BMJ Open Diabetes Research & Care

Background: Prediabetes is a critical intermediate stage in the development of type 2 diabetes mellitus and is increasingly prevalent in the Eastern Mediterranean Region. In Qatar, high levels of metabolic and lifestyle-related risk factors underscore the need for scalable, non-invasive risk stratification tools within primary care. The Prediabetes Risk Score in Qatar (PRISQ) was developed as a population-specific screening tool; however, its distribution and associated risk patterns within national primary care settings remain insufficiently characterized. This study aimed to assess the population-level distribution of PRISQ scores among adults attending primary care in Qatar and to identify key sociodemographic and clinical correlates of elevated prediabetes risk. Methods: A cross-sectional analysis was conducted among adults ([&ge;]18 years) registered with the Primary Health Care Corporation (PHCC), using data derived from the HEALTHSIGHT study. PRISQ scores were calculated based on five non-invasive clinical parameters: age, sex, body mass index, waist circumference, and blood pressure. Participants were categorized into low, moderate, and high-risk groups using established PRISQ cut-offs. Descriptive analyses summarized risk distributions, and multivariable linear regression was used to identify independent predictors of PRISQ scores. Results: Among 1,116 participants included in the final analysis, the mean PRISQ score was 26.5 {+/-} 11.0. Nearly half of the study population (47.7%) was classified as high risk for prediabetes, while 34.4% and 17.9% were categorized as moderate and low risk, respectively. Increasing age was the strongest contributor to higher PRISQ scores, followed by body mass index, waist circumference, and blood pressure (all p < 0.001). High-risk individuals were more frequently male, older, overweight or obese, and long-term residents of Qatar, with variation across nationality groups. Conclusions: A substantial proportion of adults attending primary care in Qatar are at high predicted risk for prediabetes. These findings support the utility of PRISQ as a risk stratification and engagement tool in primary care to guide early lifestyle counselling and targeted preventive interventions. Longitudinal studies are needed to assess progression to dysglycemia and to further refine risk-based screening strategies.

BackgroundInflammation-induced pancreatic islet-cell death and dysfunction are key aspects of both type 1 and type 2 diabetes. Stem cell-derived islets (SC-islets) are an emerging tool in diabetes research, however, our understanding of how inflammation affects SC-islet function is incomplete. We therefore aimed to thoroughly characterize how SC-islets respond to pro-inflammatory cytokines at the functional and transcriptomic levels in comparison with human primary islets and EndoC-{beta}H5 cells. MethodA 7-stage differentiation protocol was used to generate SC-islets with insulin-, glucagon-, and somatostatin-positive cells. SC-islets, primary human islets and EndoC-{beta}H5 cells were exposed to different doses of pro-inflammatory cytokines (IL-1{beta} + IFN{gamma} + TNF) including a high dose for up to 48 h and a low dose up to 144 h to mimic the intense islet inflammation in T1D and chronic low-grade inflammation in T2D, respectively. Differential gene expression (RNA-seq), cell death, activation of key signalling proteins, hormones, and chemokine secretion were determined. ResultsBasal expression of key islet-cell identity genes in SC-islets correlated well with that of primary islets and EndoC-{beta}H5 cells. In SC islets, cytokines dose-dependently induced activation of key proximal signalling pathways (NF{kappa}B, STAT1, and JNK), upregulation of major histocompatibility complex (MHC) class I, and increased cell death (cytotoxicity and caspase 3/7 activity). In head-to-head experiments, SC-islets displayed similar cytokine responses particularly as primary islets regarding induction of cell death, chemokine secretion, differential gene expression, and protein levels of cell death executioners (gasdermin D and caspase-7). Cytokines increased insulin release in SC-islets and primary islets, while diminishing insulin secretion in EndoC-{beta}H5 cells. Cytokines reduced glucagon release in SC-islets, which was partially restored by treatment with the incretin hormone glucose-dependent insulinotropic peptide (GIP) with or without a glucagon-like peptide 1 (GLP-1) receptor agonist (liraglutide). ConclusionSC-islets are highly responsive to inflammation with a high degree of similarity to primary islets. Our results support the use of SC-islets as a valid tool in inflammation and diabetes research.

Background & AimsDiabetes mellitus has been associated with both intestinal barrier dysfunction and peripheral neuropathy leading to increased risk of infection. The mucus layer forms a physical barrier against pathogens and is a critical component of the intestinal barrier that may be impaired in diabetes. This study aimed to assess how diabetes impacts goblet cells (GCs), mucus layer integrity, and innervation in the colon. MethodsFluorescence microscopy was used to investigate GCs, the mucus layer, and innervation in the colon of db/db mice. Custom open-access image analysis pipelines were developed to quantify GC numbers, location and content, mucus thickness, bacterial colonization, and innervation density in intestinal tissue sections. We also treated mice with the clinically used glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide to assess its capacity to reverse pathological changes to GCs and the mucus layer in a model of established type 2 diabetes (T2DM). ResultsThe mucus layer was significantly thinner in the colon of db/db mice with established diabetes and bacteria more readily colonized the epithelium and crypts. Intercrypt GC numbers were significantly reduced in db/db mice. However, there were significantly more GCs per crypt, and crypts were elongated in the db/db colon. Innervation was reduced in the mucosa and external muscle of the colon, consistent with diabetic neuropathic changes. Liraglutide treatment increased the size of GCs but had no effect on GC numbers, mucus thickness, or innervation in this model of established T2DM. ConclusionsMucus barrier dysfunction and GC hyperplasia is evident in the db/db colon. Increased microbial penetrability through the mucus layer suggests potential implications for the increased risk of gastrointestinal infection in diabetes.

Objective: In this study, we utilized a large-scale clinical database to evaluate the relationship between polypharmacy and adverse outcomes among type 2 diabetes patients in rural Montana to inform strategies that improve adherence, reduce preventable complications, and promote equitable diabetes care in underserved regions. Research Design and Methods: 591 patients from the Big Sky Care Connect Database (BSCC) with type 2 diabetes and medication history were stratified into 3 cohorts based on prescribed number of medications: (1-4 medications, non-polypharmic), (5-9 medications, polypharmic), and ([&ge;]10 medications, hyperpolypharmic). Each cohort was examined for Major Adverse Cardiovascular Events (MACE) and Diabetes Complication Severity Index (DCSI). Descriptive statistics, multivariate logistic regressions, linear regression, and Poisson regression analyses were performed. Results: Medication count was associated with male gender ({beta} = -2.1341, p < 0.001). Both medication count (IRR 1.06 per additional medication, p < 0.001) and age (IRR 1.03 per year, p < 0.001) were significant predictors of MACE. Neuropathy and nephropathy prevalence was statistically significant (p < 0.001) across patient cohorts and increased with medication count.

AimWe examined associations between smoking and HbA1c among U.S. adults, and whether these associations vary by diabetes status. MethodsWe analyzed NHANES data from 2015-2018 for adults aged [&ge;]20 years. Smoking was assessed by self-report and serum cotinine. Survey-weighted multivariable linear regression was used to evaluate the association between smoking and HbA1c in the full population (N=9,214) and in adults without diabetes (N=7,328), adjusting for demographics, blood pressure, waist circumference, lipids, and C-reactive protein. ResultsAfter adjustment for cardiometabolic covariates, there was no significant association between smoking and HbA1c in the full population (former: {beta}=0.029%, p=0.30; current: {beta}=0.053%, p=0.13). Among adults without diabetes, former smoking was not associated with HbA1c, whereas current smoking remained significantly associated (former: {beta}=-0.001%, p=0.923; current: {beta}=0.067%, p<0.001). These findings were similar when cotinine was used as the exposure measure, with active smoking ([&ge;]3.0 ng/mL) associated with higher HbA1c among non-diabetic adults (p<0.001), but not in the full population. ConclusionsAmong adults without diabetes, current but not former smoking was associated with higher HbA1c. The absence of an association in former smokers suggests that this effect may attenuate following cessation. These findings support early cessation interventions and may inform cessation counseling and diabetes screening.

Abstract Context Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor, traditionally considered stable across the lifespan, supporting a single lifetime measurement strategy. However, its longitudinal behavior during childhood and adolescence remains poorly characterized, particularly in individuals with type 1 diabetes who are at increased lifetime risk of cardiovascular disease. Objective We aimed to characterize intra- and inter-individual trajectories of Lp(a) in youth with type 1 diabetes and to assess the implications of variability for cardiovascular risk classification. Methods We conducted a retrospective single-center cohort study of children and adolescents with type 1 diabetes followed at Geneva University Hospitals between 2012 and 2023. Annual fasting Lp(a) concentrations were analyzed longitudinally. Variability was assessed in participants with more than two measurements. Clinically relevant thresholds were used to evaluate risk reclassification. Statistical analyses included paired Wilcoxon tests, Pearson and Kendall correlations, and Holm-adjusted p-values. Results A total of 287 participants contributed 1,408 Lp(a) measurements over a median follow-up of 6.2 years (IQR 2.9-9.6). At baseline, 26% had elevated Lp(a) (above or equal 300 mg/L). Among participants with serial measurements, 32% exhibited intraindividual fluctuations exceeding 50% of their maximum value. Reclassification across the 300 mg/L threshold occurred in 11.9% of participants. Lp(a) concentrations peaked between ages 10 and 13 years and declined thereafter. Modest seasonal variation was observed, with higher levels in autumn and winter (P < 0.05). Conclusions In youth with type 1 diabetes, Lp(a) demonstrates clinically relevant intraindividual variability over time. These findings suggest that reliance on a single lifetime measurement may lead to misclassification of cardiovascular risk and support repeated assessment, particularly during adolescence, to improve risk stratification.

BackgroundLifestyle interventions incorporating medically-tailored meal delivery may support rapid behavior change among pregnant individuals with gestational diabetes (GDM). PurposeTo examine the feasibility and acceptability of a multicomponent lifestyle intervention for pregnant individuals with GDM. Primary outcomes included recruitment, retention, intervention receipt, and acceptability. MethodsWe conducted a pilot randomized feasibility trial among pregnant individuals with GDM recruited from maternal fetal medicine clinics in the Hartford, Connecticut area. Participants were randomized to usual GDM care or the Meals4Moms intervention plus usual care. The intervention included medically-tailored meal delivery, personalized physical activity support, and multimodal education with digital tools. Participants completed a survey and three 24-hour dietary recalls at baseline and post-intervention. Meals4Moms participants also completed a semi-structured interview at follow-up. Intervention receipt was tracked by study staff. ResultsOf 30 individuals approached, we screened 80% (n=24), of whom 75% (n=18/24) were eligible; we randomized 8 participants. Seventy-five percent (n=6/8) completed at least one component of the follow-up assessment (100%, n=4/4 Meals4Moms, 50%, n=2/4 Usual Care). One participant spent [&ge;]80% of her total food budget (n=1/4, 25%), and no participants completed [&ge;]80% of prescribed exercise sessions (range: 0-50%). All (n=4) Meals4Moms participants reported they would be very likely to participate in the program if they had GDM again, and 100% (n=4) would be very likely to recommend the program to a friend with GDM. ConclusionsWhile the Meals4Moms intervention was highly acceptable to participants, procedural refinements are needed prior to conducting a full-scale efficacy trial.

Aims: Sarcopenia and sarcopenic obesity are associated with increased risks of cardiovascular (CV) disease and mortality. This study examined the associations of body composition and daily physical activity with mortality, CV events and cancer in patients with diabetes. Methods: This prospective cohort study included patients with diabetes treated at a specialised clinic in Japan between January 2018 and March 2023. Body composition, including visceral adipose tissue (VAT), was assessed by bioelectrical impedance analysis. Daily physical activity was evaluated using the non-exercise activity thermogenesis (NEAT) questionnaire, and handgrip strength (HGS) was measured by dynamometry. Cox proportional hazards models were used to assess associations with mortality, CV events, and cancer. Results: Among 2,024 patients (mean age 63.0 years, BMI 24.6 kg/m^2, HbA1c 7.8%), NEAT, HGS, and VAT were not independently associated with all-cause mortality. Higher VAT was associated with increased cancer risk (HR 1.485; 95% CI 1.101-2.003; p = 0.009). Higher HGS was inversely associated with CV event risk (HR 0.951; 95% CI 0.919-0.984; p = 0.004). NEAT was not associated with any outcome. Conclusions: Higher VAT was associated with increased cancer risk, whereas higher HGS was protective against CV events. Incorporating body composition and HGS assessments into clinical practice may improve risk stratification and management in patients with diabetes.

Background: Parental diabetes and obesity influence offspring phenotype, but their relative contributions remain unclear. Aim: To examine the relative contributions of parental diabetes and obesity to offspring overweight-obesity and glucose intolerance. Methods: We studied 200 offspring of mothers with diabetes in pregnancy (ODM; 176 indexes, 24 siblings), 176 mothers (133 gestational diabetes (GDM), 22 type 1, 21 type 2 diabetes), and 150 fathers. Controls included 177 offspring of non-diabetic mothers (ONDM), 177 mothers without diabetes in pregnancy, and 163 fathers. Overweight-obesity was defined by WHO criteria, central obesity as waist-to-height ratio >0.5, and glucose intolerance by ADA criteria (fasting glucose for <10 years; oral glucose tolerance test (OGTT) for >=10 years). Generalized linear mixed-effects models assessed parental determinants of offspring outcomes. Results: ODM were more overweight-obese, centrally obese, and glucose intolerant than ONDM. Younger ODM had higher capillary glucose (5.6 vs 5.1 mmol/L, p<0.001). Among ODM >=10 years, 37% had prediabetes and 5% diabetes versus 20% and 0% in ONDM. Overweight-obesity was associated with maternal (OR 7.81; 95% CI 2.19-27.85), paternal (OR 6.21; 95% CI 1.57-24.53), and biparental obesity (OR 9.59; 95% CI 2.73-33.69), but not parental diabetes. Glucose intolerance was associated only with maternal diabetes in pregnancy (OR 3.90; 95% CI 2.05-7.41). Conclusions: Preventing offspring obesity will require addressing parental obesity, whereas preventing glucose intolerance will require optimal glycemic control in the mothers before and during pregnancy.

Background: Older in-patients have a higher prevalence of diabetes and cognitive impairment. Cognitive impairment can make blood glucose management more challenging, since patients might not remember to measure blood glucose or report symptoms. Investigating the accuracy of continuous glucose monitoring (CGM) compared to usual care will inform clinical interpretations in this vulnerable population. Aim: To compare CGM derived glucose metrics and point-of-care tests (POCT) in older in-patients with T2DM and cognitive impairment and to investigate CGM accuracy compared to POCT in the hospital settings with the same population. Methods: Thirty-two older people with comorbid T2DM and cognitive impairment were recruited within a tertiary care hospital in the UK. All participants were naive to CGM and were asked to wear blinded Dexcom G7 sensors for up to 10 days. All participants received usual care in their hospital stay including the use of POCT. Key accuracy metrics comprised the mean absolute relative difference (MARD), median absolute relative difference (median ARD), and Clarke Error Grid (CEG), correlation (R2) analysis. In addition, the percentage of CGM readings falling within +/-20% of reference glucose values when the reference was >5.6 mmol/L, or within +/-1.1 mmol/L when the reference was <=5.6 mmol/L (+/-20%/1.1 mmol/L) was calculated to assess analytical and clinical accuracy. Results: Thirty participants completed the study. CGM derived mean glucose for time in range (TIR= 4-10 mmol/mol) was 36.23% (min= 0%, max= 90%), time above range (TAR >= 10 mmol/mol) was 62.87% and time below range (TBR <= 3.9 mmol/mol) was 1.03%. Mean TIR based on available POCT readings was 40.84%, TAR was 57.24% and TBR 1.81%, showing similar readings as CGM derived glucose metrics. Comparison of the two resulted in a MARD of 17.4%, and median ARD of 12.2% and the outcome of +/-20%/1.1 mmol/L analysis was 72.3%. CEG analysis revealed that 99.3% of the data points fell within the clinically acceptable zones (Zone A and Zone B), and there was a strong correlation (R2=0.82) between CGM and POCT. CGM captured more hypoglycaemic readings in our participants. Conclusion: Our study suggests that CGM and POCT derived glucose metrics are largely similar for in-patients with diabetes and cognitive impairment. CGM remains as a safe and clinically acceptable tool, and able to capture more nocturnal hypoglycaemia compared to POCT in a subgroup of patients. These initial findings show that CGM might be a viable alternative for people with comorbid T2DM and cognitive impairment.

Introduction/Aim: Type 2 diabetes (T2D) is a growing global health burden, with lifestyle behaviors playing a key role in its management. Physical activity (PA), sedentary behavior (SB), and sleep are increasingly conceptualized as interdependent components of 24-hour movement behaviors. While behavior change techniques (BCTs) are commonly used to target individual behaviors, their effectiveness across multiple behaviors in adults with T2D remains unclear. This systematic review and meta-analysis aimed to evaluate the effectiveness of behavior change interventions incorporating BCTs on PA, SB, and sleep outcomes, and to identify effective BCT clusters. Methods: A systematic search of PubMed, Web of Science, and Embase was conducted from inception to December 18, 2023. Randomized and non-randomized controlled trials including adults with T2D were eligible if they evaluated behavior change or lifestyle interventions targeting PA, SB, and/or sleep and included at least one BCT. Data extraction, BCT coding (using the BCT Taxonomy), and risk of bias assessment (Cochrane RoB 2) were performed independently by multiple reviewers. Meta-analyses using random-effects models were conducted for relevant outcomes. Subgroup analyses examined the effects of three common BCT clusters: goals and planning, feedback and monitoring, and social support. Results: Sixty-six studies (n = 18,725 participants) were included. Interventions significantly improved several PA outcomes, including steps/day (+1991 steps/day; p<0.001), total PA (SMD=0.36; p=0.02), moderate-to-vigorous PA (SMD=0.55; p<0.001), and light-intensity PA (SMD=0.62; p=0.01). Sedentary time decreased significantly (SMD=-0.32; p=0.008). Sleep quality improved (MD=-1.39; p=0.02), whereas sleep duration showed no significant change. Subgroup analyses demonstrated that BCT clusters involving goals and planning, feedback and monitoring, and social support were consistently associated with improvements in PA and SB, with comparable effect sizes to overall analyses. Effects on sleep outcomes were limited due to the small number of studies. Conclusion: Behavior change interventions incorporating BCTs effectively increase PA, reduce SB, and improve sleep quality in adults with T2D. BCTs such as goal setting, self-monitoring, feedback, and social support appear particularly beneficial. However, sleep - especially duration - remains underexplored. Future interventions should adopt a 24-hour movement behavior perspective and more explicitly integrate and report BCTs to optimize long-term diabetes management.

ObjectivesDyslipidemia is prevalent among Nigerians living with diabetes, but the rate and extent of treatment have not been well-studied. The objective of this study was to determine the prevalence, treatment rates and control of dyslipidemia among diabetes patients in northern Nigeria. MethodsWe conducted a multicenter, cross-sectional study of diabetes clinic patients. We noted cardiovascular risk factors, lipid-lowering treatments and examination findings, including body mass index, blood pressure, glycated hemoglobin, lipid profile, glomerular filtration rate and urinalysis. Outcome measures were the rate of dyslipidemia, the proportion of patients treated for dyslipidemia, and the proportion of patients with low density lipoprotein cholesterol goal and target for primary prevention of cardiovascular disease. ResultsThe study enrolled 403 participants (58.8% females), of whom 59.6% had dyslipidemia. Female gender and proteinuria were independently associated with dyslipidemia, with odds ratios of 1.74 and 2.26, respectively. Other cardiovascular risk factors of participants were hypertension (56.8%), obesity (52.6%), chronic kidney disease (36.5%), atrial fibrillation (7.9%), heart failure (5.0%), cigarette smoking (4.7%), excess alcohol use (2.0%), and previous cardiovascular disease (14.4%). In those with dyslipidemia, 51.3% took lipid-lowering treatments comprising statins (49.6%), clofibrate (1.7%) and statins combined with clofibrate (1.2%). None took other lipid-lowering treatments beside dietary control, probably due to high costs compared to statins. Only 17.1% of all participants attained the target for primary prevention of cardiovascular disease in people with diabetes. ConclusionMost patients had dyslipidemia, which was more prevalent in females. Only a sixth of all patients had attained the treatment target. Treatment for dyslipidemia was limited to statins and fibrates, contrary to guideline recommendations for the use of ezetimibe, bempedoic acid, icosapent ethyl, or PCSK9 inhibitors for those who failed intensive statin therapy. There is a need for physician adherence to practice guidelines for the treatment of dyslipidemia, and improved access to treatment in northern Nigeria.

Background: Obesity has become increasingly common among US adults with hypertension. However, national data are limited on weight-loss efforts among adults with hypertension and overweight/obesity, and whether these efforts have translated into clinically meaningful weight loss at the population level. Methods: We analyzed repeated cross-sectional data from the National Health and Nutrition Examination Survey, 1999-2023. Adults aged 20 years with hypertension and body mass index 25 kg/m2 were included. Weight-loss attempt was defined as self-report of trying to lose weight during the prior 12 months. Among those attempting weight loss, successful weight loss was defined as 5% or 10% reduction in body weight over the prior year. Survey-weighted logistic regression was used to assess temporal trends and associations between strategies and successful weight loss. Results: Overall, 57.6% reported a weight-loss attempt, increasing from 55.9% in 1999-2000 to 60.4% in 2021-2023 (P for trend=0.002). The most reported strategies were eating less food (65.3%) and exercise (52.4%). Among those attempting weight loss, 33.4% achieved 5% weight loss and 14.7% achieved 10% weight loss; neither improved over time (P for trend=0.976 and 0.174, respectively). Weight-loss surgery was strongly associated with success but was rarely reported (0.35%). Eating less fat and changing eating habits were also positively associated with successful weight loss, whereas skipped meals and use of diet foods or products were inversely associated. Conclusions: Weight-loss attempts increased, but clinically meaningful weight-loss success did not improve, highlighting a persistent gap between effort and outcome in hypertension care.

BackgroundPET-CT scans of radioactive exendin-4, a ligand of the GLP-1 receptor, are claimed to provide a biomarker of pancreatic beta cell mass (BCM), although the GLP-1 receptor is expressed also in the exocrine pancreas (PX). Parotid glands may be a reference tissue for GLP-1 receptor expression in exocrine cells of the GI system. Our aims were 1. To assess biomarker(s) of BCM derived from 68Ga-NODAGA-exendin-4 PET-CT scans in participants with long-standing type 1 diabetes (T1DM) or in subjects with obesity (OBESE); 2. To investigate the relationship between biomarker(s) of BCM and a biomarker of beta cell functional mass (BCFxM) in OBESE. MethodsT1DM (n=8, Age: 50.4{+/-}3.8 yrs; T1DM duration: 34.2{+/-}3.0 yrs; BMI: 26.6{+/-}1.1 kg/m2; HbA1c: 7.5{+/-}0.36%) and OBESE (n=9; Age:48.2{+/-}2.2 yrs; BMI: 37.4{+/-}1.1 kg/m2; HbA1c: 5.4{+/-}0.17%) underwent two studies: 1) 68Ga-NODAGA-exendin-4 PET-CT scan of both PX and parotid glands 45-60 after i.v. injection and with CT-assessment of PX volume to compute biomarkers of BCM based on SUV (BCMSUV) or clearance (CLEAR; BCMCLEAR); 2) Mixed meal test (MMT), with measurement of plasma glucose, C-peptide, GLP-1 and GIP curves to assess BCFxM with state-of-art mathematical modeling. ResultsThe C-peptide response to the MMT in T1DM participants was absent or negligible, whereas the OBESE displayed a robust BCFxM. The PX volume was smaller in T1DM than in OBESE (51.7{+/-}6.6 vs 92.9{+/-}10.9 cc; p=0.007). The biomarkers of BCM, as assessed by 68Ga-NODAGA-exendin-4 SUV or CLEAR, were 6.6-fold (p=0.003) and 5.0-fold (p=0.002) lower, respectively, in T1DM than in OBESE. BCFxM was correlated in OBESE to both biomarkers of BCM (r=0.91 p<0.001, and r=0.82 p=0.006, respectively). Conclusion/interpretation68Ga-NODAGA-exendin-4 derived biomarkers of BCM can discriminate T1DM from OBESE. In OBESE 68Ga-NODAGA-exendin-4 derived BCM appears to be a pivotal determinant of the beta cell response to MMT and may be valuable to compare and monitor BCM both in research and in clinical settings. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIChanges in pancreatic beta cell functional mass are at the heart of alterations in glucose regulation, including diabetes mellitus. Beta cell functional mass can be assessed by mathematical modeling of the in vivo beta cell response to intravenous or oral challenges. C_LIO_LIBeta cell functional mass is the product of beta cell mass times beta cell function per mass unit, i.e. the result of two distinct entities, mass and function. No in vivo methods can dissect out beta cell mass and function. C_LIO_LIPancreatic 68Ga-exendin-4 uptake, as measured by PET-CT, has been proposed as a non-invasive biomarker of beta cell mass. However, the ratio of 3.6:1 between endocrine and exocrine pancreas 68Ga-exendin 4 uptake suggests that there is room for improvement. C_LI What are the key questions?O_LIDoes an improved 68Ga-exendin4 method provide a better separation between participants with type 1 diabetes and expected zero/nil beta cell mass vs people with nondiabetic obesity? C_LIO_LIWhat is the role of beta cell mass in determining beta cell functional mass in people living with obesity? C_LI What are the new findings?O_LIThe improvement in the quantitation of beta cell 68Ga-exendin-4 binding to beta cells resulted in a clearcut separation of participants with type 1 diabetes and expected zero/nil beta cell mass from people living with obesity C_LIO_LIIn people living with obesity, beta cell mass, as assessed by 68Ga-exendin-4 PET-CT scan, is a pivotal determinant of beta cell functional mass, as assessed by mathematical modeling of a frequently sampled mixed meal test C_LI How might this impact on clinical practice in the foreseeable future?O_LIThis method has the potential to track changes in beta cell mass both between-subjects and within-subjects over time C_LIO_LINatural history of glucose (in)tolerance and the impact of disease modifier candidates in diabetes mellitus can be assessed with the present method C_LI

Plantar tissue adaptation during activity is thought to contribute to diabetic foot ulceration (DFU), yet most existing studies only measure compressive quasi-static properties. This pilot study developed an ultrasound-loadcell measurement tool, PlantarSense, and used an infrared thermometer to measure dynamic compressive and shear energy dissipation ratio (EDR) and temperature of plantar-tissue at the first metatarsal head (1stMTH) and calcaneus in people living with and without diabetes at baseline, post-walk, and post-recovery. People living with diabetes showed significantly greater post-walk temperature increases (11.0 % vs 6.9% in controls at calcaneus, p=0.03) and less complete thermal recovery than controls. Baseline compressive EDR at the 1stMTH was significantly higher in people living with diabetes (67.8% vs 56.0% in controls, p=0.04). EDR modulation was greater from shear loading (21.5%) than compression (5.4%) and post-walk induced reductions in EDR were present in all participants, but people living with diabetes showed a 20% lower recovery than controls. Impaired thermoregulation and tissue adaptation in people living with diabetes was demonstrated by plantar temperature and EDR differences in post-walk and post-recovery. Future work is needed to test more participants with a greater range of diabetes progression to quantify statistically significant plantar tissue differences to inform DFU risk management.

ObjectivesAn update to the NICE Type 2 diabetes (T2DM) guideline in February 2022 recommended an SGLT2 inhibitor be offered to people with cardiovascular disease (CVD) or heart failure (HF) as comorbidities and considered for people at high CVD risk. We report uptake of this guideline in England 18 months after its publication. DesignObservational cohort study. SettingGeneral practices contributing to the Clinical Practice Research Data Link, linked to hospital admission records. Participants587,826 people aged over 18 years with T2DM on 1st September 2023, stratified according to their CVD category (CVD only; HF only; CVD and HF; high CVD risk score; low CVD risk score) and chronic kidney disease (CKD) status, and further by age, gender, ethnicity, deprivation, and T2DM diagnosis duration. Main outcome measuresPercentage of patients with a current SGLT2 inhibitor prescription; odds ratios for association between patient characteristics and a current prescription. ResultsIn people with T2DM, the percentage with a current SGLT2 inhibitor prescription was 19.5% for people with CVD, 29.4% for people with HF, 30.5% for people with both CVD and HF, and 19.9% and 20.2% respectively for people at high and low CVD risk. In age-stratified analyses, uptake ordered from lowest to highest was as follows: low CVD risk score, high CVD risk score, CVD only, HF only, CVD and HF. In models adjusted for clinical and patient characteristics uptake was lower in people aged >60, women, Black people, and people living in areas of higher deprivation. ConclusionsWhilst prescribing of SGLT2 inhibitors continues to rise in England, an opportunity remains to increase uptake and to reduce inequalities in people with T2DM in 2026. We report inequalities by ethnicity and deprivation, and lower uptake for people with CVD without HF than people with HF, despite an equal guideline recommendation for these two groups. Additional evidence is needed on the effectiveness of SGLT2 inhibitors in frailer populations. What is already known on this topic?O_LIIn 2020 approximately 10% of people with type 2 diabetes (T2DM) and cardiovascular disease (CVD) and 14% of people with T2DM but without CVD in England had a current SGLT2 inhibitor prescription. C_LIO_LIIn February 2022 NICE recommended that an SGLT2 inhibitor should be offered to people with T2DM with heart failure or CVD, and considered for people with T2DM at high risk of CVD; network meta-analyses have found 10% to 40% lower odds of cardiovascular mortality with treatment in these groups. C_LIO_LIUptake of NICE guidelines in general practice has historically been variable, although higher when accompanied by pay-for-performance schemes such as the Quality and Outcomes Framework. C_LI What this study addsO_LIBy September 2023 the percentage of people with T2DM with a current SGLT2 inhibitor prescription had reached 19.5% in those with CVD as a comorbidity, 30.5% in those with heart failure, and 19.9% in those at high risk of CVD. C_LIO_LIWomen, people of Black ethnicity, and people living in areas of high deprivation had lower odds of a current prescription in analyses adjusted for age, gender, cardiovascular comorbidity, and renal function. C_LI How might these results change the focus of research or clinical practice?O_LIThe results highlight the need for ongoing surveillance of uptake of NICE-recommended treatments for T2DM, and consideration of actions to address barriers to uptake. This is particularly important in the context of broader eligibility for SGLT2 inhibitor treatment in type 2 diabetes in England from 2026. C_LIO_LIThese results support the development of initiatives and quality improvement programmes to improve evidence-based prescribing and address inequalities between clinical and demographic subgroups. C_LI

Type 2 Diabetes (T2D) is a growing public health burden in West Africa, yet the effectiveness of lifestyle interventions for glycemic control in this region remains unclear. This systematic review and meta-analysis evaluated the impact of lifestyle interventions on Fasting Blood Glucose (FBG) and Glycated Hemoglobin (HbA1c) levels among adults with T2D in West Africa. A systematic search of PubMed, Scopus, Africa Journals Online, and Cairn.info was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and quasi-experimental studies evaluating lifestyle interventions (physical activity, dietary modification, and combined/educational interventions) for glycemic control in adults with T2D in West Africa were included. Meta-analysis was performed via a random-effects model with restricted maximum likelihood (REML) estimation, using mean differences (MD) as the effect measure for both FBG and HbA1c outcomes. Heterogeneity was assessed via I2 statistics, and sensitivity, subgroup, and meta-regression analyses were conducted to examine potential moderators of the observed heterogeneity. Ten studies comprising 645 participants were included. Six studies reported FBG outcomes; however, two were excluded from the FBG meta-analysis due to missing control group post-test values and absence of a control group respectively, leaving four studies for pooling. A separate set of four studies contributed to the HbA1c meta-analysis. For FBG, lifestyle interventions were associated with reduction in FBG levels (pooled MD = -1.81 mmol/L, 95% CI: -2.33 to -1.30, p < 0.001), with moderate heterogeneity (I2 = 50.76%). The certainty of evidence assessed using the GRADE approach was rated as low for FBG outcomes and very low for HbA1c outcomes, reflecting concerns about imprecision and inconsistency across studies. Leave-one-out sensitivity analysis confirmed robustness of this finding, with estimates ranging from -1.707 to -2.087 mmol/L. Neither intervention duration nor sample size significantly moderated FBG effect sizes, with the model explaining approximately 15.7% of observed heterogeneity. For HbA1c, lifestyle interventions were also associated with reduction in HbA1c levels (pooled MD = -1.044%, 95% CI: -1.594 to -0.495, p = 0.0002), though heterogeneity was exceptionally high (I2 = 98.08%), limiting interpretability of the pooled estimate. Exploratory meta-regression identified intervention duration and sample size as statistically associated with HbA1c effect size, though the model was saturated given the small number of studies and findings should not be interpreted as confirmatory evidence of moderation. Conclusion: Lifestyle interventions, including supervised physical activity, dietary modification, and community-based diabetes education, were generally associated with improvements in glycemic control among adults with type 2 diabetes in West Africa. Evidence was more consistent for fasting blood glucose, while findings for HbA1c were highly heterogeneous and should be interpreted with caution. These results suggest potential benefit, but variability across studies highlights the need for more standardized and rigorously designed trials in the region.

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([&le;] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

(1) Aims and hypothesisLoss-of-function mutations in SLC30A8, encoding the zinc ion (Zn2+) transporter ZnT8 in pancreatic beta cells, lower type 2 diabetes risk dose-dependently, but the underlying mechanisms remain unclear. Here, we combine proteomic, transcriptomic and functional approaches in human stem cell-derived islet-like clusters bearing common alleles or the inactivating variant R138X. We hypothesized that this variant protects against the deleterious effect of Zn2+ depletion on cell survival and function. (2) MethodsHuman embryonic stem cells INS(GFP/w) (MEL1), and CRISPR/Cas9-derived heterozygous or homozygous R138X lines were differentiated into stem cell-derived islet-like clusters. Intracellular Zn2+ levels were reduced using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-1,2-ethanediamine (TPEN). Apoptosis was assessed by TUNEL staining and protein expression by immunofluorescence. Glucose-stimulated calcium (Ca2+) dynamics were measured using the intracellular probe (Cal590) and insulin secretion by homogenous time-resolved fluorescence. Transcriptomic profiling was performed by bulk mRNA sequencing and proteomics by liquid chromatography-tandem mass spectrometry. (3) ResultsIntracellular Zn2+ depletion increased apoptosis in wild-type islet-like clusters, whereas R138X clusters were protected. R138X heterozygous clusters showed a mild increase in GCG+ cells and R138X homozygous clusters exhibited increased NKX6.1+ cells, without affecting polyhormonal populations. These changes were reversed under Zn2+ depletion. Transcriptomic and proteomic analyses, assessing genotype effects while accounting for Zn2+ depletion, showed that R138X clusters (versus wild-type) exhibited upregulation of genes and proteins involved in vesicle trafficking, secretion, Ca{superscript 2} signaling and mitochondrial metabolism, consistent with enhanced glucose-stimulated insulin secretion in homozygous clusters. Conversely, genes and proteins associated with extracellular matrix remodeling, metal-ion handling, apoptosis and cellular stress were downregulated. R138X clusters displayed altered Ca2+ signaling, with decreased area under the curve and oscillation amplitude, but increased frequency. These differences were reversed by TPEN, while Zn2+ depletion impaired Ca2+ response in wild-type clusters. Despite lowered overall activity, R138X homozygous clusters showed enhanced overall cell-cell connectivity, reversed by TPEN treatment. The opposite effects were observed in R138X heterozygous clusters, showing improved connectivity and activity under Zn2+ depletion. (4) Conclusion and interpretationIntracellular Zn2+ depletion compromises islet-like cluster identity and function, while the R138X variant confers protection against these effects. Under Zn2+-depleted conditions, ZnT8 deficiency promotes a more mature and metabolically active state of the R138X clusters, with enhanced Ca2+ signaling and insulin secretion, supported by a structural remodeling and the downregulation of apoptosis and cellular stress. These findings highlight the therapeutic potential of targeting ZnT8 in type 2 diabetes and support its relevance for further improving cell-based therapies. Research in ContextO_ST_ABSWhat is already know about this subject?C_ST_ABSO_LIRare inactivating mutations in the insulin granule-associated zinc transporter gene, SLC30A8/ZnT8, drive lowered type 2 diabetes risk. C_LIO_LIPrevious studies have indicated that apoptosis is lowered, and glucose-stimulated insulin secretion enhanced, after ZnT8 inactivation. C_LIO_LIThe molecular mechanisms underlying these changes are unclear. C_LI What is the key question?O_LIHow do inactivating mutations in SL30A8/ZnT8 lead to lowered apoptosis and enhanced insulin secretion from stem cell-derived islet-like clusters, and is altered susceptibility to intracellular zinc depletion involved? C_LI What are the new findings?O_LIThe rare inactivating R138X mutation in SLC30A8 leads to gene dose-dependent changes in the transcriptome and proteome of islet-like clusters. C_LIO_LIChanges include upregulation of maturity and downregulation of immaturity genes. C_LIO_LIDepletion of intracellular Zn2+ exaggerates the protective effects of the inactivating mutation on apoptosis and insulin secretion C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings suggest that careful monitoring of both dietary zinc intake and of circulating levels of zinc ions, whose effects are mitigated in SLC30A8 mutation carriers, may be helpful in some populations to lower diabetes risk. C_LI

Background and purpose: Excessive sitting and genetic liability to obesity are associated with risk of obesity and hypertension, two significant risk factors for cardiovascular disease. This study aimed to investigate the interactive effects of genetic liability to obesity and excessive sitting on prevalence of hypertension. Methods: Obesity genetic liability was estimated in unrelated individuals of European ancestry (n=208,594) using previously identified genetic variants and their effect sizes for adiposity related traits. Hypertension was defined as systolic blood pressure ? 140 mmHg, diastolic blood pressure ? 90 mmHg, or the use of anti-hypertensive medications. Logistic regression was used to examine the association between obesity genetic liability and across different levels of self-reported sitting time. Results: excessive sitting and increased genetic liability were independently associated with higher odds of hypertension. The greatest odds of hypertension was observed in participants with high sitting time combined with increased genetic liability to obesity (OR=1.29; 95% CI = 1.25, 1.33, P <2 x10-16) compared to individuals with low genetic liability and low sitting time. Interaction analysis identified that in individuals with excessive sitting, the effect of genetic liability of waist circumference on hypertension was greater compared to individuals with low sitting time (P interaction=0.03). Conclusion: Combined excessive sitting and high genetic susceptibility to obesity is associated with greatest odds of hypertension. These findings highlight the importance of lifestyle in offsetting risk imposed by genetic factors.