BACKGROUND: Periodontal disease (PD) is associated with type 2 diabetes mellitus (T2DM), while periodontal treatment (PT) improves glycemic control in T2DM patients. Leptin and adiponectin belong to the adipokines family and have almost antagonistic functions in inflammatory processes and insulin sensitivity modulation. Hence, these hormones have been linked with both PD severity and glycemic control. This systematic review aims to assess the effect of PT on serum levels of leptin and adiponectin in patients with T2DM. METHODS: PubMed, Cochrane Library, and Google Scholar databases and ClinicalTrials.gov website were searched up to January 5th, 2025. Randomized and non-randomized controlled clinical trials (RCTs and CCTs) including patients with T2DM and PD who underwent PT and evaluated serum levels of leptin and adiponectin were included. Assessments of risk of bias and of certainty of evidence were performed. RESULTS: Seven trials were eligible for qualitative synthesis. A statistically significant increase in serum adiponectin levels was observed across most studies, while no such consistency was observed for leptin. The overall level of certainty of evidence was judged low in the RCTs and very low in the CCTs. Meta-analysis could not be performed due to significant methodological heterogeneity. CONCLUSIONS: Preliminary findings suggest a potential increase in adiponectin levels in T2DM patients, with possible implications for glycemic control. However, these results should be interpreted with caution due to the small number of studies and important methodological limitations. Well-designed studies with larger sample sizes and adequate adjustment for confounders are necessary to verify this observation. PLAIN LANGUAGE SUMMARY: People with type 2 diabetes often also have periodontitis, an inflammatory gum disease, which may affect their overall health. The aim of this study was to investigate whether treating periodontitis could help improve certain substances in the blood-called adiponectin and leptin-that are linked to blood sugar control and inflammation. Several studies that tested this in people with both diabetes and periodontitis were included and most of them showed that, after periodontal treatment, levels of adiponectin (which helps reduce inflammation and improve insulin sensitivity) increased. However, results for leptin were less clear. This suggests that taking care of gum health might support better diabetes management. The overall strength of evidence was low due to methodological limitations and heterogeneity among studies. Current findings should be interpreted cautiously, as available data remain preliminary. Still, more high-quality research is needed to fully understand how treating periodontitis may benefit people with diabetes.

Inflammaging refers to chronic low‑grade inflammation that develops with age and promotes multiple age‑related diseases. It arises from the close crosstalk between metabolic disturbance and inflammation, yet how this coupling acts across tissues remains poorly understood. As a hallmark of aging, sarcopenia often coincides with metabolic‑inflammatory dysfunction in the gut, liver, and adipose tissue, all tied together by insulin resistance (IR). In this review, we systematically examine the pathophysiological basis of the "metabolic-inflammatory axis" during aging, clarifying its conceptual boundaries with related terms such as "inflammaging," "immunometabolism," and "metabolic inflammation." We delineate the roles of three core molecular modules-nutrient sensing pathways (AMP‑activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)), mitochondrial stress (mitochondrial reactive oxygen species (mtROS)-p53), and epigenetic regulation (acetyl‑Coenzyme A (AcCoA)-histone acetyltransferase (HAT))-in mediating metabolic-inflammatory coupling. Using sarcopenia as a clinical anchor, we construct a tissue-specific atlas of the metabolic-inflammatory axis and elucidate the principles of organ crosstalk-and its mediators-within the gut-liver-adipose-muscle (GLAM) core axis. We then summarize current intervention strategies stratified by evidence level and identify knowledge gaps and future research directions. This review establishes a mechanistic link between molecular pathways and age-related multi-organ dysfunction, supporting a paradigm shift from single-disease management to multi-system healthspan interventions in aging.

Diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin secretion and/or insulin resistance, leading to persistent hyperglycemia. In the present study, a series of novel fused imidazole-thiazole-derived thiazole compounds were designed, synthesized, and biologically evaluated for their potential in managing diabetic complications. In vitro enzymatic assays revealed that the synthesized compounds exhibited potent inhibitory activity against key carbohydrate-hydrolyzing enzymes, namely α-glucosidase and α-amylase, which are directly involved in postprandial hyperglycemia. Among the tested compounds, the most active analogue 2 demonstrated superior inhibitory potential with IC₅₀ values of 4.60 ± 0.30 µM (α-glucosidase) and 5.10 ± 0.20 µM (α-amylase), outperforming the standard drug acarbose (IC₅₀ = 7.40 ± 0.20 µM and 8.10 ± 0.10 µM, respectively). The enhanced activity was attributed to the presence of a para-substituted trifluoromethyl (-CF₃) group, which favorably modulates the electronic properties and strengthens enzyme binding interactions. To further validate the experimental findings, molecular docking studies were conducted, which confirmed strong binding affinities of the active compounds within the enzyme active sites through key hydrogen bonding and hydrophobic interactions. Additionally, ADMET analysis suggested favorable pharmacokinetic properties and a promising safety profile of the lead compounds. Overall, the combined in vitro and in silico results indicate that these newly synthesized imidazole-thiazole derivatives represent promising candidates for the development of effective therapeutic agents aimed at the prevention and management of diabetes and its associated complications.

BACKGROUND: The prevalence of diabetes‑associated Lower Urinary Tract Symptoms (LUTS) is relatively low, and there are limited clinical studies on its associated factors. The present study proposed to investigate the predictive value of various inflammatory indices in patients with diabetes‑associated LUTS. METHODS: Utilizing data from the National Health and Nutrition Examination Survey 2005‒2008, patients were categorized into four groups: normal group, Diabetes Mellitus (DM) group, LUTS group, and diabetes‑associated LUTS group. Inflammatory indices included C-Reactive Protein (CRP), White Blood Cell (WBC) count, Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Systemic Inflammation Response Index (SIRI), and Systemic Inflammation Index (SII). Multivariate logistic regression and Restricted Cubic Splines (RCS) were employed to evaluate the relationship between inflammatory indices and diabetes‑associated LUTS. RESULTS: A total of 5680 participants were included in the final analysis, comprising 3779 females and 1901 males. The prevalence of diabetes‑associated LUTS was 6.9% in females and 2.2% in males. Diabetes-associated LUTS was associated with older age, lower educational level, hypertension, congestive heart failure, coronary heart disease, emphysema, and higher body mass index and inflammatory indices. Furthermore, multivariate logistic regression analysis revealed that WBC count was a significant factor for both female and male diabetes‑associated LUTS patients, with higher WBC levels correlating with increased diabetes‑associated LUTS risk (females: adjusted Odds Ratio [OR] = 1.115 [1.032‒1.205], p = 0.006; males: OR = 1.207 [1.083‒1.345], p = 0.001). RCS revealed a positive association between WBC count and diabetes‑associated LUTS in female and male participants. CONCLUSION: Inflammatory markers such as CRP and WBC count were higher in the diabetes‑associated LUTS group compared to the other three groups. WBC count is an associated factor for diabetes‑associated LUTS, and incorporating WBC count into clinical assessments can aid in identifying diabetes‑associated LUTS patients, thereby facilitating targeted interventions.

INTRODUCTION: Acute compartment syndrome is a relatively common condition of the leg, but thigh ACS is a rare pathology. Once recognized, treatment of thigh ACS relies on surgical release of the three main compartments of the thigh. The goal of this study was to analyze the frequency of thigh fasciotomies in patients diagnosed with thigh ACS. METHODS: The American College of Surgeons (ACS) National Surgical Quality Improvement Program database was used to analyze the incidence of thigh fasciotomies performed at participating hospitals from 2012 to 2023. Patients aged 18 y or older with a Current Procedural Terminology code for thigh fasciotomy (27,025) were included in the study. RESULTS: We identified 165 patients who received thigh fasciotomies between 2013 and 2023. The patients were on average 46.0 y old (standard deviation, 17.6), primarily male (72.1%), non-Hispanic (69.7%), independent at baseline (93.9%), with leukocytosis (61.5%), and with an American Society of Anesthesiologists class III/IV (74.6%). Thirty-d mortality was 13.3%. In performing multivariate analysis, low albumin (OR: 12.27, P = 0.02) and age group 60-69 y old (OR: 15.03, P = 0.04) were the only variables with a statistically significant risk for mortality, while diabetes mellitus (OR: 0.12, P = 0.049) was a significant protector against mortality. The modified frailty index also significantly predicted outcomes following thigh fasciotomies (P = 0.004). CONCLUSIONS: Thigh fasciotomies for ACS are rare procedures. Surgeons should be familiar with the known complications of thigh fasciotomies, and transfer to quaternary care centers for multidisciplinary care should be considered in patients who require the procedure.

PURPOSE: This study investigates the pathophysiological mechanisms, risk factors, and conditions contributing to the occurrence of paralyzing disc herniation (PDH) following L4-L5 disc herniation surgery. Despite the significance of PDH, comprehensive understanding remains limited due to the inherent challenges in recruiting patients with neurologic deficits and the variability in research methodologies. METHODS: Our retrospective analysis includes 1285 patients who underwent surgery for disc herniation over a decade, identifying an incidence rate of 7.69% for PDH among the cohort. Notable risk factors include age, obesity, diabetes mellitus, a narrow lumbar canal, and trauma. RESULTS: The recovery rate of 66.66% observed in our study aligns with existing literature, indicating a comparable average age of participants (48.64 years). CONCLUSIONS: The restricted volume of research focusing on postoperative outcomes has resulted in a lack of consensus on optimal management strategies for PDH. Consequently, the timing of intervention remains ambiguous, aside from recognized emergency situations. Our study underscores the need for further prospective research to enhance understanding and establish definitive management protocols for PDH.

AIMS: We assessed the prevalence and risk factors of erectile dysfunction (ED) in men with type 2 diabetes (T2DM) compared with men without diabetes in Catalonia, Spain. METHODS: This cross-sectional study used routinely collected primary care data from the SIDIAP database (covering ∼80% of the Catalan population) from 1st January 2010-30 th June 2023. Men ≥ 18 years with at least one primary care visit and one recorded laboratory test were included. T2DM was identified through ICD-10 codes, antidiabetic drugs, or HbA1c ≥ 6.5%; men without diabetes had no recorded diagnosis or criteria for any diabetes. ED was defined by ICD-10 codes (F52, N48.9) and/or prescriptions for approved ED treatments. Sociodemographic, lifestyle, clinical and laboratory data, comorbidities and medications were extracted. Multivariable logistic regression assessed factors associated with ED. RESULTS: Among 659,501 men (177,380 with T2DM; 492,121 without), overall ED prevalence was 9.5%. Prevalence was 1.5-fold higher in T2DM (12.6%) than in men without diabetes (8.3%), peaking at 55-64 years. Older age, longer diabetes duration, poorer glycaemic control, smoking, high-risk alcohol use, hypertension, dyslipidaemia, cardiovascular and microvascular disease, obesity and depression were independently associated with ED. CONCLUSIONS: Men with T2DM show markedly higher ED prevalence and multiple cardiometabolic risk factors. ED remains under-recognised and should be systematically assessed in primary care as both a complication and a clinical marker of cardiometabolic risk.

BACKGROUND: The disease burden of diabetes mellitus (DM) and major depressive disorder (MDD) is increasingly severe. This study aims to evaluate the global burden of these two diseases using the Global Burden of Disease (GBD) database and explore the association between vitamin D and the two diseases by leveraging the National Health and Nutrition Examination Survey (NHANES) database. METHODS: We firstly adopt a cross-sectional analysis to systematically describe the global distribution of the disease burden of DM and MDD and predict future development trends. Then, based on the NHANES database, we employ a weighted multivariable logistic regression model for the association between vitamin D levels and DM as well as MDD. RESULTS: From 1990 to 2021, the global disease burden of DM and MDD continued to escalate, with significant disparities across regions, age groups, and genders. Vitamin D levels exhibited a significant negative correlation with DM (β = -5.56, p < 0.001) and MDD (β = -6.66, p < 0.001). After multivariable adjustment, lower vitamin D levels were associated with higher prevalence of DM (OR = 1.71, P for trend <0.001) and MDD (OR = 1.59, P for trend <0.001). CONCLUSIONS: The GBD analysis revealed a severe disease burden of DM and MDD, whereas the NHANES analysis demonstrated a significant negative correlation between serum vitamin D levels and the two diseases. Independent interpretation of these two distinct databases may provide complementary perspectives from macro and micro levels for understanding the public health implications of DM and MDD.

AIMS: To evaluate the long‒term effect of a Mediterranean-based nutritional (MedDiet) intervention during pregnancy on the prevalence of metabolic syndrome (MetS) six years postpartum, and to determine the predictive value of postpartum lifestyle behaviours for MetS prevention. METHODS: A prospective follow‒up study included 1,715 women randomised during pregnancy to an intervention or control group. Anthropometric, metabolic, and lifestyle parameters were assessed six years postpartum. Multivariate models were used to identify independent predictors of MetS. RESULTS: The intervention group showed a significantly lower prevalence of MetS (7.3 vs. 10.4 %, p = 0.034) and improved metabolic parameters. Elevated pre-pregnancy BMI (OR = 7.912 [5.411‒11.57]) and Gestational Diabetes Mellitus (GDM), diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria [(OR = 2.958 [2.056‒4.256]), were the strongest MetS modifiable risk factors. ROC analysis identified that, six years postpartum, a healthy lifestyle‒MedDiet (≥7.5 points) and physical activity (≥307.5 MET·min/week)‒reduced MetS risk by up to 62 %, after adjusting for confounders. CONCLUSIONS: GDM diagnosed using IADPSG criteria identifies women at increased long-term risk of MetS confirming its cardiovascular relevance. Early MedDiet intervention (8-12 GW) during pregnancy provides sustained metabolic benefits while pre-pregnancy BMI and GDM emerge as key modifiable determinants. Lifestyle cut-off points relevant to postpartum MetS prevention were identified.

AIMS: Microalbuminuria, common in diabetes, lacks clarity as a predictor of diabetes onset. This study examines its association with incident type 2 diabetes (T2DM) and clinical implications. METHODS: This prospective cohort analysis utilized data from 411,389 UK Biobank participants with baseline urine albumin-to-creatinine ratio (UACR) measurements. Cox proportional hazards regression models, supplemented by restricted cubic spline analyses, were implemented to longitudinally evaluate the association between UACR levels and incident T2DM risk. RESULTS: Over an average follow-up duration of 13.8 years (range: 13.1-14.6 years), 15,942 new cases of diabetes were identified. After adjusting for potential confounders, the hazard ratios for incident T2DM were 1.31 (95% CI: 1.17-1.45) for UACR between 3-30 mg/mmol and 2.20 (95% CI: 1.58-3.06) for UACR > 30 mg/mmol, when compared to a reference UACR of <3 mg/mmol. These results remained stable across multiple sensitivity analyses, including those addressing potential confounding factors such as body mass index, insulin resistance, uric acid levels, and estimated glomerular filtration rate using the creatinine-cystatin C equation (eGFRcr-cys). CONCLUSION: This large-scale cohort study demonstrates that microalbuminuria serves as a clinical predictor of elevated risk for incident T2DM in adults. Routine UACR screening in high-risk populations may enhance early detection and intervention.

Individuals with type 2 diabetes are at increased risk of cardiovascular diseases (CVD). Dietary behavior plays an important role in both, the management of diabetes and the prevention of CVD. We aimed to summarize the current evidence on associations between dietary patterns and the risk of CVD outcomes in individuals with type 2 diabetes. PubMed, Embase and Cochrane library were systematically searched for prospective observational studies investigating dietary patterns in association with CVD outcomes in individuals with diabetes. Summary risk ratios (SRR) with 95% confidence intervals (CI) were calculated using random effects model. The certainty of evidence was evaluated using the GRADE approach. In total, we identified 57 studies. Moderate certainty of evidence was found for the association between the Mediterranean diet and CVD (SRR per 1 point: 0.95; 95% CI: 0.93, 0.97; n=6). Other plant-based diets such as the Dietary Approaches to Stop Hypertension (Per 5 points: 0.96; 95% CI: 0.89, 1.03; n=3), EAT-Lancet diet (Per 3 points: 0.65; 95% CI: 0.45, 0.95, n=3) or country-specific dietary guidelines (High vs low: 0.80; 95% CI: 0.76, 0.84; n=9) were associated with a lower incidence of CVD outcomes (low or very low certainty of evidence). Higher adherence to the unhealthy plant-based index and dietary inflammatory index were positively associated with CVD (low and very low certainty of evidence). No clear associations were found for overall and vegetable-based plant-based index, low-carbohydrate diets, glycemic load or glycemic index and CVD in persons with type 2 diabetes. Most studies were rated as high risk of bias due to confounding. In conclusion, the results suggest a possible beneficial association between plant-based dietary patterns and CVD outcomes in individuals with type 2 diabetes. However, the certainty of evidence was low to very low, highlighting the need for further well-designed prospective studies. REGISTRATION: PROSPERO, registration number: CRD42018110669, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=110669.

OBJECTIVE: To present a summary of recent evidence describing the clinical and economic impact of continuous glucose monitoring (CGM) in the care of people living with type 2 diabetes mellitus (T2DM). QUALITY OF EVIDENCE: Outcomes of CGM use in T2DM was searched using PubMed and Google Scholar, using specific inclusion and exclusion criteria to select evidence. Preference was given to randomized controlled trials, real-world observational studies and meta-analyses. Guidelines, consensus statements and systematic reviews were also considered. MAIN MESSAGE: An overall favorable trend was seen in support of people living with T2DM using CGM in addition to their regular therapies. CGM improves glycemic outcomes with a significant difference in change from baseline for hemoglobin A1c (A1c), time in range (TIR), time above range (TAR), time below range (TBR), and glycemic variability-all when compared to traditional self blood glucose monitoring. Patient satisfaction favored CGM use, with overall cost-efficiency improved as well. The Canadian healthcare system may benefit from CGM use with decreased hospitalizations and related costs. CONCLUSION: The value of integrating CGM to enhance the care for Canadians living with T2DM as a component of comprehensive care should be recognized. Structural barriers, including provincial inequalities in coverage for devices and access to care currently pose a barrier for many in this population.

In response to the urgent global need for sustainable, natural functional food ingredients for type 2 diabetes (T2DM) management, this study systematically investigates the hypoglycemic potential and underlying mechanisms of a novel pectic polysaccharide (LPs-1a) purified from industrial lemon peel waste. Through comprehensive structural characterization, LPs-1a was identified as a low-methoxyl RG-I-rich pectin groups with a moderate molecular weight (195.26 kDa) and a branched architecture featuring key 1 → 3, 1 → 4, and 1 → 5 glycosidic linkages, consistent with bioactive polysaccharide features. In a high-glucose-induced Min6 pancreatic β-cell injury model, LPs-1a at 200 μg/mL significantly enhanced glucose uptake and insulin secretion. Further metabolomic analysis demonstrated that LPs-1a exerts multi-pathway regulatory effects, with histidine metabolism playing a central role in its cellular repair function. These findings not only elucidate the specific structure-activity relationship of lemon peel-derived polysaccharides but also highlight LPs-1a as a scientifically grounded, natural candidate for the development of functional foods, dietary supplements, or nutraceuticals aimed at supporting glycemic control. This work provides a valuable strategy for the high-value utilization of agricultural by-products, contributing to both health innovation and sustainable resource management.

Current immunotherapies for autoimmune diseases lack sufficient specificity and often compromise protective immunity, underscoring the need for precision-based approaches. Here, we identify x-mAb, a germline-encoded IgM autoantibody derived from dual-expresser lymphocytes of patients with type 1 diabetes (T1D), as a potent agent for precision immunotherapy. In the nonobese diabetic mouse model, x-mAb prevents disease onset, induces durable remission, and preserves functional pancreatic islets without disrupting systemic immune homeostasis. Mechanistically, x-mAb selectively targets islet-reactive CD4 and CD8 tissue-resident memory (Trm) T cells in pancreas and pancreatic lymph nodes, as shown by MHC tetramer staining and in vivo tracking. x-mAb engagement downregulates CD69, a key Trm retention molecule, resulting in a marked reduction of pathogenic pancreatic T cells. Critically, x-mAb recognizes analogous CD69+ Trm-like peripheral T cells in T1D patients and downregulates CD69 ex vivo, indicating a conserved and therapeutically targetable mechanism across species. Structural modeling revealed that x-mAb engages TCRαβ through multiple contact sites, with the most stable interactions targeting a conserved CDR3α SGGGGS motif shared by diabetogenic human and mouse clonotypes. Based on these findings, we propose natural IgM autoantibodies as a previously unrecognized reservoir for precision biologics that selectively target autoreactive T cells while preserving immune competence.

INTRODUCTION: Assess current diabetic kidney disease (DKD) screening practices in adolescents with type 2 diabetes (T2D), identify the comfort level of pediatric endocrinologists in interpreting and treating kidney dysfunction, and investigate barriers and facilitators to implementation of estimated glomerular filtration rate (eGFR) as an adjunctive surveillance metric. METHODS: An anonymous survey was distributed via email to North American pediatric endocrinologists. RESULTS: 115 pediatric endocrinologists (Canada, n=40, USA, n=75) with mean 12.4 (SD 10.3) years in practice, largely from tertiary care centers, completed the survey. Most respondents screen for DKD at T2D diagnosis and annually thereafter. Exposure to an electronic medical record screening prompt was associated with complete adherence. Random urine albumin-to-creatinine ratio was the most common test, while most respondents never ordered an eGFR for DKD surveillance. Discomfort with eGFR interpretation was common, with only one-quarter recognizing hyperfiltration as a clinical concern. Respondents would be more likely to use eGFR if it was externally validated, endorsed by a major society, or incorporated into clinical practice guidelines, with automated electronic medical record reporting as the preferred implementation method. CONCLUSION: Pediatric endocrinologists demonstrate fidelity to pediatric T2D DKD screening clinical practice guidelines; however, comfort with eGFR interpretation in this setting remains limited. .

Obesity is associated with gut dysbiosis, chronic inflammation, and insulin resistance. We assessed proportional change in fecal microbial populations in a pilot study (n=34) of peri/postmenopausal women with BMI ≥28 kg/m2 who were randomized to receive either 3.25 g/day of omega-3 fatty acids or a placebo during a weight loss intervention. Body composition was assessed using DXA, and fecal and blood samples were collected. Median weight change was -10%. Among participants who lost ≥10% of their weight, those assigned to omega-3 fatty acids showed the greatest decrease in the Firmicutes/Bacteroidetes phyla ratio and displayed favorable changes in systemic biomarkers. Notable increases in the proportional abundance of short-chain fatty acid (SCFA)-producing microbes including Phocaeicola vulgatus and Alistipes putredinis were observed in women receiving omega-3, which correlated with improvements in breast cancer biomarkers such as bioavailable estradiol, adiponectin-to-leptin ratio, and C-reactive protein levels. Women administered omega-3 fatty acids displayed increased % change in plasma SCFA propionate and decreased butyrate, suggesting intervention differentially modulated circulating bacterial-derived SCFA metabolites. High dose omega-3 fatty acids, when added to a behavioral weight loss intervention, promoted beneficial shifts to the gut microbiome and associated with improved breast cancer risk factors biomarkers.

INTRODUCTION: Metabolic reprogramming is a hallmark of cancer. Plasma metabolomics offers a minimally invasive approach for identifying metabolic alterations that may provide insights into tumor progression. OBJECTIVES: We aimed to characterize plasma metabolomic profiles in patients with oral squamous cell carcinoma (OSCC) and evaluate their clinical relevance. METHODS: Plasma samples from 43 OSCC patients and 129 cancer-free controls, matched at a 1:3 ratio based on age, sex, and body mass index, were analyzed using gas chromatography-mass spectrometry (GC-MS). A random forest algorithm was applied to identify key metabolic features distinguishing OSCC from controls. The clinical significance of the top metabolites was assessed and validated in another OSCC cohort (n = 27). RESULTS: A total of 113 compounds were putatively annotated and analyzed based on relative abundances. A ten-feature panel demonstrated good classification performance (area under the curve = 0.87; Matthews correlation coefficient = 0.703). The ten features are maltose, glucose, xylulose, δ-gluconolactone, fructose, indoleacetic acid, α-hydroxybutyric acid, glutamic acid, cysteine, and the monoacylglyceride MG(18:1(9Z)/0:0/0:0), suggesting dysregulated carbohydrate metabolism and oxidative stress as the major plasma metabolomic alterations in OSCC. Notably, α-hydroxybutyric acid levels were elevated in patients with regional lymph node metastasis compared with those without. CONCLUSION: Our findings underscore the intricate interplay between altered glucose metabolism, redox imbalance, and OSCC. α-hydroxybutyric acid, a marker of oxidative stress and an indicator of insulin resistance, may be associated with metastatic progression.

The type 2 diabetes-cognitive decline link is a potent independent risk factor for cognitive impairment and dementia. However, preventive strategies often neglect diabetes-specific risks, and reviews generally rely on cross-sectional data. This systematic review of observational cohort studies was conducted to synthesize longitudinal evidence on the multidimensional predictors of cognitive impairment in older adults with type 2 diabetes. PubMed, CINAHL, PsycINFO, and Cochrane Library were searched. Included studies followed older adults with type 2 diabetes for at least six months and evaluated biological, behavioral, psychological, or interpersonal predictors of cognitive impairment. Data were narratively synthesized and study quality was assessed using the Newcastle-Ottawa Scale. Forty-three studies met the inclusion criteria. Biological predictors were the most extensively studied (n = 31). Nine studies addressed behavioral factors, two examined social and environmental predictors, and no studies investigated psychological factors. Higher HbA1c levels, glucose variability, severe hypoglycemia, vascular complications, and inflammatory/metabolic markers significantly predicted higher cognitive impairment risk. Poor diet, low physical activity, and sleep disorders were associated with cognitive decline. Social determinants of health and limited social contact were linked to higher dementia risk, although evidence remains sparse. This review highlights the critical need to prioritize modifiable predictors, especially diabetes-specific biological markers and health behaviors, to prevent or delay cognitive impairment in older adults with type 2 diabetes. Future research should focus on developing individualized, multidimensional preventive interventions that incorporate behavioral and contextual factors. Additionally, validated multifactorial risk prediction models are needed to identify high-risk populations and inform tailored care.

India's escalating burden of obesity and metabolic disease is characterized by a distinctive "thin-fat" phenotype, in which individuals with normal or near-normal body mass index exhibit disproportionate visceral adiposity, reduced skeletal muscle mass, and heightened susceptibility to insulin resistance. Conventional obesity models centered primarily on caloric imbalance fail to adequately explain this pattern, underscoring the need for a more integrative pathophysiological framework. Emerging evidence implicates gut microbiome dysbiosis, impaired fermentation of dietary fibers, reduced short-chain fatty acid (SCFA) signaling, altered bile acid metabolism, metabolic endotoxemia, and dysregulated adipose tissue crosstalk as key contributors to metabolic vulnerability in South Asian populations. This commentary synthesizes mechanistic insights into the gut-metabolic axis and examines their relevance to India's phenotype-specific challenges. Key pathways, including SCFA-mediated incretin secretion, Toll-like receptor 4 (TLR4)-driven inflammatory signaling, angiopoietin-like protein 4 (ANGPTL4)-mediated lipid partitioning, and microbiota-dependent bile acid biotransformation, are discussed as interconnected drivers of metabolic dysfunction. Emerging clinical evidence from randomized controlled trials evaluating synbiotic and prebiotic-botanical formulations is also discussed, highlighting their potential benefits as adjuncts to lifestyle modification. Given India's dietary patterns and widespread deficiency of fermentable fiber intake, synbiotics may represent a scalable and biologically coherent strategy to support metabolic health. However, heterogeneity of formulations, interindividual microbiome variability, and limited long-term outcome data necessitate cautious interpretation. Advancing precision microbiome-targeted interventions will require population-specific research, multi-omics integration, and rigorous clinical evaluation.

INTRODUCTION: Although type 1 diabetes (T1D) technology has improved health outcomes for many, some people continue to experience severe hypoglycemic events (SHEs). This study reviews the history of SHEs and impaired awareness of hypoglycemia (IAH) compound risk for future SHEs, and describes the lived experiences of SHEs among adult people with T1D (pwT1D) with recurrent SHEs (≥ 2/year) and IAH who use continuous glucose monitors (CGMs). METHODS: In this online survey study with eligible CGM-users from the T1D Exchange Registry, participants were asked open-ended questions on the impact of SHEs on their lives, then responses were analyzed thematically. Participants reporting ≥ 2 SHEs in the last year and IAH were included in the analytic sample. RESULTS: Participant (n = 158) responses were coded into 12 thematic categories. A total of 82% of participants reported one or more of the following themes: Emotional and Psychological Impact of SHEs, Social/Relationships Impacts, and Attempts to Prevent and Cope. Specifically, nearly half of participants described the Emotional and Psychological Impact of SHEs (49.4%), with fear around hypoglycemia being especially prominent (e.g., "I worry I might pass out and not wake up…"). Over one-third of participants described impacts of SHEs on their Social Relationships (33.5%), including increased distress from their loved ones. Remaining themes described impacts on numerous other domains of life. CONCLUSION: Adult pwT1D using CGMs who had recurrent SHEs and IAH experience substantial burden in their daily lives. New therapeutic options to help this population eliminate SHEs and meet T1D treatment goals would be especially beneficial.