BACKGROUND Renal cysts and diabetes syndrome (RCAD), caused by heterozygous variants or whole-gene deletions in the HNF1B gene, is a rare, multisystem disorder often detected prenatally by ultrasound findings of bilateral cystic or hyperechogenic kidneys. CASE REPORT We present the case of a 21-year-old woman (G3P2) at 19 weeks of gestation referred for detailed fetal evaluation due to bilateral hyperechogenic, polycystic kidneys and severe oligohydramnios. After counselling, an amnioinfusion was performed to enable amniocentesis and cytogenetic testing. Chromosomal microarray analysis identified a 1.4 Mb interstitial deletion at 17q12 (arr 17q12(34,850,785_36,248,926)x1), encompassing the HNF1B gene and consistent with RCAD syndrome. Family history revealed maternal renal cysts and paternal early-onset diabetes. Despite conservative management and monitoring, the pregnancy was complicated by intrauterine infection, leading to fetal death. CONCLUSIONS This case report expands the spectrum of prenatal findings associated with RCAD and emphasizes the importance of integrating ultrasonographic, genetic, and familial data in the diagnostic pathway. Chromosomal microarray analysis remains a pivotal tool for prenatal detection of HNF1B deletions and for differentiating RCAD from other cystic kidney diseases, such as autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD), which require targeted gene sequencing. Recognition of RCAD in the prenatal setting enables precise counselling, recurrence risk assessment, and postnatal follow-up planning for affected families.

Sirtuin1 (SIRT1) is a histone deacetylase that plays a critical role in insulin sensitivity. Vildagliptin (Vilda) is dipeptidyl peptidase-4 inhibitor approved as oral antidiabetic agent. Docosahexaenoic (DHA) could attenuate hyperglycemia and insulin resistance. The current study was conducted to evaluate the effect of DHA versus Vilda on insulin resistance and hyperglycemia in type 2 diabetes (T2D) rat model via SIRT1/Akt/PI3K. Eighty male Wistar rats were divided into five groups: normal control, diabetes control (the diabetic rats fed high carbohydrate-high fat diet for four weeks, followed by a single intraperitoneal injection of 35 mg/kg streptozotocin, Vilda + diabetic (diabetic rats received 6 mg/kg vildagliptin), DHA + diabetic (diabetic rats received 300 mg/kg DHA), and DHA only group (normal non-diabetic rats received 300 mg/kg DHA). All treatments were given orally for 4 weeks. Each of Vilda and DHA significantly (p < 0.001) decreased blood glucose (131.40. ± 6.10 mg/L and 137.10 ± 7.37, respectively vs. 449.9 ±46.28 1.84 mg/L), increased insulin levels (7.77 ±0.26  µIU/mL and 7.56 ± 0.42, respectively vs. 3.86 ± 0.37 ), decreased HOMA-IR (2.52 ± 0.09 and 2.55 ± 0.091, respectively vs. 4.26 ± 0.34),   decreased pancreatic malondialdehyde (MDA) (3.84 ± 0.29 nmol/mg protein and 3.18 ± 0.21, respectively vs. 6.65 ± 0.71), increased gluthathione (2.18±0.11μmol/mg protein and 2.51±0.09, respectively vs. 1.00±0.29), catalase (104.50±6.74 nmol/mg protein and 122.30±6.20, respectively vs. 70.30±13.98), increased glutathione peroxidase activity (GPx) (0.76±0.19 U/mg protein and 0.99±0.16, respectively vs. 0.47± 0.14) and increased superoxide dismutase activity (SOD) (6.43±1.15 U/mg protein and 8.13±1.16, respectively vs. 3.98±1.4) compared with diabetic group. DHA & Vilda significantly (p < 0.001) improved lipid profile (total cholesterol, triglycerides, LDL-C & HDL-C). DHA was superior to Vilda in increasing levels of glutathione (2.51 ± 0.09 µmol/mg protein vs. 2.18 ± 0.11), catalase activity (122.30 ± 6.20 nmol/mg protein vs. 104.50 ± 6.74 ), SOD activity (8.13±1.16 U/mg vs. 6.43±1.15) and GPx activity (0.99±0.16 U/mg protein vs. 0.76±0.19). Moreover, both Vilda and DHA significantly increase gene expression of SIRT1, Akt, and PI3K and markedly restored normal pancreatic tissue architecture compared with diabetic control group. DHA was comparable to Vilda as insulinotropic and anti-hyperglycemic agent in T2D rats via activation of SIRT1/Akt/PI3K pathway & reducing oxidative stress.

AIMS/HYPOTHESIS: Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses reactive oxygen species and regulates mitochondrial dynamics. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. The physiological role of ROMO1 remains unclear. METHODS: To determine the role of Romo1 in vivo, we used gene targeting in mice to ablate Romo1 in the whole mouse and to conditionally knock out Romo1 in the pancreatic beta cell. Mitochondrial functional analyses were performed on isolated mouse and human islets lacking Romo1/ROMO1. RESULTS: We show that ROMO1 is essential for embryonic development, as Romo1 null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 which catalyse mitochondrial inner and outer membrane fusion. Knockout of Romo1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice (4 months) due to an insulin secretion defect. Isolated islets from male, but not female, mice showed impaired glucose-stimulated insulin secretion. While mitochondria from female mice were morphologically normal, mitochondria in Romo1 adult beta cell knockout (RABKO) cells from male mice were swollen and fragmented, with a reduction in mtDNA content. Knockout of Romo1 did not affect basal respiration in males or females, but deletion of Romo1 in both sexes in mice and of ROMO1 in isolated human islets reduced spare respiratory capacity, which involved the specific loss of respiratory activity at complex II/succinate dehydrogenase. Ageing of female RABKO mice resulted in loss of spare respiratory capacity and glucose intolerance. CONCLUSIONS/INTERPRETATION: Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and spare respiratory capacity and is required for effective nutrient coupling to insulin secretion in the beta cell. These observations point to a critical role for spare respiratory capacity in the maintenance of euglycaemia and to the potential for targeting ROMO1/complex II to promote glucose coupling in settings of insulin insufficiency.

AIMS/HYPOTHESIS: Lactation is associated with reduced maternal risk of future diabetes mellitus and cardiovascular disease. Human milk oligosaccharides (HMOs), bioactive glycans produced in the mammary gland and already detectable in the maternal circulation during pregnancy, are hypothesised to exert endocrine and metabolic effects. We investigated circulating HMOs in the postpartum period, and assessed their short-term modulation by glucose and insulin, and the relationship between plasma and milk HMO profiles. METHODS: At 5-7 weeks postpartum, 28 women (16 with prior gestational diabetes [GDM]; 18 who were breastfeeding) underwent both a 75 g oral glucose tolerance test (OGTT) and a hyperinsulinaemic-euglycaemic clamp. HMOs were quantified in plasma and milk using HPLC. RESULTS: Seventeen HMOs were detected in milk, of which six were also detected in plasma at concentrations that were approximately 10,000-fold lower but were highly correlated across the two compartments. The lactosamine-based glycans 3'-sialyllactosamine (3'SLN) and 6'-sialyllactosamine (6'SLN) were only found in plasma. Lactation status had no significant impact on plasma HMO levels, except for a lower 6'SLN level in breastfeeding women. Women with prior GDM showed lower HMO concentrations in milk when fasting. Plasma HMOs exhibited short-term changes during both tests: during the OGTT, the levels of the fucosylated HMOs 2'-fucosyllactose (2'FL), lacto-N-fucopentaose 1 (LNFP1) and lacto-N-difucohexaose (LNDFH) significantly decreased, while that of 3'-sialyllactose (3'SL) increased; during the clamp, the levels of all fucosylated HMOs and 3'SL declined, whereas that of 3'SLN increased with rising insulin levels. In milk, only the levels of 2'FL and lactodifucotetraose (LDFT) decreased significantly during the clamp. During the clamp, the area under the curve (AUC) of plasma oligosaccharides partly correlated with BMI and metabolic clearance rate. CONCLUSIONS/INTERPRETATION: Circulating HMOs persist during lactation and are acutely regulated by glucose and insulin. The differential response of fucosylated and sialylated species suggests metabolic regulation of HMO biosynthesis, secretion or clearance. These findings support the concept of HMOs as candidate signal molecules in maternal metabolism, linking lactation with postpartum metabolic adaptation.

AIMS/HYPOTHESIS: Homozygous carriers of a loss-of-function variant in the sucrase-isomaltase (SI) gene (c.273_274delAG) are unable to digest sucrose and parts of starch. The variant is common only in Indigenous Arctic populations such as the Greenlandic Inuit and has been associated with a healthier metabolic profile. In a unique gene-diet intervention, we aimed to study whether the SI genotype modulates the effect of two different diets on glucose homeostasis and lipids. METHODS: A genotype-based randomised crossover trial was conducted in homozygous SI carriers and non-carriers in Nuuk and Maniitsoq (Greenland), with two 3 day interventions and a 7 day wash-out period. Participants were ≥18 years, had no gastrointestinal disorders, diabetes nor carried an Inuit-specific high-risk type 2 diabetes variant in TBC1D4. The interventions were as follows: a Greenlandic fish- and meat-rich diet; and an isoenergetic Western diet with 11% energy from sucrose. The order of the diets was randomised by the participants using a dice and participants and personnel were not blinded. The primary outcome was glucose variability measured as CV. Fasting blood samples were drawn before and after each intervention for measurement of lipids, insulin and C-reactive protein. We assessed genotype × diet interaction effects using linear mixed models. The study was reported in accordance with the CONSORT 2010 statement: extension to randomised crossover trials and the consolidated criteria for strengthening reporting of health research involving Indigenous peoples (the CONSIDER statement). RESULTS: Seventeen carriers and 16 non-carriers completed the intervention. CV was higher on the Western diet than on the Greenlandic diet for non-carriers (β=5.23% [95% CI 3.02, 7.45]) but not for the carriers (β 1.27% [-0.86, 3.4]). Carriers had a 20% lower CV on the Western diet compared with non-carriers (p=0.015). Carriers had lower fasting insulin levels than non-carriers at baseline, and the Greenlandic diet decreased the levels in non-carriers by 22.7 pmol/l (95% CI 5.1, 40.3) but not in carriers (p=0.009). We observed no SI × diet interaction effects on lipids levels. CONCLUSIONS/INTERPRETATION: Homozygous loss-of-function SI carriers show better glycaemic management than non-carriers on a Western diet, suggesting SI inhibition as a potential treatment target. TRIAL REGISTRATION: ClinicalTrials.gov NCT05375656 FUNDING: Independent Research Fund Denmark, Greenland Research Council and Brugseni.

Diabetes heightens cardiovascular risk. The selective sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) shows cardiovascular benefits in heart failure, type 2 diabetes and chronic kidney disease. While EMPA protects against myocardial ischemia/reperfusion injury (MIRI) in diabetic and non-diabetic hearts, its mechanisms and impact on specific endpoints, including autophagy, angiocrine signaling, and metabolic flexibility, remain incompletely defined. We explored the systemic and myocardial effects of chronic EMPA pretreatment on these endpoints in diabetic and non-diabetic animals subjected to MIRI. In streptozotocin (STZ, 65 mg/kg) diabetic rats, EMPA (15 mg/kg/d, 4 weeks) reduced water intake without affecting hyperphagia or weight loss. EMPA ameliorated glucose and lipid profiles, tended to restore myocardial GLUT4 and counteract alterations in myocardial hydroxymethylglutaryl-CoA synthase (HMGCS2) and 3-oxoacid CoA-transferase 1 (OXCT1) levels. EMPA improved biomarkers of myocardial damage (BNP, NT-proBNP, CK-MB, galectin 3), inflammation (cardiac NLRP3, plasma IL-1β), oxidative stress (plasma SOD and malondialdehyde), angiocrine imbalance (VEGF and apelin), fibrosis, and collagen deposition, while showing a tendency to improve autophagy and apoptosis signaling. Ex vivo, EMPA improved baseline contractility and post-ischemic recovery of left ventricular pressure (dLVP from baseline: ~+4% in STZ+EMPA vs. -25% in STZ; ~+3% in EMPA vs. -28% in MIRI), enhanced coronary flow recovery, and reduced cardiac contracture, infarct size, and coronary LDH leakage in both diabetic and non-diabetic hearts. These effects may be associated with post-ischemic histological improvements, reduced vascular congestion, increased eNOS phosphorylation, activation of cardioprotective pathways, and inhibition of mPTP opening. Consistently, EMPA enhances wound healing and preserves eNOS phosphorylation in high-glucose (HG) human cardiac microvascular endothelial cells. In human cardiomyocytes, EMPA reduced hypoxia/reoxygenation (H/R) cell death, preserved nitrate and nitrite levels-effects abolished in the presence of L-NAME-and improved mitochondrial membrane potential in HG and/or H/R conditions. EMPA improved metabolic health and protected myocardial and coronary function likely via a permissive microvascular and myocardial phenotype that limits reperfusion injury, supporting its use against MIRI in normal and diabetic settings.

Biguanides, especially metformin, are essential for managing type 2 diabetes, a major global health concern. They show favorable pharmacokinetic and pharmacodynamic profiles and have been in clinical use for decades, although their therapeutic mechanisms have yet to be fully elucidated beyond their primary role in hepatic glucose production. Recent investigations have highlighted the significant roles of the gastrointestinal tract, gut microbiota, and tissue-resident immune cells in modulating metformin efficacy. Metformin is of interest for repurposing across various disorders, including cancer, aging, inflammation, and microbial infections. These manifestations are a consequence of their pleiotropic molecular effects and of treatment benefit, which depend on dose or duration. Nevertheless, the associated lactic acidosis, as well as other rare and serious adverse effects, requires a full knowledge of their toxicity profile and organ responses. Novel nanotechnology-based strategies can provide new opportunities to improve the therapeutic index of biguanides by enhancing bioavailability, increasing tissue specificity, and reducing systemic toxicity. In this review, we have examined the complex pharmacology of biguanides, discussed organ-specific therapeutic and toxicological effects, and critically evaluated targeted delivery to optimize their clinical utility through nanotechnology interventions.

OBJECTIVE: Traditional clinical trials place a substantial burden on participants owing to the need for frequent, tightly controlled site visits, which can limit access and participation. Advances in digital health allow for decentralized clinical trials (DCTs), with site visits replaced by virtual contact and data collection, potentially reducing burden and broadening access. This proof-of-concept study assessed the operational feasibility of a fully remote, digitalized DCT. METHODS: This was a 12-week observational study conducted in Denmark; adults with type 2 diabetes were recruited via social media. Following e-consent, participants were provided with continuous glucose monitoring (CGM) devices and an activity tracker, with data collected via smartphone apps. All visits and support were conducted remotely. Primary endpoints were: proportion consenting via e-signature (weeks -2 to 0), proportion with ≥ 70% unblinded CGM coverage (weeks 2-12), and percentage of scheduled telemedicine visits and questionnaires completed (weeks 0-12). Safety was monitored remotely through adverse event (AE) reporting during telemedicine visits. RESULTS: Most study places were filled within 2 days of advertisement. Of 166 invited individuals, 100% consented electronically; 156 were enrolled, and 87% completed the study. Among participants starting unblinded CGM, 95% achieved ≥70% data coverage, meeting international completeness standards. Adherence to remote interactions was high: 97% attended all telemedicine visits, and 77% completed all questionnaires; 72% completed all scheduled remote interactions. Satisfaction with the study and CGM devices was very high, although adherence to the activity tracker was low (12% with ≥70% coverage) owing to technical issues. Safety monitoring via remote AE reporting revealed no unexpected findings. CONCLUSIONS: A fully remote study was feasible to set up and conduct in Denmark, with rapid recruitment, high retention, and high compliance with CGM and telemedicine visits. DCTs have the potential to reduce participant burden, improve recruitment, and increase the representativeness of clinical trial populations.

OBJECTIVE: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and healthy lifestyles play a crucial role in maintaining individual cardiovascular health. Given that both CVD progression and lifestyles are dynamic in nature, assessing the association between healthy lifestyles score (HLS) and CVD risk at a single time point may have certain limitations. This study aims to identify HLS trajectories via group-based trajectory model and analyse the relationship between these trajectories and CVD risk. DESIGN: This cohort study completed the baseline survey in 2016 and conducted at least one follow-up annually from 2019 to 2024, with the first occurrence of CVD as the outcome. The epidemiological investigation included questionnaire surveys, anthropometric and physiological measurements and serum biochemistry tests. The group-based trajectory model was constructed via SAS V.9.4 PROC TRAJ and the results were visualised via R (V.4.2.2). SETTING: This study involved a rural cohort in southern Xinjiang, China. PARTICIPANT: A total of 2313 participants from four communities were included in this study, with a median (IQR) follow-up time of 6.86 (5.75-8.44) years. RESULTS: The differences in HLS across years were significant (p0.001), whereas the differences between the CVD group and the healthy control group were significant only in 2016 (p0.001), 2019 (p0.001) and 2024 (p0.001). This study identifies five distinct HLS trajectory groups (long-term low, mid-level stable increase, mid-level unstable increase, high-level decrease and ideal trajectory). Compared with the ideal trajectory group, the long-term low-level group presented the highest risk of CVD incidence (HR 6.23, 95% CI 3.38 to 11.49), followed by the mid-level unstable increase group (HR 4.14, 95% CI 2.30 to 7.45) and the mid-level stable increase group (HR 3.14, 95% CI 1.73 to 5.70). The results of stratified analysis by gender, age, hyperlipidaemia, diabetes mellitus and hypertension are consistent with the main findings. CONCLUSIONS: Distinct trajectories of HLS corresponded to differing CVD risks. Moreover, both sustained low and unstable healthy lifestyles significantly contribute to CVD risk. Therefore, the early adoption and maintenance of healthier lifestyles provide long-term benefits in reducing CVD risk.

INTRODUCTION: Indigenous peoples living with diabetes face unique challenges accessing comprehensive specialty diabetes care. A small diabetes virtual care clinic oriented towards Indigenous individuals, and those in rural and remote communities, has provided care to over 400 individuals. OBJECTIVES: We characterised the distinguishing features of care provided at this clinic and used the Consolidated Framework for Implementation Research 2.0 (CFIR) to explore the enablers and barriers to implementing this model of care, from the perspective of the clinic's staff and providers. RESEARCH METHODS AND DESIGN: Guided by CFIR, we conducted eight semi-structured interviews with six clinic staff members. Deductive thematic analysis was used to identify relevant enablers and barriers. RESULTS: The aspirational features of care were cultural safety, comprehensiveness and virtual delivery. The implementation of this model of care was enabled by an internal culture of relational care; a nimble, resourceful, pragmatic and client-centred approach to virtual delivery; wayfinding and resources from key external organisations; community engagement and a small team of motivated and independent providers. Key barriers included the lack of physical interactions and uncertain or limited resources and funding. CONCLUSION: The identified enablers and barriers to implementing an Indigenous-focused virtual diabetes care clinic have implications for future interventions to improve rural Indigenous chronic disease care, and for governments and adjacent organisations tasked with meeting Canada's Truth and Reconciliation Commission's calls to action in healthcare. Further research examining the effectiveness of virtual diabetes care at this clinic is ongoing.

BACKGROUND: Cardiac complications arising from diabetes mellitus manifest as structural and functional myocardial alterations independent of traditional cardiovascular risk factors. The intricate molecular underpinnings driving disease evolution and the spectrum of cellular diversity remain inadequately characterized. Our investigation sought to systematically elucidate the transcriptional architecture and intercellular signaling frameworks in diabetes-associated myocardial dysfunction through integrated omics methodologies. METHODS: We executed parallel bulk and single-cell transcriptomic profiling of cardiac specimens from diabetic disease models. Gene expression disparities were determined via DESeq2 employing stringent thresholds (|log₂FC| > 1; FDR < 0.05). Quality control applied specific thresholds (200-6000 genes/cell, <20% mitochondrial content), with clustering resolution optimized at 0.8 for main cell types and 1.2 for fibroblast subclustering. Single-cell datasets underwent Seurat-based processing with t-distributed stochastic neighbor embedding for population delineation. WGCNA employed soft-thresholding (R² > 0.85), minimum module size of 30 genes, and merge cut height of 0.25. Co-expression module detection within fibroblast subsets was achieved through weighted correlation network construction. Functional annotation leveraged GO and KEGG repositories. CellChat analysis incorporated permutation-based significance testing (n=100, p < 0.05) with CellPhoneDB validation. Intercellular signaling topology was reconstructed using CellChat, emphasizing macrophage migration inhibitory factor circuitry. RESULTS: Transcriptional profiling unveiled 2,000 dysregulated transcripts against 28,840 stable genes, demonstrating substantial reprogramming during pathogenesis. Single-cell resolution exposed profound cellular heterogeneity encompassing myocytes, endothelium, fibroblasts, myeloid cells, and specialized populations including metabolic coordinators and stress-activated subsets. Granular fibroblast dissection revealed 21 molecularly distinct subtypes (designated M1-M21), underscoring remarkable intra-lineage diversity. Enrichment analyses highlighted perturbations in matrix architecture, inflammatory cascades, and proliferative control. Network analysis identified co-regulated gene clusters governing matrix remodeling, inflammation, and metabolic homeostasis. Communication mapping positioned MIF signaling as a pivotal intercellular coordination axis, with stress-responsive cells functioning as nodal integrators throughout disease progression. CONCLUSIONS: This integrative multi-platform investigation provides comprehensive molecular characterization of diabetes-induced cardiac pathology, revealing extensive cellular heterogeneity and intricate communication networks that extend previous single-cell cardiac studies.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are major contributors to both short- and long-term morbidity. Among the adverse outcomes associated with HDP is severe maternal morbidity (SMM). Although the various HDP subtypes differ in their timing of onset, clinical presentation, and severity, little is known about how this heterogeneity is associated with the risk of SMM. This study examines the association between subtypes of HDP and SMM. STUDY DESIGN: We examined hospital administrative data for pregnancies resulting in live or stillbirth ≥20 weeks' gestation at the Prisma Health Midlands and Upstate facilities in South Carolina from 2016 to 2024 (n = 96,161). We compared individuals with no hypertensive disorder vs. those with chronic hypertension with superimposed pre-eclampsia with or without severe features or with unspecified severity, chronic hypertension without superimposed pre-eclampsia, pre-eclampsia with and without severe features or with unspecified severity, and gestational hypertension. HDP were defined using International Classification of Disease codes. HDP were classified into mutually exclusive groups based on the highest severity level reached during the pregnancy. Adjusted Poisson regression models with robust error variance were used to determine the association between each HDP and non-transfusion SMM as defined by the Centers for Disease Control, as well as SMM including blood transfusions of ≥1200 mL. The primary adjusted models included maternal race/ethnicity, parity, smoking, marital status, insurance, plurality, and preexisting diabetes mellitus, and secondary adjusted models included maternal race/ethnicity, parity, smoking, marital status, insurance, and comorbidity index score as defined by the California Maternal Quality Care Collaborative. RESULTS: Of 96,161 birthing individuals, 27,460 (28.6%) had HDP. HDP were more prevalent among Black birthing individuals, as well as those who smoked, were obese, delivered by cesarean, were unmarried, or had public insurance. Most comorbid conditions were more prevalent among individuals with HDP compared with those without and SMM indicators varied by HDP type. All HDP were associated with increased risk of non-transfusion SMM [chronic hypertension with superimposed pre-eclampsia with severe features adjusted risk ratio (aRR): 9.75 (95% CI: 8.04-11.83), chronic hypertension with superimposed pre-eclampsia without severe features aRR: 4.45 (95% CI: 2.30-8.59), chronic hypertension with pre-eclampsia of unspecified severity aRR: 5.32 (95% CI: 4.36-6.48), chronic hypertension without pre-eclampsia aRR: 2.20 (95% CI: 1.67-2.90), pre-eclampsia with severe features aRR: 6.24 (95% CI: 5.44-7.16), pre-eclampsia without severe features aRR: 3.57 (95% CI: 2.67-4.77), pre-eclampsia of unspecified severity aRR: 3.49 (95% CI: 2.73-4.46), gestational hypertension aRR: 1.72 (95% CI: 1.46-2.02)]. Results were similar for SMM including blood transfusions of ≥1200 mL. When the comorbidity index score was included, most risk estimates remained elevated but were attenuated (Table). CONCLUSION: In this large cohort, all HDP examined individually and stratified by severity level, were associated with increased SMM risk. Chronic hypertension with superimposed pre-eclampsia with severe features, followed by pre-eclampsia with severe features had the greatest SMM risk. Analyses that treat hypertensive disorders as a composite exposure or fail to account for severity may mask important differences in risk. These findings have direct implications for patient counseling, clinical decision-making, and risk stratification. Strengths of this study include the classification of HDP by both type and severity. Limitations include reliance on hospital administrative data for HDP classification, which may introduce misclassification bias; some missing maternal BMI data, which may lead to underestimation of comorbidity index scores; lack of postpartum data; and not accounting for antihypertensive treatments, which may be associated with SMM outcomes.

BACKGROUND: Long-term consumption of fatty meats is associated with metabolic diseases, partly due to induction of low-grade metabolic acidosis. OBJECTIVES: Our objective was to test the metabolic effects of pH-enhanced (ammoniated) beef in diet induced obese C57BL/6J mice. We hypothesized that adipose tissue function will be improved by consuming a diet containing pH-enhanced ammoniated beef, compared to non-pH-enhanced beef, and these effects would be modulated by dietary fat content and sex. METHODS: Eighty C57BL/6J mice were randomized into four groups (n = 20/group; 10 males and 10 females) and fed diets differing in pH enhancement (ammoniation using ammonium hydroxide) and fat content for 12 weeks (Low-fat beef -LFB, ammoniated LFB - LFBN, high-fat beef - HFB and ammoniated HFB - HFBN). Body weights were measured weekly. Visceral (gonadal) white adipose tissue (VAT) was collected for histology, RNA (qRT-PCR) and protein (Western blotting) analyses. Three-way ANOVA analyses were performed to identify main effects of fat content, ammoniation, sex, and their interactions. RESULTS: Interactions between sex and dietary fat content modulated results for weight gain (F (1, 64) = 9.601, P = 0.0029), fat pad mass (F (1, 63) = 36.48, P < 0.0001), and adipocyte area (F (1, 39) = 24.47, P < 0.0001). Interactions between sex and ammoniation significantly affected fat pad mass (F (1, 63) = 4.341, P = 0.0413) and adipocyte area (F (1, 39) = 4.171, P = 0.0479). Importantly, ammoniation significantly improved glucose tolerance (F (1, 59) = 16.74, P = 0.0001), irrespective of sex and dietary fat. Interactions between sex and dietary fat content modulated other results throughout the study. CONCLUSIONS: Diets containing ammoniated beef reduced gonadal fat pad mass and adipocyte size, and improved glucose tolerance in mice with diet induced obesity, while interactions between dietary fat content and sex modulated results throughout.

BACKGROUND: Diabetes mellitus leads to microvascular and macrovascular complications that significantly impact quality of life. Previous cross-sectional studies may overestimate complication impacts due to methodological limitations. We performed a longitudinal study to assess within-patient associations between diabetes complication severity and quality of life in type 1 and 2 diabetes, providing contemporary utility estimates for cost-effectiveness analyses. METHODS: This longitudinal cohort study used Swiss diabetes registry data (2015-2022). Patients with type 1 and 2 diabetes completing ≥2 annual EQ-5D-3L questionnaires were included. We used the adapted Diabetes Complications Severity Index (aDCSI) to quantify complication severity. Associations were examined using mixed-effects regression models, adjusted for patient characteristics and survey time. RESULTS: Among 896 participants (422 type 1, 474 type 2), 83% had ≥1 complication at baseline. Type 1 patients reported better quality of life than type 2 (EQ-5D: 0.96 vs 0.88; VAS: 82.1 vs 75.5). Higher aDCSI scores were associated with reduced quality of life in both diabetes types. Women and insulin-treated patients reported lower scores. Only 4.9% developed complications. No quality of life decrement over time was observed. CONCLUSION: Diabetes complications reduce quality of life, with myocardial infarction (-0.05 EQ-5D utility) in type 2 and renal failure (-19 VAS points) in type 1, with decrements smaller than previous estimates.