2DM therapy.

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg^-1 day^-1), EMO (200 or 400 mg kg^-1 day^-1) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO's actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG's glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG's glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG's adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy.

Background: Type 2 diabetes mellitus represents a global health challenge, with chronic hyperglycemia leading to a spectrum of microvascular and macrovascular complications. This narrative review provides a comprehensive and integrated analysis of the nerve growth factor (NGF) axis as a key, yet underrecognized, pathogenic mechanism. Methods: This narrative review was conducted in accordance with scholarly standards for non-systematic syntheses (SANRA). We included both clinical and preclinical studies focusing on NGF/proNGF biology and interventions across major diabetes complications. Discussion: Growing evidence highlights NGF as a pivotal mediator at the crossroads of neuronal, vascular and metabolic pathways. In diabetes, a disrupted balance between mature NGF and its precursor proNGF, favors the detrimental p75NTR pathway, leading to increased cellular stress, inflammation and apoptosis. In this narrative review, we examine how a decline in mature NGF and a relative excess of proNGF contribute to the pathophysiology of diabetic complications across various organ systems. We highlight the dual role of the NGF axis: while NGF-TrkA signaling consistently confers neuroprotective and vasculoprotective benefits, unchecked proNGF-p75NTR activity amplifies tissue damage. Conclusions: Collectively, the evidence identifies NGF as a candidate biomarker for both early tissue distress and therapeutic monitoring. We conclude by outlining key priorities for future research, including the development of standardized assays and the initiation of well-designed clinical trials to translate these promising strategies for early detection and treatment of diabetes-related complications.

Obesity and its related disorders, such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), represent a worldwide health challenge, which is driven primarily by the dysfunction of the adipose tissue-gut-liver axis. This article compiles mechanistic and translational data on curcumin and its analogs as multi-organ regulators targeting this axis. Curcumin plays a pleiotropic role by modulating adipogenesis, lipid metabolism, inflammation, fibrosis, and thermogenic remodeling in adipose tissue, tailoring gut microbial diversity, gut barrier integrity, and metabolic endotoxemia. Curcumin in the liver attenuates steatosis, oxidation, and fibrosis by inhibiting lipogenesis, increasing β-oxidation, and modulating the NF-κB and TGF-β signal pathways. These actions result in overall systemic insulin sensitivity and energy balance. On the contrary, the clinical application of curcumin is restricted due to its low solubility, instability, and poor bioavailability. New formulations (nanoparticles/liposomes/micelles) together with structurally enhanced analogs such as tetrahydrocurcumin and monocarbonyl analogs (C66, B2BrBC) exhibited superior pharmacokinetic and tissue-targeting properties in preclinical models. Pilot and randomized clinical trials suggest that curcumin supplementation enhances glucose and lipid metabolism, reduces liver fat content, and modulates inflammatory markers; however, results across studies remain heterogeneous. Large, high-quality multicenter trials using rigorously standardized, bioavailable curcumin formulations are still required to reliably establish the efficacy and safety of curcumin in metabolic diseases. Next steps involve comparing curcumin analogs, conducting multi-omics analyses to understand host-microbiota-organ crosstalk, and determining cooperative approaches with lifestyle and pharmacological interventions. Taken together, curcumin and its next-generation derivatives may offer a novel therapeutic approach to intervene in the adipose tissue-gut-liver axis for the treatment of obesity-related metabolic diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug-drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly prescribed medications without dose adjustment, although strong enzyme inducers such as rifampin can reduce systemic exposure, and pharmacodynamic interactions may still arise. However, existing evidence is largely derived from short-term studies in healthy volunteers, with limited data in special populations and minimal evaluation of metabolite- or transporter-mediated interactions. This review summarizes the available in vitro and in vivo pharmacokinetic and DDI data for SGLT2 inhibitors, identifies key knowledge gaps related to polypharmacy, metabolite effects, and vulnerable patient groups, and outlines future research priorities to ensure their safe and effective use in real-world clinical practice.

Background/Objectives: Proinsulin, the precursor to insulin, has limited activity on the insulin receptor. Proinsulin levels increase with increasing insulin resistance in type 2 diabetes due to incomplete processing by the β-cell. To assess whether the development of peptides that could convert circulating proinsulin to insulin in the blood would provide therapeutic value, we used a quantitative systems pharmacology (QSP) model of glucose homeostasis. In silico hypothesis testing such as this is an example of how modeling can inform decisions in drug discovery. Methods: In silico hypothesis testing involved (1) the addition and qualification of proinsulin biology into a preexisting QSP model, (2) the creation and validation of virtual patients (VPs) for subpopulations of type 2 diabetics based on phenotypic traits, and (3) the simulation of clinical trials evaluating the therapeutic value of the conversion of circulating proinsulin to insulin in the VPs created. Results: Proinsulin conversion led to a ~0.2% reduction in HbA1c in VPs at varying stages of diabetes, a decrease that does not hold meaningful therapeutic value. The lack of significant impact on HbA1c was likely a result of the surprisingly small effect on plasma insulin levels from proinsulin, which has a significantly slower secretion and clearance rate. Although patients with higher proinsulin/insulin ratios showed the largest reductions, clinically significant ≥ 0.5% reduction in HbA1c required ratios of proinsulin/insulin above the reported physiological range. Conclusions: This effort demonstrates how in silico hypothesis testing using QSP modeling can provide insights on the probability of success of novel interventions with minimal time and resources. These efficiencies are a means of overcoming the pressures on the pharmaceutical industry to do more with less in providing therapies that improve the lives of patients.

Background: Impaired bone health is a recognized complication of type 1 diabetes. This study evaluated the effects of low-carbohydrate (LC) and Mediterranean (MED) diets on bone turnover markers in adolescents and young adults. Methods: In a 24-week randomized controlled trial, 40 individuals aged 12-21 years, with type 1 diabetes, were assigned to an LC or MED intervention (20 participants per group). C-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at baseline and 24 weeks. Results: The groups had similar baselines. At 24 weeks, the between-group difference in delta glucose time in range was not statistically significant; median daily carbohydrate intake was 86 g (68-95) in LC and 130 g (102-173) in MED (p < 0.001). Comparing LC to MED, the median BMI z-score was lower (-0.1 [-0.3 to -0.1] vs. 0.0 [-0.1 to -0.1], p = 0.10), and calcium (p = 0.035) and magnesium intakes (p = 0.030) were lower. These associations did not remain statistically significant after false-discovery-rate correction. The median-adjusted alkaline phosphatase level decreased significantly in the LC group (p = 0.009). The median CTX changed following LC from 395 pg/mL (232-591) to 423 pg/mL (289-591) (p = 0.278); and following MED, from 357 pg/mL (244-782) to 296 pg/mL (227-661) (p = 0.245). P1NP changed in LC from 95 ng/mL (68-112) to 88 ng/mL (62-97) (p = 0.056) and in MED from 76 ng/mL (54-198) to 71 ng/mL (55-122) (p = 0.594). Conclusions: Exploratory analyses of bone turnover markers showed insignificant differences following LC and MED diets.

To investigate the associations between longitudinal body roundness index (BRI) trajectories and the risk of incident diabetes mellitus (DM) using data from the China Health and Retirement Longitudinal Study (CHARLS).

Group-based trajectory modeling (GBTM) identified distinct BRI trajectories (Waves 1-3, 2011-2016). Their associations with DM incidence (Wave 4, 2017-2018) were assessed using multivariate Cox models. The predictive performance of a single baseline BRI was compared with body mass index (BMI) and waist circumference (WC) via receiver operating characteristic (ROC) analysis. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) evaluated the incremental value of adding BRI trajectories to a conventional risk model. Subgroup and sensitivity analyses, including a landmark approach, assessed robustness.

Among 4,150 participants, 103 developed DM. Three stable BRI trajectories were identified: low-stable (49.0%), moderate-stable (41.3%), and high-stable (9.7%). Compared with the low-stable group, the high-stable group had a significantly increased DM risk with a fully-adjusted hazard ratio (HR) of 2.63 (95% confidence interval [CI]: 1.41-4.91). A single baseline BRI showed comparable discrimination to BMI and WC (AUC ≈ 0.63). Longitudinal trajectories of BRI, BMI, and WC all identified high-stable subgroups with elevated risk (HRs: BRI = 2.63, BMI = 2.16, WC = 2.31), with overlapping confidence intervals. However, adding BRI trajectories to a conventional model significantly improved risk reclassification (NRI = 10.76%, 95% CI: 2.40-19.47) and discrimination (IDI = 0.27%, 95% CI: 0.03-0.52). Results were consistent across subgroups and sensitivity analyses.

Sustained high BRI exposure, captured by longitudinal trajectory modeling, is independently associated with increased DM risk. While BRI trajectories were not statistically superior to BMI or WC trajectories, the longitudinal framework itself adds value over single-time-point assessments by more robustly identifying individuals with persistent high adiposity-related risk, highlighting the utility of monitoring long-term body shape stability for early risk stratification.