Type 2 Diabetes Research Articles

The association of osteoarthritis with metabolic disorders

Osteoarthritis (OA) is the most common form of synovial joint arthritis that causes chronic pain and disability to a large number of people worldwide. Most often, osteoarthritis affects the joints of the knees, hips, spine and hands. The Global Burden of Disease (GBD, 2021) estimates that osteoarthritis will be the fourth leading cause of disability by 2030, with enormous healthcare costs for treatment, as well as significant indirect costs due to loss of productivity and premature retirement. The aim of our research is to determine in what way prevalent metabolic syndrome is among participants with osteoarthritis of one of the synovial joints (knees, hips, hands), and whether metabolic disorders are a risk factor for the development and worsening of osteoarthritis. A prospective clinical study was conducted at the Public Health Institution Health Center Živinice, from July 2022 to May 2024, on a random sample of 200 participants with a confirmed clinical diagnosis of osteoarthritis (OA), who were divided into a group with metabolic syndrome and a group without metabolic syndrome based on the NCEP ATP III panel criteria for metabolic syndrome. The prevalence of knee osteoarthritis is significantly higher compared to the prevalence of hip and hand osteoarthritis, and it is greater among participants with a higher BMI (in participants with the highest BMI, knee osteoarthritis occurs with a 100% probability) and with the presence of metabolic syndrome, especially in more severe forms, specifically radiologically confirmed osteoarthritis, regardless of age and gender. Unlike OA knees the prevalence of OA hips and hands shows no correlation with BMI and metabolic syndrome. Multiple comparative analysis of differences in the average severity of osteoarthritis of the knee of subjects with normal glycemia / prediabetes / diabetes type 2 it showed a statistically significant difference in the average severity of knee osteoarthritis in subjects with regular blood sugar compared to subjects with prediabetes/diabetes mellitus type 2 regardless of age and gender. This means that with an increase in blood sugar levels, the degree of severity of osteoarthritis of the knee increases, since each subsequent Group has a higher average value of this indicator (p<0.05; CI 95%).

Assessment of cardiac and skeletal muscle metabolites using 1H-MRS and chemical-shift encoded magnetic resonance imaging: Impact of diabetes, RAGE, and DIAPH1.

Diabetes affects metabolism and metabolite concentrations in multiple organs. Previous preclinical studies have shown that receptor for advanced glycation end products (RAGE, gene symbol Ager) and its cytoplasmic domain binding partner, Diaphanous-1 (DIAPH1), are key mediators of diabetic micro- and macro-vascular complications. In this study, we used 1H-Magnetic Resonance Spectroscopy (MRS) and chemical shift encoded (CSE) Magnetic Resonance Imaging (MRI) to investigate the metabolite and water-fat fraction in the heart and hind limb muscle in a murine model of type 1 diabetes (T1D) and to determine if the metabolite changes in the heart and hind limb are influenced by (a) deletion of Ager or Diaph1 and (b) pharmacological blockade of RAGE-DIAPH1 interaction in mice. Nine cohorts of male mice, with six mice per cohort, were used: wild type non-diabetic control mice (WT-NDM), WT-diabetic (WT-DM) mice, Ager knockout non-diabetic (RKO-NDM) and diabetic mice (RKO-DM), Diaph1 knockout non-diabetic (DKO-NDM), and diabetic mice (DKO-DM), WT-NDM mice treated with vehicle, WT-DM mice treated with vehicle, and WT-DM mice treated with RAGE229 (antagonist of RAGE-DIAPH1 interaction). A Point Resolved Spectroscopy (PRESS) sequence for 1H-MRS, and multi-echo gradient recalled echo (GRE) for CSE were employed. Triglycerides, and free fatty acids in the heart and hind limb obtained from MRS and MRI were compared to those measured using biochemical assays. Two-sided t-test, non-parametric Kruskal-Wallis Test, and one-way ANOVA were employed for statistical analysis. We report that the results were well-correlated with significant differences using MRI and biochemical assays between WT-NDM and WT-DM, as well as within the non-diabetic groups, and within the diabetic groups. Deletion of Ager or Diaph1, or treatment with RAGE229 attenuated diabetes-associated increases in triglycerides in the heart and hind limb in mice. These results suggest that the employment of 1H-MRS/MRI is a feasible non-invasive modality to monitor metabolic dysfunction in T1D and the metabolic consequences of interventions that block RAGE and DIAPH1.

Hypoglycaemia Prevention, Awareness of Symptoms, and Treatment (HypoPAST): protocol for a 24-week hybrid type 1 randomised controlled trial of a fully online psycho-educational programme for adults with type 1 diabetes

BackgroundManagement of type 1 diabetes (T1D) requires the use of insulin, which can cause hypoglycaemia (low blood glucose levels). While most hypoglycaemic episodes can be self-treated, all episodes can be sudden, inconvenient, challenging to prevent or manage, unpleasant and/or cause unwanted attention or embarrassment. Severe hypoglycaemic episodes, requiring assistance from others for recovery, are rare but potentially dangerous. Repeated exposure to hypoglycaemia can reduce classic warning symptoms (‘awareness’), thereby increasing risk of severe episodes. Thus, fear of hypoglycaemia is common among adults with T1D and can have a negative impact on how they manage their diabetes, as well as on daily functioning, well-being and quality of life. While advances in glycaemic technologies and group-based psycho-educational programmes can reduce fear, frequency and impact of hypoglycaemia, they are not universally or freely available, nor do they fully resolve problematic hypoglycaemia or associated worries. This study aims to determine the effectiveness of a fully online, self-directed, scalable, psycho-educational intervention for reducing fear of hypoglycaemia: the Hypoglycaemia Prevention, Awareness of Symptoms, and Treatment (HypoPAST) programme.MethodsA 24-week, two-arm, parallel-group, hybrid type 1 randomised controlled trial, conducted remotely (online and telephone). Australian adults (≥ 18 years) with self-reported T1D and fear of hypoglycaemia will be recruited, and allocated at random (1:1) to HypoPAST or control (usual care). The primary outcome is the between-group difference in fear of hypoglycaemia (assessed using HFS-II Worry score) at 24 weeks. A sample size of N = 196 is required to detect a 9-point difference, with 90% power and allowing for 30% attrition. Multiple secondary outcomes include self-reported psychological, behavioural, biomedical, health economic, and process evaluation data. Data will be collected at baseline, 12 and 24 weeks using online surveys, 2-week ecological momentary assessments, website analytics and semi-structured interviews.DiscussionThis study will provide evidence regarding the effectiveness, cost-effectiveness and acceptability of a novel, online psycho-educational programme: HypoPAST. Due to the fully online format, HypoPAST is expected to provide an inexpensive, convenient, accessible and scalable solution for reducing fear of hypoglycaemia among adults with T1D.Trial registrationAustralian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000894695 (21 August 2023).

DNA methylation in the TXNIP gene is associated with type 2 diabetes in Pacific Peoples living in NZ

Abstract Background Pacific Peoples living in Aotearoa New Zealand (NZ) have higher rates of type 2 diabetes (T2D) and have benefited less from improvements in cardiovascular health outcomes when compared with other populations in NZ. DNA methylation markers of T2D have been identified in non-Pacific populations and could be used to monitor the cumulative effects of T2D on cardiovascular disease risk. However, no study has yet investigated the relationships between T2D and DNA methylation in Pacific Peoples living in NZ. Purpose This study aimed to quantify the relationship between DNA methylation and T2D in two cohorts of Pacific Peoples living in NZ. Methods Whole-blood DNA methylation at over 850,000 loci was measured on Illumina MethylationEPIC arrays in 288 Pacific participants from the Pasifika Heart Study (PHS, n=191), a community cohort, and the Multi-Ethnic NZ Study of Acute Coronary Syndromes (MENZACS, n=97), a cohort of patients with acute coronary syndromes. In the PHS, the median age was 41 years, and 98 (51%) participants were female. In MENZACS, the median age was 53 years, and 18 (19%) participants were female. In both cohorts, T2D cases were defined by either previous diagnosis (n=58) or had an HbA1c measurement >58 mmol/mol (n=7). We compared 65 participants with T2D and 223 participants without T2D of Samoan (n=116), Tongan (n=66), Fijian (n=61), Cook Island Māori (n=22), Niuean (n=9), or of Other/Multiple Pacific (n=14) ethnicity in a meta epigenome-wide association study (EWAS). EWAS comparisons were adjusted for age, sex, and imputed blood cell composition. We compared the difference in means at differentially methylated loci between the European and Pacific MENZACS participants using a two-sample z statistic. For the 525 European participants, 85 had T2D, the median age was 57 years, and 149 (28%) were female. Results One locus cg19693031, in the thioredoxin interacting protein (TXNIP) gene, exhibited differential methylation between those with T2D and those without in the meta EWAS (false discovery rate =6.9x10-9). In the PHS we observed a mean reduction in cg19693031 methylation of 7.0% (95% CI, 5.0, 8.9) between those with T2D and those without. Similarly in the MENZACS Pacific participants we observed a mean reduction in cg19693031 methylation of 10.9% (95% CI, 7.6, 12.4) between those with T2D and those without. The MENZACS European participants with T2D had a mean reduction in cg19693031 methylation of 6.5% (95% CI, 5.3, 7.7, p<0.001) compared to those without T2D. The difference in means in T2D cases and controls between MENZACS Pacific and European participants was non-significant (p =0.08). Conclusion DNA methylation at cg19693031 is associated with T2D in Pacific Peoples living in NZ and may be a sensitive marker of T2D in Pacific Peoples with acute coronary syndromes. DNA methylation at this locus may provide valuable information on the relationship between T2D and cardiovascular disease.Miami plot of Pacific T2D EWAST2D methylation by population in MENZACS

Diabetes and the risk of cardiovascular events and all-cause mortality among older adults: an individual participant data analysis of five prospective studies.

Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults. We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D. The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98]). T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults.

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.

Effects of dapagliflozin in heart failure according to duration of type 2 diabetes: a patient-level meta-analysis of DAPA-HF and DELIVER

Abstract Introduction Type 2 diabetes (T2D) is a common comorbidity in heart failure (HF), and long-standing T2D is associated with worse outcomes. Purpose To investigate the efficacy and safety of dapagliflozin, compared with placebo, according to duration of T2D in patients with HF and established T2D. Methods We conducted a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the effects of dapagliflozin, compared with placebo, in patients with HF with reduced ejection fraction and HF with mildly reduced/preserved ejection fraction, respectively. T2D duration was categorized as <5 years, 6-10 years, and >11 years. The primary outcome was a composite of worsening HF or cardiovascular death. Results Of the 4,784 patients with a history of T2D, 1,879 (39.3%) had a T2D duration of <5 years, 1,074 (22.4%) 5-10 years, and 1,831 (38.3%) >11 years. Patients with longer-duration T2D were older, more often female, and White, and had a higher HbA1c, body mass index, and left ventricular ejection fraction. They were more likely to have ischaemic heart disease, peripheral artery disease, hypertension, and chronic kidney disease, but were less likely to have atrial fibrillation/flutter. Although patients with longer-duration T2D had longer duration of HF, they were not more likely to have a prior HF hospitalization or worse New York Heart Association functional class. Despite similar N-terminal pro-B-type natriuretic peptide levels, patients with longer-duration T2D had a higher risk of the primary outcome, even after adjustment for potential confounders (<5 years, reference; 6-10 years, HR 1.25 [95% CI, 1.06-1.46]; >11 years, HR 1.33 [1.15-1.54]). The benefit of dapagliflozin on the primary outcome was consistent across T2D duration category: <5 years, HR 0.85 (95% CI, 0.69-1.04); 5-10 years, HR 0.65 (0.51-0.83); >11 years, HR 0.84 (0.70-1.01) (Pinteraction=0.18). Dapagliflozin reduced the risk of secondary clinical outcomes and increased (improved) mean KCCQ scores from baseline to 8 months, regardless of T2D duration (Table). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of T2D duration. Conclusions Dapagliflozin reduced the risk of worsening HF or cardiovascular death, and improved symptoms, in patients with HF and T2D, irrespective of T2D duration.

Novel mitochondria-targeted therapy AP39 limits mitochondrial dysregulation and diastolic dysfunction in 2D & 3D human models of diabetic cardiomyopathy

Abstract Introduction Mitochondrial dysregulation has been implicated in many complications of diabetes. Mitochondrial-targeted therapies AP39 and SS31 are renoprotective, but their cardioprotective potential in diabetes has not been fully resolved. Purpose We investigated AP39 and SS31 in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-hCM) and endothelial cells (iPSC-hEC) independently in 2D culture, as well as collectively in a 3D cardiac organoid (iPSC-hCO) model also comprising fibroblasts (iPSC-hFB), under type 2 diabetes (T2D)-like conditions. Methods Cells (iPSC-hCM, iPSC-hEC, iPSC-hFB; foreskin-2 cell line) were exposed to either 5.55mM glucose (control) or T2D conditions (20mM glucose plus fatty acids, endothelin-1 and cortisol) ± AP39 (50nM) or SS31 (1µM) for 48h. Cardiac organoids were subjected to 5.55mM glucose (control) or T2D for 4 days, with AP39 (50nM) or SS31 (1µM) added on day 2. Data are expressed as mean±SEM (fold) with n=4-6 from 2-3 independent experiments. One-way ANOVA with Dunnett`s post hoc analysis was performed with P<0.05 considered significant. Results 2D human cells: After 48h, T2D increased mitochondrial superoxide in iPSC-hCM (2.4±0.1 fold vs control) and iPSC-hEC (3.2±0.29 fold vs control), both P<0.05 (measured by MitoSOX). This was blunted by both AP39 (to 1.1±0.17) and SS31 (to 1.5±0.17) in T2D iPSC-hCM (P<0.05), with similar impact in iPSC-hEC, to 2.9±0.26 and 1.3±0.16 fold, both P<0.05. T2D increased cell death in both iPSC-hCM (1.6±0.09 fold vs control) and iPSC-hEC (1.6±0.12 fold, both P<0.05 measured by propidium iodide staining. Interestingly, AP39 selectively blunted cell death in T2D iPSC-hCM (to 1.1±0.06, P<0.05), mimicked by SS31 in T2D iPSC-hEC only (to 1.0±0.10, P<0.05). Further, T2D-induced mitochondrial hyperpolarisation in iPSC-hCM (1.5±0.09 fold vs control, assessed using TMRM), was only protected by AP39 (1.2±0.06 fold, P<0.05), but not SS31. 3D human cardiac organoids: After 4 days, T2D increased total contraction duration (1.6±0.10 fold control), time to peak (1.7±0.11) and relaxation duration (1.5±0.13, indicative of diastolic dysfunction), assessed by Olympus IX71 with a DP72 camera. All 3 contractile parameters were attenuated with AP39 (to 1.5±0.06, 1.3±0.09 and 1.0±0.04 fold, respectively) or SS31 (to 1.1±0.05, 1.2±0.15 and 1.2±0.12 fold, respectively), all P<0.05. T2D increased mitochondrial superoxide (2.7±0.16 fold control), blunted by AP39 (to 1.8±0.16) and SS31 (to 1.9±0.17), both P<0.05. Cellular injury measured by LDH was evident in T2D iPSC-hCO (2.1±0.23 fold control) was limited by AP39 (to 1.2±0.09) and SS31 (to 1.1±0.07), both P<0.05. Conclusion Our results highlight the cardioprotective potential of AP39 and SS31 to limit mitochondrial dysregulation, cell death and contractile dysfunction in human in vitro models of T2D. These findings may facilitate their clinical progression as therapeutic options for diabetic cardiomyopathy.

The impact of type 2 diabetes on short term myocardial morphological, functional, and energetic recovery post coronary artery bypass surgery in patients with ischemic heart disease

Abstract Background Type 2 diabetes (T2D) confers three times higher mortality in patients with ischemic heart disease (IHD). Moreover, amongst patients with IHD those with diabetes were shown to have higher long-term mortality from heart failure despite angiographic or surgical revascularisation with coronary artery bypass grafting (CABG). Impaired myocardial structural, functional, and energetic recovery may underpin this epidemiological observation. Consequently, using cardiovascular magnetic resonance and phosphorus-magnetic resonance spectroscopy scans, we aimed to assess the effect of T2D comorbidity on myocardial structural, functional, perfusion, and energetic recovery post-CABG in patients with IHD. Methods Seventy-seven IHD patients with (n=39) and without T2D (n=38) awaiting CABG were recruited. One-month pre- and 6-months post-CABG, cardiac phosphocreatine to ATP ratio (PCr/ATP), global longitudinal shortening (GLS) and 6-minute walk-distance (6MWD) were assessed in the study cohorts. The rest and adenosine-stress myocardial blood flow (MBF) assessments were only performed 6-months post-CABG. Results Pre-CABG, IHD-T2D patients had higher LV concentricity (LV mass to LV end diastolic volume ratio) (IHD-T2D:0.84[0.74,0.93],IHD-noT2D:0.72[0.67,0.77]g/mL,P=0.03]. worse PCr/ATP T2D (IHD-T2D:1.5[1.4,1.7],IHD-noT2D:1.8[1.6, 2.0];P=0.03) and shorter 6-minute walk distance (IHD-T2D:338[307,370],IHD-noT2D:399[364,434]m,P=0.007). There were no significant differences in LV volumes, ejection fraction or GLS between the two groups pre-CABG. Post-CABG, there was no longer a significant difference in cardiac energetics or 6-minute walk distances between the two groups due to a significant improvement in PCr/ATP in the IHD-T2D group. LV concentricity remained significantly elevated in the IHD-T2D group post CABG (IHD-T2D:0.82[0.75,0.88],IHD-noT2D:0.73[0.68,0.79]g/mL,P=0.04). Neither group showed a significant change in LVEF or GLS from the pre-CABG values, and post-CABG there were no differences in the rest or stress myocardial blood flows between the two groups. Conclusions Six months after CABG, neither IHD patients with T2D, nor IHD patients without T2D show any significant changes in LV structural remodelling or in contractile function. T2D does not jeopardise the short-term recovery in myocardial energetics or exercise distance post-CABG, with IHD patients with T2D showing more pronounced improvements post-CABG in both these assessments than patients without T2D. Larger longitudinal studies are needed to better understand the mechanisms of adverse longer-term cardiovascular outcomes suggested by epidemiological studies in IHD patients with T2D.

Plasma proteomics of all-cause and cause-specific mortality in individuals with and without type 2 diabetes: Results from two population-based KORA cohorts

Abstract Background Protein biomarkers may contribute to the identification of vulnerable subgroups for premature mortality in middle-aged and older adults. Purpose Given the distinctive impact of type 2 diabetes (T2D) on mortality rates and protein levels, this study aimed to explore the association of proteins with all-cause and cause-specific mortality separately among individuals with and without baseline T2D and to assess their impact on the prediction of all-cause mortality. Methods Using proximity extension assay technology, we measured 233 cardiovascular (CV) disease- and inflammation-related proteins in two population-based KORA (Cooperative Health Research in the Region of Augsburg) cohorts. The discovery KORA S4 study, with 15.6 years of follow-up, included 1545 participants (T2D group: 116 total, 62 CV, 31 cancer-related and 23 other-cause deaths; non-T2D group: 321 total, 114 CV, 120 cancer-related and 87 other-cause deaths). The validation KORA-Age1 study, with 6.9 years of follow-up, included 1031 participants (T2D group: 76 total, 45 CV, 19 cancer-related and 12 other-cause deaths; non-T2D group: 169 total, 74 CV, 39 cancer-related and 56 other-cause deaths). Cox regression was used to examine associations of proteins with all-cause and cause-specific mortality. Furthermore, eXtreme Gradient Boosting was applied for identification of the most relevant proteins for the prediction of all-cause mortality stratifying by baseline T2D status. The predictive performance of the protein-based model and combined model including both proteins and clinical risk factors was compared to a clinical risk factor-based model using the C-index, category-free net reclassification index (cfNRI), and relative integrated discrimination improvement (IDI). Results After validation, we identified 48 proteins associated with all-cause mortality in the T2D group and 64 in the non-T2D group, respectively (37 overlapping proteins). Out of these, 45, eight, and 32 were associated with CV, cancer-related, and other-cause mortality in the T2D group, while 53, 42, and 48 were associated with the respective cause-specific mortality outcomes in the non-T2D group in the pooled analysis of both studies. The combined model improved the prediction of all-cause mortality in both the KORA S4 and KORA-Age1 cohorts among individuals with baseline T2D (KORA-Age1: ΔC-index: 0.065, 95%=0.009-0.129; cfNRI: 0.370, 95%=0.203-0.812; IDI: 0.129, 95%=0.059-0.253) as well as those without T2D (KORA-Age1: ΔC-index: 0.037, 95%=0.015-0.071; cfNRI: 0.370, 95%=0.236-0.632; IDI: 0.053, 95%=0.028-0.104), respectively, compared to the clinical model. Conclusion This study discovered shared and unique proteins in individuals with and without T2D, unveiling the complex dynamics of mortality. Moreover, our findings support the role of proteins in improving prediction of premature mortality beyond clinical risk factors in different T2D subgroups, providing insights for future prevention strategies.

Baseline patient reported outcomes in patients with peripheral artery disease and type 2 diabetes from STRIDE: a phase 3, 52-week, randomised, double-blind, placebo-controlled trial

Abstract Introduction Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic steno-occlusive arterial lesions in the lower extremities and can lead to intermittent claudication, severe functional impairment and reduced health-related quality of life (HRQoL). People living with type 2 diabetes (T2D) are at higher risk of developing PAD than those without T2D. The most common clinical manifestation of PAD, functional impairment, can be stratified based on severity using Fontaine classification (stages I-IV). There are a limited number of therapies approved for the management of PAD related functional impairment and no glucose-lowering medication has been shown to improve functional capacity in people with PAD and T2D. STRIDE is a phase 3 clinical trial investigating once-weekly subcutaneous (s.c.) semaglutide treatment in people with PAD (Fontaine IIa claudication) and T2D. Purpose To report the patient-reported outcomes (PROs) at baseline from STRIDE and elucidate the impact that PAD has on the functional capacity and HRQoL in this early-stage symptomatic PAD population with T2D. Methods STRIDE enrolled 792 participants with PAD (Fontaine IIa claudication) and T2D who were randomised to receive either 1 mg once-weekly s.c. semaglutide or placebo for 52 weeks. The primary outcome of STRIDE is the change in maximum walking distance at week 52 on a constant load treadmill. Baseline PRO assessments included two Patient Global Impression of Severity (PGI-S) questions and three patient-reported questionnaires: the six items version of the Vascular Quality of Life questionnaire (VascuQoL-6), the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Short Form 36 (SF-36). Results Baseline responses to both PGI-S questions showed that two thirds of patients reported a moderate-to-severe limitation in their ability to walk (64.9%) and reported that the impact of poor blood circulation in their legs on their HRQoL was also moderate-to-severe (62.5%) (Figure 1A and B). The baseline VascuQoL-6 median score was 15 (score range: 6-24, with a low score indicating more severe impact) and details of impact on the six domains are presented in Table 1. Baseline responses to the WIQ indicated that 20.1% of participants found the degree of difficulty to walk 200 meters either ‘much difficulty’ or were ‘unable to do so’ and 21.8% reported the same when climbing 2 flights of stairs. The secondary supportive outcome assessed in the SF-36 questionnaire was the domain physical functioning where a median baseline value of 38.09 was observed (score range: 19.03-57.60, with a low score indicating more impact). Conclusion Participants in STRIDE, characterized as having early-stage symptomatic PAD, have reported moderate-to-high impact on their physical functioning and HRQoL at baseline. These findings highlight the need for better therapies that improve the functional capacity and HRQoL in people with PAD and T2D.

Prevalence of stage B heart failure in healthy adults and people with type 2 diabetes

Abstract Introduction People with Type 2 Diabetes (T2D) are at increased risk of heart failure, and as such are classified as having Stage A Heart Failure (SAHF). Those with additional evidence of raised filling pressures, biochemical or structural cardiac changes, without heart failure symptoms, are deemed to have Stage B heart failure (SBHF). Identifying patients with SBHF may help determine those at highest risk of disease progression. Purpose The aim of this work was to assess the prevalence of SBHF in a cohort of asymptomatic healthy volunteers and people with T2D characterised according to current American Heart Association/American College Cardiology/Heart Failure Society of America. Methods A single-centre, prospectively recruited cohort of middle-aged asymptomatic adults with T2D and healthy volunteers, with no history or signs of cardiovascular disease, underwent comprehensive cardiac phenotyping with transthoracic echocardiography and circulating brain natriuretic peptide. Healthy volunteers with risk factors for heart failure, including hypertension and obesity, were excluded from analysis. Prevalence of SBHF was determined by comparing cardiovascular data to proposed standards, left ventricular ejection fraction and global longitudinal strain parameters were omitted from analysis due to data availability. Results We included 383 T2Ds (diabetes duration 9(5,15) years) and 65 healthy volunteers (Table 1); 91% of those with T2D and 65% of healthy volunteers met ≥1 criteria for SBHF (Table 2). Median number of SBHF criteria met in the T2D cohort was 3 (2,4); in particular, a large proportion of the cohort met defined cut offs for relative wall thickness (70.6%), lateral e’ (62.2%), septal e’ (54.1%) and LV wall thickness (47.4%). Of the 65 healthy volunteers, median number of SBHF criteria met was 1 (0,2.5). In healthy volunteers, SBHF was most commonly defined by lateral e’ (40.0%), septal e’ (38.3%), relative wall thickness (32.2%), left atrial volume indexed (22.4%) and serum brain natriuretic peptide (23.3%). Of note, brain natriuretic peptide levels met current SBHF parameters in 18.8% of healthy volunteers and 9.9% people with T2D, which may be attributable to the exclusion of obesity in the healthy volunteer group. Conclusion Using currently proposed standards, a high proportion of middle-aged asymptomatic people with T2D, and healthy volunteers without any risk factors for heart failure, would be categorised as having SBHF. These data strongly suggest that the majority of the proposed parameters for the definition of SBHF are not specific for a UK population and if applied will incorrectly classify many asymptomatic people at high risk of developing heart failure.

Mediating pathways between attention deficit hyperactivity disorder and type 2 diabetes mellitus: evidence from a two-step and multivariable Mendelian randomization study.

Type 2 diabetes (T2D) is a global health burden, more prevalent among individuals with attention deficit hyperactivity disorder (ADHD) compared to the general population. To extend the knowledge base on how ADHD links to T2D, this study aimed to estimate causal effects of ADHD on T2D and to explore mediating pathways. We applied a two-step, two-sample Mendelian randomization (MR) design, using single nucleotide polymorphisms to genetically predict ADHD and a range of potential mediators. First, a wide range of univariable MR methods was used to investigate associations between genetically predicted ADHD and T2D, and between ADHD and the purported mediators: body mass index (BMI), childhood obesity, childhood BMI, sedentary behaviour (daily hours of TV watching), blood pressure (systolic blood pressure, diastolic blood pressure), C-reactive protein and educational attainment (EA). A mixture-of-experts method was then applied to select the MR method most likely to return a reliable estimate. We used estimates derived from multivariable MR to estimate indirect effects of ADHD on T2D through mediators. Genetically predicted ADHD liability associated with 10% higher odds of T2D (OR: 1.10; 95% CI: 1.02, 1.18). From nine purported mediators studied, three showed significant individual mediation effects: EA (39.44% mediation; 95% CI: 29.00%, 49.73%), BMI (44.23% mediation; 95% CI: 34.34%, 52.03%) and TV watching (44.10% mediation; 95% CI: 30.76%, 57.80%). The combination of BMI and EA explained the largest mediating effect (53.31%, 95% CI: -1.99%, 110.38%) of the ADHD-T2D association. These findings suggest a potentially causal, positive relationship between ADHD liability and T2D, with mediation through higher BMI, more TV watching and lower EA. Intervention on these factors may thus have beneficial effects on T2D risk in individuals with ADHD.

Effect of diabetes mellitus type 2 and sulfonylurea on colorectal cancer development: a case-control study

Background and aimsColorectal cancer (CRC) is a significant global health concern, with studies estimating a rise in new cases to 2.5 million by 2035. Type 2 diabetes (T2D) is also a growing issue, with an estimated 642 million adults affected by 2040. However, the relationship between T2D, its medications, and CRC remains unclear.Materials and methodsThis case-control study includes 810 controls without CRC and 684 cases with CRC admitted to Rasoul-Akram and Firouzgar Hospitals from September 2019 to 2023. Adjusted and unadjusted odds ratios (OR) were calculated to investigate the effect of T2D and sulfonylurea consumption on the chance of CRC development, using univariate and multivariate logistic regression analyses. The relationship between T2D and the clinicopathological features of the tumor was investigated.ResultsThe results show that the effect of T2D on CRC is significant based on unadjusted OR (OR = 1.39, CI = 1.07, 1.81) and insignificant in adjusted OR (OR = 0.67, CI = 0.37, 1.20). The effect of sulfonylurea consumption on CRC was significant in both unadjusted (OR = 2.39, CI = 1.40, 4.09) and adjusted ORs (OR = 2.35, CI = 1.12, 4.91). All analyses related to the relationship between T2D and tumor clinicopathological characteristics were insignificant.ConclusionThis study found an insignificant association between type 2 diabetes and the chance of CRC development in an adjusted state. Sulfonylurea consumption was also associated with a higher chance of CRC development among patients with T2D. These findings have implications for clinical practice and public health strategies in CRC prevention for patients with T2D.

Risk of Incident colorectal carcinoma in patients with type 2 diabetes on SGLT-2 inhibitor users: a population-based cohort study

Abstract Background Patients with type 2 diabetes (T2D) are at substantially higher risk for developing colorectal carcinoma (CC) than the general population. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use on the development of incident CC in patients with T2D, but the findings are inconsistent. Purpose This study aimed to examine the association between SGLT-2i use and incident CC risk in patients with T2D. Methods We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database (2015–2021). The primary outcome was the risk of incident CC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Therefore, multiple Cox regression modeling was conducted to analyze the association between SGLT-2i use and incident CC risk in patients with T2D. Results 268,495 propensity score-matched pairs of patients with T2D using SGLT-2i and non-using SGLT-2i, 1557 and 1264 incident CCs were recorded, respectively. There was a decreased risk of incident CC for SGLT-2i users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.79, 95% CI 0.74–0.84) compared with non-SGLT-2i users. The sensitivity test for the propensity score 1:2-matched analyses showed similar result (adjusted HR 0.79, 95% CI 0.74–0.85). Conclusions This population-based cohort study found that SLGT2i user was associated with a lower risk of CC by 21% compared to non-SGLT-2i users in T2D patients. More studies are needed to credibly evaluate the effects of SGLT-2i therapy on CC prevention in patients with T2D.

Hyponatremia and risk of new-onset heart failure in patients with type 2 diabetes - a real-world study of 70,000 patients

Abstract Background Hyponatremia is common in patients with heart failure and in patients with type 2 diabetes (T2D), and is a risk marker for increased morbidity and mortality. However, it is unclear whether hyponatremia in patients with T2D is associated with an increased risk of new-onset heart failure. Purpose To investigate whether hyponatremia is associated with an increased risk of new-onset heart failure in patients with T2D. Methods From Danish nationwide registers, all patients with T2D with no history of heart failure were identified from 2013-2021. Patients with at least two samples of plasma sodium measured (at least one month apart), during the first six months following their T2D diagnosis, were included with follow-up start six months after T2D diagnosis as well. Patients were categorized in two groups according to the mean plasma sodium concentration at baseline: 1) sodium >137 mmol/L; and 2) sodium <137mmol/L. Cumulative incidence curves and Cox proportional hazards models (crude and adjusted for age, sex, comorbidities, and potential hyponatremia-inducing medications including diuretics, anticonvulsants, and antidepressants) were used to investigate the association of sodium concentration with the incidence of heart failure during follow-up. Incidence rates of heart failure per 1000 person-years were calculated across the spectrum of the measured sodium levels. Results We included 69,750 patients where 57% were male and the median age was 63 (interquartile range: 54-71). At index, 57,723 (83%) patients had a mean sodium concentration of >137 mmol/L and 12,027 (17%) patients had a mean sodium concentration <137 mmol/L (hyponatremia). Patients with a sodium level <137 mmol/L were associated with a significantly higher hazard rate of heart failure compared to patients with sodium concentrations >137 mmol: adjusted hazard ratio (HR) 1.27 (95% confidence interval 1.15-1.41, p-value <0.001). In analyses where sodium concentration was considered a continuous variable, increasing concentration of 1 mmol/L was associated with a decreasing hazard rate of heart failure: adjusted HR 0.96 (0.94-0.97, p-value <0.001). Conclusions Hyponatremia was common and associated with a significantly higher risk of new-onset heart failure in patients newly diagnosed with T2D. Whether hyponatremia could be a new treatment target to prevent heart failure in T2D remains to be determined.Cumulative incidence of heart failureIncident heart failure

Sleep characteristics in relation to cardiovascular disease incidence and mortality in individuals with diabetes

Abstract Background/Introduction Evidence regarding the potential health effects of sleep characteristics among individuals with type 2 diabetes (T2D) is limited. Purpose We aimed to examine sleep characteristics in relation to subsequent risk of cardiovascular disease (CVD), including coronary heart disease (CHD), and stroke, and all-cause and cause-specific mortality among individuals with T2D. Methods We prospectively followed 21,902 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1986-2018, Health Professionals Follow-Up Study: 1986-2018). Sleep characteristics, including sleep duration, snoring, sleep apnea, and sleep quality, were repeatedly assessed using self-reported questionnaires at baseline and follow-up. Associations of sleep characteristics with CVD risk and mortality were assessed using Cox proportional hazards models with adjustments for demographic, dietary and lifestyle factors, and medical history. Results During 170,355 and 196,458 person-years of follow-up in participants with T2D, there were 2,486 incident CVD events and 3,922 deaths, respectively. Compared with sleeping for 7-8 h/day, the multivariable-adjusted hazard ratios (HRs) of sleeping for ≤5 h/day were 1.21 (1.02, 1.45) for CVD incidence, 1.24 (1.20, 1.51) for CHD incidence, 1.40 (1.24, 1.58) for total mortality, 1.52 (1.20, 1.92) for CVD mortality, and 1.27 (1.01, 1.61) for other non-CVD and non-cancer mortality, while the HRs of ≥10 h/day were 1.42 (1.21, 1.66) for total mortality, and 1.63 (1.20, 2.10) for other non-CVD and non-cancer mortality. Furthermore, compared with participants without habitual snoring, those with habitual snoring had a 21%, 24%, 18%, and 33% higher risk for CVD incidence, CHD incidence, CVD mortality, and total mortality, respectively. Compared with participants without diagnosed sleep apnea, those with sleep apnea had a 27%-58% higher risk for CVD incidence, CVD mortality, and total mortality. In addition, lower habitual sleep quality, including sleep difficulties and restless sleep, was associated with a substantially higher risk of CVD, CHD, or CVD mortality. No associations were observed between sleep characteristics with risk of stroke and cancer mortality in individuals with T2D. Conclusions Short and long sleep durations as well as habitual snoring, sleep apnea, and lower sleep quality were independently associated with higher risks of CVD incidence and mortality, particularly CVD mortality in individuals with T2D.

Interleukin-6 and suPAR are associated with diastolic function in type 1 diabetes: The Thousand & 1 Study

Abstract Background Heart failure (HF) is a common complication in individuals with type 1 diabetes (T1D). Inflammation is an important contributor to the pathogenesis and progression of both T1D and HF – especially HF with preserved ejection fraction (HFpEF). Diastolic dysfunction is a hallmark of HFpEF. Despite this, the association between diastolic function and inflammatory biomarkers is not well-known in individuals with T1D. Methods The Thousand & 1 study of individuals with T1D without known heart disease was studied. Diastolic parameters, including E/e’, was obtained by echocardiography and associated with Interleukin-6 (IL-6), soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hsCRP). These inflammatory biomarkers were analysed as continuous variables and dichotomized in above/below 3 pg/mL (IL-6), 4 ng/mL (suPAR), and 4 mg/L (hsCRP). In multivariable regression analysis, adjustments were made for age, gender, body mass index, duration of diabetes, HbA1c, systolic blood pressure, left ventricular ejection fraction, glomerular filtration rate, albuminuria status, use of statins, tobacco use and physical activity levels. In an additional analyse, we also adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP). Results We included 1,014 individuals (52% male, mean age 50±15). IL-6 was elevated in 207 individuals, suPAR in 182 individuals, and hsCRP in 863 individuals. Mean E/e’ was 7.6 and mean left ventricular ejection fraction was 58±5%. In fully adjusted models, inflammatory biomarkers were significantly associated with diastolic function. Thus, individuals with IL-6 > 3 pg/mL had 0.6 (95% confidence intervals: 0.2 to 1.0), P=0.001) higher E/e’ compared to individuals with IL-6 < 3 pg/mL. For every doubling of suPAR levels, E/e’ increased by 0.5 (0.2 to 0.9, P=0.003). For every doubling of hsCRP levels, E/e’ increased by 0.1 (0.02 to 0.2, P=0.022). Individuals with elevated levels of all three biomarkers had 1.9 (0.5 to 3.2, P=0.006) higher E/e’ compared to low levels of all three biomarkers. Including NTproBNP to the model did essentially not change the estimates. Conclusions Firstly, in T1D, elevated levels of IL-6, suPAR and hsCRP are associated with diastolic function assessed by E/e’, independent of traditional risk factors including NT-proBNP. Secondly, IL-6, suPAR and hsCRP may contain information about diastolic function in T1D which is not detected by NT-proBNP.Figure 1Figure 2

LE8 score in relation to cardiovascular disease and mortality in individuals with diabetes

Abstract Background Evidence regarding the potential health effects of Life’s Essential 8 (LE8) score among individuals with type 2 diabetes (T2D) is limited. Purpose We aimed to examine the associations of LE8 score with risk of cardiovascular disease (CVD) and mortality, among individuals with T2D. Methods We prospectively followed 19,915 Chinese participants with T2D at baseline or diagnosed during follow-up (Kailuan Study: 2006-2020), who were free of CVD at diagnosis of diabetes. Diet, lifestyle, and health conditions were repeatedly assessed every 2 years. The LE8 score (range, 0-100), was calculated based on 8 components: diet quality, physical activity, smoking status, sleep health, BMI, blood lipids, blood glucose, and blood pressure. We used time-varying cox models to model the associations. Results During a median follow-up of 11.5 years in participants with T2D, there were 3,295 incident CVD cases and 3,123 deaths. Higher LE8 score was associated with lower risk of CVD incidence and total mortality among participants with diabetes. The multivariate-adjusted hazard ratios and 95%CIs for the highest quintile of LE8 score compared with the lowest quintile were 0.56 (0.53, 0.59) for CVD incidence, 0.57 (0.53, 0.62) for heart disease incidence, 0.53 (0.49, 0.57) for stroke incidence, and 0.73 (0.69, 0.78) for total mortality (all p trend<0.001). Furthermore, compared with participants with stable or decreased LE8 score after diabetes diagnosis, those with increased LE8 score had 17%-42% lower risk of CVD incidence, heart disease incidence, stroke incidence, and total mortality. These associations persisted in subgroup analysis stratified by age, sex, BMI, smoking status, alcohol intake, family history of diabetes and CVD, and follow-up time. Conclusions Higher LE8 score was associated with a substantially lower risk of CVD incidence and total mortality among adults with T2D. These findings further support the tremendous benefit of adhering to a high CVH, defined as the LE8 in reducing the subsequent burden of cardiovascular complications and improving overall health in individuals with T2D.Main TableMain Figure

Interleukin-6 and suPAR improves prediction of all-cause mortality in type 1 diabetes - the Thousand & 1 Study

Abstract Background Cardiovascular diseases (CVD) are the leading cause of mortality in type 1 diabetes (T1D). Inflammation frequently accompanies T1D and is suggested as an important contributor to the pathogenesis and progression of CVD. However, current risk prediction models for T1D lack biomarkers of inflammation. Methods A prospective study of individuals with T1D without overt heart disease was evaluated. Interleukin-6 (IL-6), soluble urokinase-type plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein (hsCRP) were analysed. In Cox proportional hazards model, adjustments were made for variables in the Steno T1 Risk Engine: age, sex, duration of diabetes, HbA1c, systolic blood pressure, glomerular filtration rate, albuminuria status, use of statins, tobacco use and physical activity. The model included the biomarkers as continuous variables, and a "combination" category was defined as simultaneously elevated suPAR > 4 ng/mL and IL-6 > 3 pg/mL. The net reclassification improvement (NRI) and C-statistics were calculated. Results For included individuals (n=1,014, 52% male, mean age 50±15), follow-up was 100% after median of 12.2 years (interquartile range: 11.8 to 12.9).In the fully adjusted model, IL-6 and suPAR were both associated with all-cause mortality (IL-6 hazard ratio (HR): 1.6 (95% confidence interval: 1.04 to 2.4), suPAR HR: 1.9 (1.2 to 2.9). HsCRP was not associated with the outcome. The combination category showed even stronger association: HR 2.7 (1.4 to 5.1). When added to the Steno T1 Risk Engine, IL-6, suPAR, and their combination all added discriminatory power in predicting all-cause mortality assessed by NRI; IL-6: 38% (19 to 58), suPAR: 45% (25 to 65), combination 56% (36 to 76). C-statistics showed similar results for only suPAR. Area under the curve for suPAR: from 0.84 to 0.86 (P=0.049), IL-6: 0.84 to 0.85 (P=0.338), combination: 0.84 to 0.86 (P=0.066). Conclusions IL-6 and suPAR are independently associated with all-cause mortality in T1D without known heart disease. Assessment of IL-6 and suPAR in T1D may enhance risk prediction.Figure 1Figure 2