Objective: The association between diabetes and coronary stent failure is poorly established with second-generation drug-eluting stents (DES). We aimed to evaluate the risk of stent failure in patients with diabetes compared to subjects without diabetes after implantation of second-generation DES. Research design and Methods: All patients in Sweden who received second-generation DES between 2010 and 2020 were included and categorized into three groups: type 1, type 2 diabetes, and subjects without diabetes (reference group). The primary endpoint was stent failure, defined as in-stent restenosis or stent thrombosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox regression models. Sensitivity analyses were performed to address missing data in covariates and account for death as a competing risk. Results: The study included 160,523 patients: 2,406 with type 1, 43,377 with type 2 diabetes and 114,740 without diabetes. Seventy-one percent were male. Over a mean follow-up of 4.5 years, 5,510 stent failure events occurred. The fully adjusted HR for stent failure was 2.28 (95% CI 1.97–2.65) for type 1 and 1.35 (95% CI 1.27–1.44) for type 2 diabetes, compared to subjects without diabetes. Sensitivity analyses confirmed the robustness of the findings, with both in-stent restenosis and stent thrombosis contributing to the increased risk. Conclusion: We observed a significantly higher risk of second-generation DES stent failure in individuals with type 1 diabetes followed by those with type 2 diabetes, compared to subjects without diabetes. This elevated risk was attributed to both in-stent restenosis and stent thrombosis.

The estimated glucose disposal rate (eGDR), calculated from glycated hemoglobin (HbA1c), hypertension status and BMI, is a proxy for insulin resistance. We examined the association between eGDR and the risk of first myocardial infarction (MI) and post-MI mortality in individuals with type 1 and type 2 diabetes. Using nationwide health registry data (2006–2020), we identified individuals with type 1 and type 2 diabetes. Follow-up started at the first time a complete eGDR could be calculated. eGDR was then handled as a time-updated exposure until first MI, with person-time assigned according to the most recent available value. Among those with MI, follow-up for post-MI mortality started at the event, and covariates were fixed at their last value before MI. Hazard ratios (HRs) with 95 Myocardial infarction is a major complication of diabetes. Estimated glucose disposal rate is a proxy of insulin resistance. Its contribution to cardiovascular risk across diabetes types remains unclear. Does estimated glucose disposal rate predict first myocardial infarction in people with diabetes? Lower estimated glucose disposal rate predicts first myocardial infarction. The association was stronger in type 1 than in type 2 diabetes. Estimated glucose disposal rate may identify individuals at high risk of myocardial infarction.

Prestroke hyperglycemia and insulin resistance (IR) independently correlate with poor stroke outcomes in type 2 diabetes (T2D), although their causative effect is undetermined. Interestingly, an increasing body of evidence points toward the importance of IR in determining stroke outcomes. Filling this gap is fundamental to identifying effective anti-T2D strategies to improve stroke prognosis in people with T2D. The aim of this study was to determine experimentally whether normalizing IR rather than hyperglycemia before stroke improves stroke outcomes in T2D. To address this research question, hyperglycemia or IR was normalized with intermediate-acting insulin or long-acting selective glucagon receptor agonist (La-GCGRa), respectively, in obese/T2D mice before inducing stroke. Functional recovery (primary outcome) was assessed by neurological testing. Systemic inflammation, infarct size, and neuroinflammation (secondary outcomes) were assessed by ELISA and immunohistochemistry, respectively. The results showed that insulin treatment normalized hyperglycemia without affecting IR and did not improve functional recovery. On the contrary, La-GCGRa normalized IR without affecting hyperglycemia and improved functional recovery. This effect occurred in association with reduced systemic and stroke-induced neuroinflammation. Neither treatment affected infarct size. The data demonstrate that targeting IR in T2D is crucial for improving stroke outcomes and may have significant implications for human therapy.Article Highlights Hyperglycemia and insulin resistance independently correlate with poor stroke outcomes in type 2 diabetes, although their causative role is unclear. The aim of this study was to determine experimentally whether normalizing insulin resistance rather than hyperglycemia before stroke improves stroke outcomes in type 2 diabetes. To answer this question, we specifically normalized either hyperglycemia or insulin resistance in obese, type 2 diabetic mice before inducing stroke. We show that targeting insulin resistance rather than hyperglycemia before stroke in type 2 diabetes is crucial to improving stroke outcomes.

BACKGROUND AND AIMS:The prognosis of adult-onset type 1 diabetes (T1D) and prognostic factors are sparsely investigated. This study assessed mortality, major adverse cardiovascular events (MACE), and prognostic factors in adult-onset T1D, particularly focusing on those diagnosed at age ≥40. METHODS:Participants were people diagnosed with adult-onset T1D (n = 10 184) or type 2 diabetes (T2D, n = 375 523) in 2001-20 from the Swedish National Diabetes Register and 509 172 population controls from the Total Population Register, followed until 2022. Hazard ratios (HR) and population attributable risk fraction (PAR%) were estimated. RESULTS:People with T1D had higher incidence of MACE (HR 1.30 [95% confidence interval 1.17, 1.45]), all-cause mortality (1.71 [1.60, 1.84]), and mortality from cardiovascular or non-cardiovascular diseases, cancer, or infection than population controls. They had lower MACE incidence (0.67 [0.60, 0.75]) and higher mortality from diabetic coma or ketoacidosis (7.04 [4.54, 10.9]) than people with T2D. Smoking (PAR% 10.7%) and glycated haemoglobin (HbA1c) ≥ 53 mmol/mol (10.4%) accounted for most deaths while overweight/obesity (19.8%), smoking (8.4%), and high HbA1c (8.8%) accounted for most MACE events in T1D. Results were similar for T1D diagnosed at age ≥40, although they had lower insulin pump use and higher HbA1c than people diagnosed earlier. CONCLUSIONS:Adult-onset T1D carries excess risk of death and MACE compared with population controls but less MACE risk than T2D. Individuals diagnosed after age 40 had similar excess risk and poorer glycaemic control than those diagnosed earlier, underscoring the need for improved management. Key prognostic factors were smoking, poor glycaemic control, and overweight/obesity.

>Calcineurin(CN) is a calcium-and calmodulindependent serine/threonine that has been studied in many model organisms including yeast, filamentous fungi, plants, and mammals. Its biological functions range from ion homeostasis and virulence in lower eukaryotes to T-cell activation in humans by human nuclear factors of activated T-cells. CN is a heterodimeric protein consisting of a catalytic subunit,

Rationale: Stress granules (SGs) are membraneless organelles that are formed in response to various stresses. Multiple cellular processes have been reported to be involved in SG formation. However, the signaling cascades that coordinate SG formation remain to be elucidated. Methods: By performing two high-content imaging-based phenomic screens, we identified multiple signaling components that form a possible signal transduction pathway that regulates SG formation. Results: We found that Sch9 and Ypk1 function in an early step of SG formation, leading to a decrease in intermediate long-chain base sphingolipids (LCBs). This further downregulates the polyubiquitin precursor protein Ubi4 through upregulating the deubiquitinase Ubp3. Decreased levels of cellular free ubiquitin may subsequently facilitate Lsm7 phase separation and thus trigger SG formation. Conclusion: The signaling pathway identified in this work, together with its conserved components, provides valuable clues for understanding the mechanisms underlying SG formation and SG-associated human diseases.

Background/objectives: Being overweight increases the predisposition to obesity and type 2 diabetes (T2D), which significantly elevate stroke risk and the likelihood of severe post-stroke disability. Dietary nitrate (NO3−) supplementation can mitigate obesity and metabolic impairments, making it a promising approach to halt overweight people from developing overt obesity/T2D, thereby potentially also improving stroke outcome. We determined whether NO3− supplementation prevents overweight mice from progressing into obesity and T2D and whether this intervention improves stroke outcome. Methods: An overweight condition was induced via 6 weeks of a high-fat diet (HFD), after which animals were randomized to either a HFD or a HFD with NO3− supplementation. After 24 weeks, when HFD-mice without NO3− developed obesity and T2D, all animals were subjected to transient middle cerebral artery occlusion and stroke outcome was assessed via behavioral testing and infarct size. The effect of NO3− on post-stroke neuroinflammation, neurogenesis, and neovascularization was analyzed by immunohistochemistry. Results: Sustained NO3− supplementation in overweight mice did not prevent obesity or insulin resistance. However, it attenuated weight gain, prevented hyperglycemia, and significantly improved functional recovery after stroke, without affecting infarct size. Moreover, NO3− decreased post-stroke neuroinflammation by reducing microglial infiltration. NO3− did not affect stroke-induced neurogenesis or vascularization. Conclusion: These results highlight the potential of NO3− supplementation to prevent metabolic impairment in the overweight population and improve stroke prognosis in this large group of people at risk of stroke and severe stroke sequelae.

To examine the association between within-person variability in glycated hemoglobin A1c (HbA1c) and blood pressure (BP) with retinopathy and nephropathy in type 1 diabetes (T1D). This nationwide cohort included 9,358 individuals from the Swedish National Diabetes Register with T1D <5 years at inclusion (1998–2017) and ≥8 years follow-up. Variability in HbA1c, systolic BP (SBP), and diastolic BP (DBP) was calculated as updated SDs. Associations with microvascular complications were analyzed using logistic regression with generalized estimating equations, adjusted for demographic and clinical covariates. Mean age at inclusion was 14.2 years, mean diabetes duration 1.2 years, and 44

The mechanistic target of rapamycin (mTOR) signaling pathway appears central to the aging process as genetic or pharmacological inhibition of mTOR extends lifespan in most eukaryotes tested. While the regulation of protein synthesis by mTOR has been studied in great detail, its impact on protein misfolding and aggregation during stress and aging is less explored. In this study, we identified the mTOR signaling pathway and the linked Seh1-associated complex as central nodes of protein aggregation during heat stress and cellular aging, using Saccharomyces cerevisiae as a model organism. Based on a synthetic genetic array screen, we found that reduced mTOR activity, achieved through deletion of TCO89, an mTORC1 subunit, almost completely prevents protein aggregation during heat stress and aging without reducing global translation rates and independently of an Hsf1-dependent stress response. Conversely, increased mTOR activity, achieved through deletion of NPR3, a Seh1-associated complex subunit, exacerbates protein aggregation, but not by overactivating translation. In summary, our work demonstrates that mTOR signaling is a central contributor to age-associated and heat shock-induced protein aggregation, and that this is unlinked to quantitatively discernable effects on translation and Hsf1.

Cellular protein homeostasis relies on a complex network of protein synthesis, folding, sub-cellular localization, and degradation to sustain a functional proteome. Since most of these processes are energy-driven, proteostasis is inescapably afflicted by cellular metabolism. Proteostasis collapse and metabolic imbalance are both linked to aging and age-associated disorders, yet they have traditionally been studied as separate phenomena in the context of aging. In this study, we indicate that reduced proteostasis capacity is a result of a metabolic imbalance associated with age. We observed increased accumulation of L-serine and L-threonine in replicative old cells of Saccharomyces cerevisiae, indicating an imbalance in amino acid metabolism with replicative aging. Replicating this metabolic imbalance in young cells through deletion of serine-dependent transcriptional activator, CHA4, resulted in increased aggregation of endogenous proteins along with misfolding-prone proteins Guk1-7ts-GFP and Luciferase-GFP in both young and old cells. Aggregate formation in the cha4Δ strain required a functional sensor of mitochondrial dysfunction and an activator of the retrograde signaling gene, RTG2. CHA4 and RTG2 exhibited genetic interaction and together regulated mitochondrial metabolism, replicative lifespan, and aggregate formation in young cells, connecting metabolic regulation with proteostasis and aging. Constitutive activation of retrograde signaling through overexpression of RTG2 or deletion of MKS-1, a negative regulator of Rtg1-Rtg3 nuclear translocation, resulted in faster resolution of aggregates upon heat shock through RTG3 and was found to be independent of molecular chaperone upregulation.

Objective: To evaluate the effectiveness of empagliflozin in reducing all-cause mortality (ACM), hospitalization for heart failure (HHF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), and end-stage renal disease (ESRD) in routine clinical practice in the Nordic countries of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study. Methods: This noninterventional, multicountry cohort study used secondary data from four Nordic countries (Denmark, Sweden, Finland, and Norway). Propensity score (PS) matched (1:1) adults with type 2 diabetes (T2D) initiating empagliflozin (a sodium-glucose cotransporter-2 inhibitor) during 2014-2018 who were compared to those initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i). Cox proportional hazards regression modelling was used to assess the risk for ACM, HHF, MI, stroke, CVM, and ESRD. Meta-analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) from random-effects models were calculated. Results: A total of 43,695 pairs of PS-matched patients were identified. Patients initiating empagliflozin exhibited a 49% significantly lower risk of ACM (HR: 0.51, 95% CI 0.40-0.64) compared to DPP-4i. Additionally, empagliflozin was associated with a 36% significantly lower risk of HHF (HR: 0.64, 95% CI 0.46-0.89), a 52% significantly lower risk of CVM (HR: 0.48, 95% CI 0.37-0.63), and a 66% significantly lower risk of ESRD (HR: 0.34, 95% CI 0.15-0.77) compared to DPP-4i. No significant differences were observed in the risk of stroke and MI between patients initiating empagliflozin compared with those initiating a DPP-4i. Results were generally consistent for subgroups (with/without pre-existing CV disease or congestive heart failure) and in sensitivity analyses. Conclusion: Empagliflozin initiation was associated with a significantly reduced risk of ACM, HHF, CVM, and ESRD compared with initiation of DPP-4i in patients with T2D when examining routine clinical practice data from Nordic countries.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles.

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

Background: People with type 1 diabetes generally view it easier to exercise when having continuous information of the glucose levels. We evaluated whether patients with type 1 diabetes managed with multiple daily insulin injections (MDI) exercised more after initiating continuous glucose monitoring (CGM) and whether the improved glycemic control and well-being associated with CGM translates into improved blood lipids and markers of inflammation. Method: The GOLD trial was a randomized cross-over trial over 16 months where patients used either CGM or capillary self-monitoring of blood glucose (SMBG) over six months, with a four-month wash-out period between the two treatment periods. We compared grade of physical activity, blood lipids, apolipoproteins, and high-sensitivity C-reactive protein (hsCRP) levels during CGM and SMBG. Results: There were 116 patients with information of physical activity estimated by the International Physical Activity Questionnaire (IPAQ) during both CGM and SMBG. No changes were found during CGM or SMBG, IPAQ scores 3305 versus 3878 ( P = .16). In 136 participants with information of blood lipid levels with no change in lipid-lowering medication during the two treatment periods, HbA1c differed by 4.2 mmol/mol (NGSP 0.39%) between SMBG and CGM treatment ( P < .001). No significant changes existed in low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, apolipoprotein A1, apolipoprotein B1, or hsCRP, during CGM and SMBG. Conclusion: Although many patients experience it easier to perform physical activity when monitoring glucose levels with CGM, it does not influence the amount of physical activity in persons with type 1 diabetes. Blood lipids, apolipoprotein, and hsCRP levels were similar during CGM and SMBG.

BackgroundThe impact of glycemic control in the risk of stent failure in subjects with type 2 diabetes (T2D) is currently unknown.ObjectivesThis study sought to study whether poor glycemic control is associated with a higher risk of stent failure in subjects with T2D.MethodsThis observational study included all patients in Sweden with T2D who underwent implantation of second-generation drug-eluting stents (DES) during 2010 to 2020. The exposure variable was the updated mean of glycated hemoglobin (HbA1c). Individuals were stratified by glycemic control, with HbA1c 6.1% to 7.0% (43-53 mmol/mol) as the reference group. The primary endpoint was the occurrence of stent failure (in-stent restenosis and stent thrombosis). The main result was analyzed in a complete cases model. Sensitivity analyses were performed for missing data and a model with death as a competing risk.ResultsThe study population consisted of 52,457 individuals (70,453 DES). The number of complete cases was 24,411 (29,029 DES). The median follow-up was 6.4 years. The fully adjusted HR was 1.10 (95% CI: 0.80-1.52) for HbA1c of ≤5.5% (≤37 mmol/mol), 1.02 (95% CI: 0.85-1.23) for HbA1c of 5.6% to 6.0% (38-42 mmol/mol), 1.25 (95% CI: 1.11-1.41) for HbA1c of 7.1% to 8.0% (54-64 mmol/mol), 1.30 (95% CI: 1.13-1.51) for HbA1c of 8.1% to 9.0% (65-75 mmol/mol), 1.46 (95% CI: 1.21-1.76) for HbA1c of 9.1% to 10.0% (76-86 mmol/mol), and 1.33 (95% CI: 1.06-1.66) for HbA1c of ≥10.1% (≥87 mmol/mol). Sensitivity analyses did not change the main result.ConclusionsWe found a significant association between poor glycemic control and a higher risk of stent failure driven by in-stent restenosis.

Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44

Background The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes. Methods and Results Between 2006 and 2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all‐cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo‐observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62±12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75±10.8 years; women, 38.1%), and individuals without diabetes (73±13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change −0.48% [95% CI, −0.52% to −0.44%]) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, −0.33% [95% CI, −0.43% to −0.24%]), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, −0.18% [95% CI, −0.53% to 0.17%]). Similar trends were observed with regard to 1‐year death, cardiovascular death, and major adverse cardiovascular events. Conclusions During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.

This cohort study investigates whether risk factors other than glucose control are associated with the development of diabetic retinopathy.