Diabetes Therapy Research Articles

Antioxidant Potential and In Vitro Antidiabetic Activity of Paeonia japonica (Makino) Miyabe & Takeda Extract and Its Isolated Compounds

This study explored the potential of Paeonia japonica (Makino) Miyabe & Takeda (P. japonica) as a natural treatment for diabetes. A methanol extract of the root of P. japonica and its fractions were investigated for their antioxidant and antidiabetic properties. The ethyl acetate (EtOAc) fraction was the most potent, displaying strong antioxidant activity and inhibiting enzymes that break down carbohydrates (α-amylase and α-glucosidase), which could reduce blood sugar levels. Furthermore, the EtOAc fraction inhibited glucose uptake in 3T3-L1 cells and stimulated the gene responsible for cellular glucose uptake (GLUT4), suggesting improved insulin sensitivity. It also effectively reduced the formation of harmful advanced glycation end products linked to diabetic complications. The isolation of bioactive compounds from the EtOAc fraction revealed the presence of 4-O-methylgallic acid and ellagic acid, which potentially contributed to the observed antidiabetic effects. Overall, this study highlights the EtOAc fraction of P. japonica as a promising source for developing natural diabetes therapies. The findings suggest its potential for regulating various diabetic pathways, warranting further research for drug development.

Truncated Albumins as Novel Surrogate Biomarkers in Diabetes Therapy: Epiphenomena and Potential Clinical Applications.

Aims/Hypothesis: Among various albumin posttranslational modifications (PTMs), N- and C-terminal truncations (HSA-DA and HSA-L) have also shown biomarker potential in disease states. We examined albumin truncation longitudinal trends and correlations during diabetes therapy toward possible future clinical applications. Methods: In a preliminary longitudinal therapy investigation, mass spectrometry was employed to track PTMs of human serum albumin (HSA), including glycation (GA), cysteinylation (CA or HNA1; reversible), di/trioxidation (OA or HNA2; irreversible), and truncation (TA). These modifications were correlated with ongoing therapy in four distinct subject groups: type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity (PDOB), and healthy controls (NORM), observed over a follow-up period extending up to 280 days. Results: Diabetes was associated with significant reduction ("deficiency") of measured albumin truncations (For HSA-DA: T2DM = 0.32 ± 0.3%, p = 2E-08; T1DM = 1.02 ± 0.4%, p = 3E-05; PDOB = 1.61 ± 0.2%, p = 0.004; compared to NORM = 2.08 ± 0.2%). Albumin truncation reduction was more striking in T2DM (HSA-DA: T2DM vs. T1DM: p = 0.004). Improvements in glycemic control and decrease of albumin glycation during diabetes therapy were associated with concomitant increase of albumin truncations toward the "healthy" normal ranges, and vice versa ("mirror image" trends). Accordingly, albumin truncation correlated inversely with albumin glycation (HSA-DA vs. GA: R = -0.53, p = 1E-09). Conclusions: The "epiphenomenon" of albumin truncation (reflecting the severity of mean hyperglycemia and also insulin resistance) can possibly provide novel, sensitive, and complementary biomarkers (e.g., via simpler HSA-DA peptide fragment immunoassays) to monitor efficacy of diabetes therapy and also progression from "healthy" to prediabetes and type 2 diabetes, highlighting potential diagnostic and prognostic utility in clinical diabetes care.

Post Hoc Analysis of SURPASS-1 to -5: Efficacy and Safety of Tirzepatide in Adults with Type2 Diabetes are Independent of Baseline Characteristics.

Newer incretin-based therapies for type2 diabetes (T2D) have the potential to substantially reduce glycated hemoglobin (HbA1c) and weight with a low associated risk of hypoglycemia. This study aimed to assess the percentage of participants randomized to tirzepatide or comparator who achieved the composite endpoint of HbA1c ≤ 6.5% and weight reduction ≥ 10% without hypoglycemia across prespecified baseline characteristics: T2D duration (≤ 5, > 5-10, or > 10years), sex, HbA1c (≤ 8.5% or > 8.5%), age (< 65 or ≥ 65years), and body mass index (< 30, 30 to < 35, or ≥ 35kg/m2). This post hoc analysis of SURPASS-1 through -5 evaluated adult study participants with T2D treated with tirzepatide 5, 10, or 15mg versus placebo or active comparator. Missing HbA1c and weight values were imputed from mixed models for repeated measures. Logistic regression was used to compare tirzepatide versus comparators for the percentage of participants reaching the composite endpoint. Across subgroups, the composite endpoint was achieved by a median of approximately 30%, 45%, and 54% of participants who received tirzepatide 5, 10, and 15mg, respectively; this was consistent across baseline subgroups, except that a greater percentage of women than men achieved the composite endpoint. The most common treatment-emergent adverse events were gastrointestinal in nature. In this post hoc analysis, tirzepatide achieved the composite outcome of glycemic control and weight loss with no hypoglycemia, irrespective of baseline characteristics. This may help clinicians as they select suitable treatment in diverse populations. ClinicalTrials.gov: NCT03954834, NCT03987919, NCT03882970. NCT03730662, and NCT04039503.

Abstract 4137914: Eligibility for Semaglutide in US Adults with Diabetes and Potentially Preventable Cardiovascular Events Projected from the SUSTAIN-6 Trial

Background: The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with type 2 diabetes mellitus (T2DM). Purpose: To estimate the number of US adults with T2DM that may be eligible for semaglutide based on SUSTAIN-6 eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SUSTAIN-6. Methods: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2011– 2020 who had eligibility criteria from SUSTAIN-6. This included an HbA1c&gt;7.0%, age &gt; 50 with established CVD, heart failure, or chronic kidney disease or an age &gt; 60 with at least one CVD risk factor. We estimated the number of primary composite and secondary CVD endpoints that would occur based on SUSTAIN-6 treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on median 2.1 year follow-up time). Results: Among 5002 (projected to 34.0 million [M]) adults we identified with T2DM, we estimated 1,132 (6.9 million) (20.3%) to fit SUSTAIN-6 eligibility criteria. Compared to SUSTAIN-6 trial participants, our sample was slightly older, had a higher proportion of Black participants, shorter duration of diabetes, lower HbA1c and diastolic blood pressure, but similar body mass index and systolic blood pressure. Prior history of ischemic heart disease, myocardial infarction, and stroke were also less common in our NHANES sample. From SUSTAIN-6 semaglutide and placebo primary composite CVD event rates of 6.6% and 8.9%, respectively, we estimated 456,060 and 614,990 events would occur, respectively, for a total of 159,930 preventable CVD events, or 75,681 on an annualized basis. We similarly estimated annualized preventable events for secondary outcomes as shown in the Figure. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting SUSTAIN-6 eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including semaglutide.

Abstract 4136116: Metformin Therapy for Reperfusion Injury Consolidates Cardioprotection in the High-Risk Elderly Heart

Introduction: Metformin (MET), a first-line diabetes therapy, exhibits cardioprotective effects during acute ischemia and reperfusion (I/R). Cardiac injury is enhanced in the aging heart in murine and humans. Acute, high dose MET treatment at the onset of reperfusion (R) markedly reduced infarct size (MI) in the high risk aged heart via modulation of mitochondrial complex I. However, the effect of subsequent chronic, standard dose MET to consolidate and possibly enhance cardioprotection and survival following I/R in the aged heart remains unknown. Hypothesis: Administration of chronic standard dose of MET will ameliorate mortality and morbidity following MI through rescuing an impaired adaptive metabolic remodeling. Methods: Aged (22-24 month) C57BL6/J mice were subjected to sham operations or 45 min of ischemia by LAD ligation followed by R. All mice received acute, high dose MET (2 mM, i.v.) at the onset of R followed by randomization to chronic MET (300 mg/kg/day) in drinking water versus vehicle (VEH) administered for 14 days. Cardiac function was determined by echocardiography weekly. IonOptix Myocyte Calcium and Contractility System measured the contractile functions and transient calcium signaling of isolated cardiomyocytes. Results: The Kaplan-Meier survival analysis showed that chronic MET treatment following acute treatment at the onset of R significantly reduced mortality compared to VEH group. Although chronic MET treatment did not further reduce MI size, echo and histology showed that chronic MET preserved diastolic function, prevented left ventricular hypertrophy and reduced collagen deposition following I/R in aging. Moreover, isolated cardiomyocytes from MET treated hearts showed improvements in contractile function, transit calcium signaling, and the coupling between contractility and calcium levels as compared to the cardiomyocytes from VEH group hearts. Immunoblotting results showed that Sens2/AMPK metabolic signaling was significantly upregulated by chronic MET post-MI, indicating the metabolic homeostasis modulated by MET is a critical factor involved in the beneficial effects of chronic MET on limiting I/R-induced myocardial damage that leads to deleterious remodeling in aging. Conclusions: The mortality and morbidity of MI in the high risk aged heart is attenuated with acute, high dose of MET treatment followed by chronic standard dose MET treatment to consolidate protection via rescuing the impaired adaptive metabolic response in aging.

Alginate–Poly[2-(methacryloyloxy)ethyl]trimethylammonium Chloride (PMETAC) Immunoisolating Capsules Prolong the Viability of Pancreatic Islets In Vivo

Background/Objectives: This study focuses on the development and evaluation of novel alginate–poly[2-(methacryloyloxy)ethyl]trimethylammonium chloride (PMETAC) microcapsules for encapsulating pancreatic islets to address insulin deficiency in diabetes. Methods: In previous research, we fabricated and characterized PMETAC microcapsules, evaluating their stability and permeability in vitro. This study further probes the capsules in vivo, focusing on the functional activity of the encapsulated islets post-transplantation, their viability extension, and the assessment of the immunoprotective, antifibrotic properties, and biostability of the capsules. Results: Rabbit-derived islets were encapsulated and transplanted into diabetic rats. The encapsulated islets maintained insulin secretion for up to 90 days, significantly longer than non-encapsulated ones, which ceased functioning after 7 days. Histological analysis demonstrated high biocompatibility of the PMETAC coating, resulting in minimal fibrotic overgrowth around the capsules. Conclusions: The study highlights the critical role of immunoprotection and the tendency to reduce fibrosis in prolonging islet function. These findings suggest that PMETAC-coated capsules offer a promising solution for cell-based therapies in diabetes by improving graft longevity and reducing fibrotic overgrowth.

Linarin Identified as a Bioactive Compound of Lycii Cortex Ameliorates Insulin Resistance and Inflammation Through the c-FOS/ARG2 Signaling Axis.

Insulin resistance (IR) is a central pathophysiological process underlying numerous chronic metabolic disorders, including type 2 diabetes and obesity. Lycii Cortex, a widely used traditional Chinese herb, has demonstrated potential benefits in preventing and managing diabetes and IR. Whereas, the specific bioactive compounds responsible for these protective effects and their underlying mechanisms of action remain elusive. This study aimed to identify the bioactive components within Lycii Cortex that contribute to its anti-diabetic effects and to elucidate the molecular mechanisms underlying its beneficial actions on insulin resistance. Network pharmacology and molecular docking analyses were employed to identify the potential active compounds in Lycii Cortex and their corresponding target proteins. An invitro model of IR was established using palmitic acid (PA)-treated HepG2 cells. Cell viability was assessed using the CCK-8 assay, while glucose uptake was evaluated by 2-NBDG staining and extracellular glucose measurement. To validate the invitro findings, an invivo model of obesity-induced IR was established using high-fat diet (HFD)-fed mice. The network pharmacology analysis preliminarily identified 13 candidate chemicals and 10 hub LyC and IR-related genes (LIRRGs). Molecular docking analysis demonstrates that Linarin as the potential active component exhibits the greatest potential to target c-FOS for preventing obesity-induced IR. Enrichment analysis suggested that Linarin-targeted pathways are correlated with inflammation. Invitro experimental validation demonstrated that Linarin was capable of protecting against PA-induced IR in HepG2 cells evidenced by improving glucose uptake ability and reducing extracellular glucose content. Additionally, we found that Linarin ablated PA-induced increase in the expression of c-FOS and inflammatory cytokines. Furthermore, in PA-treated cells, silencing c-FOS markedly improved glucose consumption, and reduced inflammation and Arginase 2 (ARG2) expression. Similarly, as exposure to PA, silencing ARG2 also ameliorated glucose uptake and inflammation, while not affecting c-FOS expression. Invivo experiments further showed that Linarin administration remarkably improved glucose tolerance and insulin sensitivity, and reduced the fat mass and body weight in HFD-induced obese mice. In this study, Linarin has been identified as the bioactive compound of Lycii Cortex to ameliorate obesity-related IR and inflammation through the c-FOS/ARG2 signaling cascade. These findings underscore the therapeutic potential of Linarin and provide valuable insights into developing novel intervention strategies for type 2 diabetes therapy.

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Disease modifying therapies in diabetes and endocrinology

Disease modifying therapies in diabetes and endocrinology

Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes

This study examines the impact of the combination of sitagliptin and L-theanine on the testis tissue of rats with experimental diabetes. Diabetes mellitus, a chronic metabolic illness, significantly reduces quality of life and can cause male infertility by decreasing sperm count, motility, and testosterone levels. Rats were allocated to five separate groups: control, diabetes, L-theanine, sitagliptin, and combination therapy. The measurements encompassed blood glucose levels, body weight, serum insulin levels, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The histological examination of testicular tissue was conducted using H&E, PASH, caspase-12, and PCNA staining techniques, in addition to a TUNEL assay to detect apoptosis. Levels of oxidative stress indicators, including glutathione peroxidase (GPX), malondialdehyde (MDA), and catalase, were also evaluated. The results showed that the group of individuals with diabetes had significantly higher levels of blood glucose, apoptotic indices, GPX, catalase, and MDA levels and activities in comparison with the control group. Although both the L-theanine and sitagliptin groups exhibited some improvement, the combination therapy demonstrated the most significant decrease in histopathological damage and apoptotic markers. These results indicate that the combination of sitagliptin and L-theanine may significantly decrease testicular damage caused by diabetes, making it a promising therapeutic strategy.

The long-term outcome of pulmonary vein isolation in paroxysmal atrial fibrillation is significantly influenced by diabetes mellitus in general as well as by an antidiabetic therapy

Abstract Introduction Over the last decades pulmonary vein isolation became a cornerstone in the interventional treatment of paroxysmal atrial fibrillation. Postprocedural recurrences of atrial fibrillation are present in patients with and without concomitant cardiovascular diseases. Purpose The aim of this study was to assess the influence of diabetes mellitus and an antidiabetic therapy on the long-term outcome, defined as freedom of atrial fibrillation, of pulmonary vein isolation in patients with paroxysmal atrial fibrillation Methods All patients underwent pulmonary vein isolation using the combination of a radiofrequency ablation catheter, a pulmonary mapping catheter and a 3D electroanatomic mapping system. Every procedure was carried out according to current clinical and scientific standards. Procedural, clinical and follow-up data were stored for later statistical analysis. All patients received 4 follow-ups in total. In the first 12 postprocedural months patients were followed up after 3, 6 and 12 months. Furthermore, there was one long-term follow-up up to 6 years after the procedure. Results A total of n=1282 patients were included in the study. 39.2% of the patients were female and 60,8% were male. At the timepoint of the procedure the mean age was 63.7 years. The mean follow-up time was 2.2 years. For n=1144 of the included patients the presence respectively the absence of diabetes mellitus was documented. 8.0% (n=92) of these patients had the diagnosis of diabetes mellitus, from which 73.9% (n=68) were and 26.1% (n=24) were not under an antidiabetic therapy. Regarding the long-term outcome, patients without diabetes mellitus had significantly better results (log rank p=0.039). The according Kaplan-Meier-Analysis is shown in figure 1. Patients with diabetes mellitus were significantly older (69.5 years) when compared to patients without diabetes mellitus (63.1 years). However, when data was adjusted for age and gender, diabetes mellitus was still an independent, significant predictor of the recurrence of atrial fibrillation after pulmonary vein isolation. In addition, diabetics under an antidiabetic therapy had a significantly better long-term outcome than the untreated ones (log rank p=0.011). Figure 2 shows the according Kaplan-Meier-Analysis. Conclusion Diabetes mellitus has a significant influence on the long-term outcome of pulmonary vein isolation in patients with atrial fibrillation (log rank p=0.039). Patients without diabetes mellitus showed significantly better outcomes when compared to patients with diabetes mellitus also when adjusting the data for age and gender. Furthermore, the presence of an antidiabetic therapy in diabetics influences the long-term outcomes significantly (log rank p=0.011).

Cardiovascular diseases risk assessment: the Italian Health Examination Survey 2023 - CUORE Project

Abstract Background The reduction of NCDs premature mortality is pursued by the WHO; risk conditions targets are recommended as well as population-level monitoring of cardiovascular disease (CVD) risk. The Italian Ministry of Health (MoH) has strengthened prevention/health promotion and supported periodic CVD risk assessment through national health examination surveys (HESs), funded by the MoH-CCM and conducted within the CUORE Project. Methods In 2023 a new HES started including the 10-year fatal and non-fatal CVD risk assessment based on knowledge of sex, age, smoking habit, measured systolic blood pressure and fasting total and HDL serum cholesterol, and presence of diabetes (on measured fasting serum glycemia and/or treatment) and anti-hypertensive therapy. Up to now, data from random samples of residents in 7 Regions (of 20 regions) distributed in North, Centre and South of Italy, aged 35-69 years, without previous CVD, are available (585 men, 617 women). Determinations were assayed by a central lab. CUORE Project functions developed on and for the Italian adults were used. Results Mean values of the CVD risk assessment resulted 6.9% (95% CI: 6.3-7.4) in men and 2.3% (2.1-2.5) in women. For men aged 35-44 years risk was 1.6% (1.5-1.8), for 45-54 years 3.8% (3.5-4.2), for 55-64 years 10.0% (9.0-10.9), for 65-69 years 17.6% (16.4-18.9); for women was 0.5% (0.4-0.6), 1.0% (0.9-1.1), 3.3% (2.9-3.7) and 6.0% (5.5-6.6) respectively. Prevalence of CVD risk less than 5% was 57% (49-64) in men and 88% (84-93) in women, of 10-15% risk were 22% (15-28) of men and 9% (5-14) of women, of 15-20% risk were 5% (1.6-8.0) of men and 0% of women, of over 20% risk were 2% (0-3.6) of men and 0% of women. Conclusions Compared to 2008, these data showed stable mean levels of CVD risk both in men and women at any age-classes and stable prevalence of CVD risk classes. CVD risk perception represents a challenge in primary prevention especially for young age groups and women. Key messages • In the Italian general population, CVD risk assessment remained stable compared to 15 years ago. • CVD risk perception represents a challenge in primary prevention.

The CNP analogue vosoritide reduces arrhythmia in diabetic cardiomyopathy via cGMP-dependent PDE2 stimulation on cellular and organ level

Abstract Background Detrimental arrhythmia occurs frequently in patients with diabetic cardiomyopathy (DiabCM), but safe and effective therapies are limited. Diabetes-associated neuropathological alterations increase the sympathetic tone, leading to hyperactivation of β-adrenoceptor-mediated cAMP signalling in cardiomyocytes (CM). Increased activity of deleterious cAMP-dependent kinases causes pro-arrhythmic dysregulation of intracellular Ca2+ homeostasis. Phosphodiesterases (PDE) can reduce cAMP levels. Exceptionally, the cAMP-hydrolysing activity of PDE2 can be cGMP-dependently increased by C-type natriuretic peptide (CNP). Thus, the CNP analogue vosoritide (approved for the treatment of achondroplasia) might mediate this cGMP/cAMP crosstalk, reducing arrhythmia. Purpose Here, we aim to study whether the cGMP-dependent activation of PDE2 by vosoritide (VO) is sufficient to reduce arrhythmia and arrhythmogenic triggers in DiabCM. Methods Diabetes was induced by 5 consecutive injections of streptozotocin (50 mg/kg) in control (WT) mice and mice with a CM-specific PDE2 knockout (KO). All experiments were performed 5 weeks later. Cardiac function was characterised by echocardiography. Primary ventricular CM were isolated to assess protein expression and phosphorylation levels by Western blot (WB) and cAMP levels by ELISA. Patch-clamp and Ca2+ imaging experiments were used to investigate pro-arrhythmic triggers. Arrhythmic events were quantified in ex vivo perfused hearts after ischaemia-reperfusion (I/R) injury. Results Compared to healthy controls, diabetic animals showed impaired systolic function with a ~9 % reduction in ejection fraction. The significant increase in E/E’ ratio by ~34 % indicated a diastolic dysfunction. Interestingly, the cardiac function was further worsened in diabetic PDE2 KO. WB analysis revealed upregulation of the CNP receptor NPR-B and PDE2 in diabetic CM and altered regulation of proteins involved in cAMP-dependent Ca2+ cycling such as protein kinase A, Ca2+/calmodulin-dependent kinase II and phospholamban. Interestingly, VO significantly reduced isoprenaline (Iso)-induced cAMP levels in diabetic CM. The effect of VO was prevented by specific PDE2 inhibition with BAY 60-7550 (BAY). Furthermore, VO was able to reduce the Iso-induced increase in L-type Ca2+ current, whereas BAY or genetic PDE2 deletion counteracted this effect. Accordingly, VO significantly decreased the Iso-triggered Ca2+ spark frequency by ~40 %. Concomitant PDE2 inhibition or PDE2 KO prevented this anti-arrhythmic effect. Finally, ECG analysis revealed that VO clearly reduced arrhythmia development after I/R in ex vivo perfused diabetic hearts via PDE2 activation. Conclusion Our data indicate that vosoritide-induced PDE2 stimulation may attenuate abnormal cardiac Ca2+ cycling and thereby reduce arrhythmia in diabetic hearts. Thus, vosoritide may be repurposed as a novel anti-arrhythmic drug in DiabCM.

Significant of Blood Glucose Time-Series Forecasting with Temporal Fusion Transformer Model for Type 1 Diabetes

Blood glucose (BG) prediction has advanced to a state of the art thanks to deep learning models, which have been demonstrated to enhance type 1 diabetes (T1D) therapy. Nevertheless, most current models are limited to single-horizon prediction and have several practical drawbacks, including poor interpretability. In this study, we develop a novel approach to optimize the forecasting model in the training processes using the Optuna function, cross-validation, and the latest dataset. We offer a novel deep learning framework for multi-horizon BG prediction: the temporal fusion transformer (TFT). TFT employs a self-attention mechanism to extract long-term temporal dependencies and enables a model with an auto-tuning adjustment approach on hyperparameters and a cross-validation function on univariate and multivariate input models. On a clinical dataset with T1D subjects, namely ShanghaiT1DM (16 subjects), D1NAMO (9 subjects), and OhioT1DM (6 subjects) datasets, it achieved an average root mean square error (RMSE) of the three datasets used. The TFT model gave a lower error score than the baseline models of neural hierarchical interpolation for time series (N-HiTS)and long short-term memory (LSTM) with the values of 10.08+0.31 mg/dL and 12.34+0.62 mg/dL on the univariate input model and 9.18+1.21 mg/dL and 14.33+0.52 mg/dL on the multivariate input model for the prediction horizons of 30 and 60 minutes, respectively. This result explained that the TFT model was adequate for carrying out multi-horizon BG value-level forecasting and potentially deploying on-edge devices to improve clinical efforts to manage BG levels for T1D patients in real-time application.

Insights in Nutrition to Optimize Type 1 Diabetes Therapy.

Nutrition is an essential part of therapy for type 1 diabetes and is constantly evolving, offering growing opportunities to prevent this disease, slow down its evolution, and mitigate it. An attempt was made to bring together the current state of knowledge. In the path from the preclinical phase of the disease to its clinical onset, there is a phase known as the "honeymoon period" or partial remission, where different possible dietary options for combatting this disease have been presented. The most commonly used dietary models were compared, and the most frequent co-existing pathologies, such as overweight, non-alcoholic fatty liver disease, dyslipidemia, celiac disease, and metabolic instability, were addressed from their nutritional and dietary perspectives to provide clinicians with an updated framework of knowledge and support researchers in further investigations into the topic. Finally, a glimpse into the possible interplay between nutrition and the gut microbiome, food security, and ultra-processed food is provided. It is hoped that clinicians treating people with type 1 diabetes will be provided with further opportunities for the daily management of their patients through personalized nutrition.

Emerging concepts and success stories in type 1 diabetes research: a roadmap for a bright future.

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy.

Profiling of Potential Anti-Diabetic Active Compounds in White Tea: An Integrated Study of Polyphenol-Targeted Metabolomics, Network Pharmacology, and Computer Simulation.

Diabetes remains a critical global public health challenge, posing a growing threat to human health and well-being. White tea is a lightly fermented tea and one of the six traditional tea categories in China. Owing to its rich content of bioactive compounds such as catechins and alkaloids, it has demonstrated potential anti-diabetic properties. However, its precise bioactive components, mechanisms of action, and relevant molecular targets require further investigation. In this study, an integrated approach combining polyphenol-targeted metabolomics, in vitro antioxidant assays, α-glucosidase inhibition tests, network pharmacology analysis, GEO database exploration, molecular docking, and molecular dynamics simulations was employed to identify the potential anti-diabetic compounds, targets, and mechanisms of white tea. The findings revealed that white tea is particularly abundant in 10 bioactive compounds, including epigallocatechin gallate, epicatechin gallate, and catechin, all of which exhibit significant anti-diabetic potential. These compounds were found to exert their effects by interacting with core molecular targets, namely cathepsin V (CTSV) and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), and engaging in pathways related to signal transduction, apoptosis, and immune responses. This study establishes a strong theoretical basis for advancing white tea research and underscores new opportunities for applying natural products in diabetes therapy.

Placental small extracellular vesicles from normal pregnancy and gestational diabetes increase insulin genetranscription and content in β cells.

Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from β cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human β cell line, EndoC-βH3, to investigate their effects on β-cell function in vitro. Our results indicate that human β cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the β cells. Moreover, these vesicles upregulated the expression of Annexin A1, a protein known to increase insulin content. This upregulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

Nanomaterial-Enhanced Microneedles: Emerging Therapies for Diabetes and Obesity.

Drug delivery systems (DDS) have improved therapeutic agent administration by enhancing efficacy and patient compliance while minimizing side effects. They enable targeted delivery, controlled release, and improved bioavailability. Transdermal drug delivery systems (TDDS) offer non-invasive medication administration and have evolved to include methods such as chemical enhancers, iontophoresis, microneedles (MN), and nanocarriers. MN technology provides innovative solutions for chronic metabolic diseases like diabetes and obesity using various MN types. For diabetes management, MNs enable continuous glucose monitoring, diabetic wound healing, and painless insulin delivery. For obesity treatment, MNs provide sustained transdermal delivery of anti-obesity drugs or nanoparticles (NPs). Hybrid systems integrating wearable sensors and smart materials enhance treatment effectiveness and patient management. Nanotechnology has advanced drug delivery by integrating nano-scaled materials like liposomes and polymeric NPs with MNs. In diabetes management, glucose-responsive NPs facilitate smart insulin delivery. At the same time, lipid nanocarriers in dissolving MNs enable extended release for obesity treatment, enhancing drug stability and absorption for improved metabolic disorder therapies. DDS for obesity and diabetes are advancing toward personalized treatments using smart MN enhanced with nanomaterials. These innovative approaches can enhance patient outcomes through precise drug administration and real-time monitoring. However, widespread implementation faces challenges in ensuring biocompatibility, improving technologies, scaling production, and obtaining regulatory approval. This review will present recent advances in developing and applying nanomaterial-enhanced MNs for diabetes and obesity management while also discussing the challenges, limitations, and future perspectives of these innovative DDS.

Therapy concepts in type 1 diabetes mellitus treatment: disease modifying versus curative approaches.

For many autoimmune diseases, including type 1 diabetes mellitus (T1DM), efforts have been made to modify the disease process through pharmacotherapy. The ultimate goal must be to develop therapies with curative potential by achieving an organ without signs of parenchymal cell destruction and without signs of immune cell infiltration. In the case of the pancreas, this means regenerated and well-preserved beta cells in the islets without activated infiltrating immune cells. Recent research has opened up the prospect of successful antibody combination therapy for autoimmune diabetes with curative potential. This goal cannot be achieved with monotherapies. The requirements for the implementation of such a therapy with curative potential for the benefit of patients with T1DM and LADA (latent autoimmune diabetes in adults) are considered.