Diabetes mellitus (DM) significantly accelerates vascular diseases like peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (MΦs) singularly and synergistically are important contributors to DM-associated vascular dysfunction. Single-cell (sc) profiling technologies are revealing the true heterogeneity of ECs and MΦs, but how this cellular diversity translates to cell-cell interactions, and consequentially vascular function, remains unknown. We leveraged scRNA sequencing and spatial transcriptome (ST) profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We generated a transcriptome and interactome map encompassing the major arterial cells and highlighted Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a top T2D-induced gene in mononuclear phagocytes (MPs), with concomitant increases of TREM2 ligands in ECs. We verified DM-associated TREM2 induction in cell and mouse models, and found that TREM2 inhibition decreases pro-inflammatory responses in MPs and ECs, as well as increases EC migration in vitro. Furthermore, TREM2 inhibition using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in DM mice subjected to hindlimb ischemia, suggesting that TREM2 promotes ischemic injury in DM. Finally, in human PAD, co-existing DM was associated with greater expression of TREM2 and its interaction with ECs, with a further increase in ischemic tissue compared to patient-matched non-ischemic tissue. Collectively, our study presents the first atlas of human diabetic vessels with single cell and spatial resolution, and identifies TREM2-EC interaction as a key driver of diabetic vasculopathies, the targeting of which may offer an opportunity to ameliorate vascular dysfunction associated with DM-PAD.

Arterial and venous graft spasm can occur during harvesting or immediately after coronary artery bypass grafting (CABG), leading to increased perioperative morbidity and affecting graft patency rates. Bypass grafts harvested from diabetic patients are particularly prone to spasm. This study aimed to elucidate the functional characteristics of human bypass grafts for the internal mammary artery (IMA) and saphenous vein (SV), from both diabetic and non-diabetic patients, and to determine how diabetes affected their responses to spasmogenic and relaxant agents. SV and IMA graft rings isolated from diabetic and non-diabetic patients during CABG were placed in an isolated organ bath system. Contractions to potassium chloride (10-100 mM) and phenylephrine (10-8-10-4 M) were evaluated, and relaxation responses to acetylcholine (10-9-10-4 M) and sodium nitroprusside (10-8-10-4 M) were assessed to evaluate endothelial and smooth muscle function, respectively. We observed increased responses to phenylephrine, an alpha-1 adrenoceptor agonist, in both IMAs and SVs, as well as an increased responses to potassium chloride, a non-receptor agonist, in SVs in diabetic patients compared to non-diabetic patients. We did not observe any deterioration in endothelium-dependent relaxations in either SV or IMA grafts under diabetic conditions. This study is the first to demonstrate that diabetes exacerbates potassium chloride-induced contractions in human SV grafts. Understanding the differences in potassium chloride-induced contraction profiles between arterial and venous grafts is essential in optimizing graft spasm management and improving the patency rates of bypass grafts.

Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.

Dysglycaemia is a known risk factor for cardiovascular disease and microcirculatory dysfunction is associated with an increased cardiovascular disease risk. The aim of this study was to investigate the prevalence of impaired microcirculation, coronary atherosclerosis, and arterial stiffness in individuals with normo- and dysglycaemia.

The study included 3,300 participants with microcirculatory measurements and information on glycaemic status, aged 50-65 years, from the Linköping site of the Swedish CArdio-Pulmonary bioImage Study (SCAPIS). Microvascular function was assessed in forearm skin using an arterial occlusion and release protocol determining peak blood oxygen saturation (OxyP). Data on pulse wave velocity (PWV) and the Coronary Artery Calcification Score (CACS) were collected. Participants were categorised into three glycaemic categories: normoglycaemia, prediabetes and diabetes.

OxyP was lower in the prediabetes group - 1.2%-units, 95% CI (-1.8 to -0.6) and in study participants with diabetes - 2.4%-units, 95% CI (-3.1 to -1.6) compared to the normoglycaemic group 84.3%, 95% CI (83.6 to 84.9). PWV and CACS were higher in participants with dysglycaemia. Prevalent impaired function at three vascular levels (lowest quartile of OxyP + PWV ≥ 10 m/s and CACS ≥ 100) were observed in 0.8%, 2.3% and 7.6% in the glycaemic categories respectively. The difference between the normoglycaemic and the diabetes category and the difference between the pre-diabetes and the diabetes category was significant, p = < 0.05.

Patients with prediabetes and diabetes are more likely to have impaired microcirculation in the forearm skin and macrovascular disorders such as arterial stiffness and atherosclerosis in the coronary arteries compared to normoglycaemic individuals.

To investigate the risk factors for ischemic stroke in elderly patients with hypertension and type 2 diabetes mellitus.

A total of 112 elderly patients with hypertension and type 2 diabetes, treated at Jiangmen Central Hospital from January 2023 to December 2023, were selected and categorized into a stroke group and a non-stroke group, each comprising 56 patients. The two groups were examined for demographic data, risk variables were evaluated by multifactorial logistic regression analysis, and the predictive value was determined using ROC curves.

The comparison of hyperhomocysteinemia (HHcy), fibrinogen (FIB), and high-density lipoprotein cholesterol (HDL-C) between the non-stroke and stroke groups revealed statistically significant differences (P < 0.05). Logistic regression analysis indicated that HHcy (OR 16.936; 95% CI 1.946-146.071; P = 0.010), FIB (OR 1.773; 95% CI 1.238-2.540; P = 0.002), and HDL-C (OR 0.182; 95% CI 0.043-0.775; P = 0.021) were significant factors in the onset of ischemic stroke among elderly patients with hypertension and type 2 diabetes. ROC curve analysis revealed that the area under the curve (AUC) for FIB, HDL-C, and HHcy in diagnosing stroke associated with hypertension and type 2 diabetes mellitus in the elderly were 0.704, 0.640, and 0.598, respectively, while the AUC for the combined diagnosis of all three was 0.784.

HHcy, FIB, and HDL-C independently influence the occurrence of ischemic stroke in elderly patients with hypertension combined with type 2 diabetes mellitus, and their combined enhanced predictive capability for ischemic stroke occurrence.

Computed tomography coronary angiography provides a non-invasive evaluation of coronary artery disease that includes phenotyping of atherosclerotic plaques and the surrounding perivascular adipose tissue (PVAT). Image analysis techniques have been developed to quantify atherosclerotic plaque burden and morphology as well as the associated PVAT attenuation, and emerging radiomic approaches can add further contextual information. PVAT attenuation might provide a novel measure of vascular health that could be indicative of the pathogenetic processes implicated in atherosclerosis such as inflammation, fibrosis or increased vascularity. Bidirectional signalling between the coronary artery and adjacent PVAT has been hypothesized to contribute to coronary artery disease progression and provide a potential novel measure of the risk of future cardiovascular events. However, despite the development of more advanced radiomic and artificial intelligence-based algorithms, studies involving large datasets suggest that the measurement of PVAT attenuation contributes only modest additional predictive discrimination to standard cardiovascular risk scores. In this Review, we explore the pathobiology of coronary atherosclerotic plaques and PVAT, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management.

Pulse wave velocity (PWV) has been explored to predict cardiovascular health in adults. Less is known about neonatal PWV. We evaluated the association between arterial stiffness of neonates of mothers (NoM) with diabetes and childhood health. Neonatal brachial-femoral PWV (bfPWV) was measured after birth and neonates followed for a median of 5.2 years [1 month-6.6 years]. 36 pregnant women with pregestational diabetes mellitus PGDM (n = 12), gestational diabetes mellitus (GDM) (n = 13), and controls (n = 11) were enrolled. Neonates were similar in weight, gestational age, and delivery mode. 26 neonates had follow-up data including weight, height and blood pressure. More mothers with PGDM had poor glycemic control compared to mothers with GDM (83% vs. 8%; p = 0.0002). PWV was higher in NoM with PGDM than controls (3.4 ± 0.5 vs. 2.6 ± 0.8 m/s; p = 0.04). At follow-up, children of mothers with diabetes (n = 16) had higher weight percentile (78.5 ± 27.9 vs 49.5 ± 34.6%; p = 0.02) and diastolic blood pressure (DBP) (68 ± 13.6 vs 57.3 ± 4.3 mmHg; p = 0.01) than controls (n = 10). No correlation emerged between neonatal PWV and childhood body mass index (BMI) or maternal HbA1c. Results suggest maternal diabetes affect neonatal arterial stiffness and childhood blood pressure; however, the mechanism is unclear. The long-term implications of these findings warrant further investigation.

Diabetes mellitus is a prevalent chronic disease that is becoming increasingly common worldwide and can lead to a number of dangerous complications. The Wnt signaling pathway is important for the onset and progression of diabetes. Wnt3a is a typical Wnt ligand that can increase the stability of β-catenin, control TCF7L2 expression, promote β-cell proliferation, and reduce apoptosis.

The involvement of the Wnt3a/β-catenin/TCF7L2 signaling pathway in the development of diabetes and associated problems related to the kidneys is reviewed in this article.

We believe that a thorough comprehension of the molecular connections between diabetes and signaling pathways will eventually lead to improved diabetes management.

The prognosis of patients with coronary artery disease is adversely affected by elevated fasting plasma glucose (FPG) levels. However, the relationship between FPG levels and in-hospital cardiac arrest (IHCA) remains unclear.

The objective of this study was to investigate the association between FPG levels and IHCA in patients diagnosed with acute coronary syndrome (ACS).

Data from a total of 31,726 ACS patients fitted with inclusion and exclusion criteria across 241 hospitals in the Improving Care for Cardiovascular Disease in China-ACS project from November 2014 to July 2019 were collected. Different logistic regression models were utilized to examine the associations of FPG levels with IHCA. Sensitivity analyses were then conducted to assess the robustness of the findings. Marginal effect analyses were also employed to evaluate the impact of different therapies.

A total of 335 cases of IHCA and 293 in-hospital mortality were recorded throughout the study. A non-linear relationship between FPG levels and IHCA was identified after adjusting for the covariates. Specifically, a significant association was found between elevated FPG levels (≥6.1 mmol/L) and an increased risk of IHCA. These findings remained consistent across different subgroup analyses including both the diabetic and non-diabetic patients. Additionally, the marginal effect analyses revealed that percutaneous coronary intervention could lower the high FPG-related risk.

The study findings showed a positive correlation between FPG levels and a higher incidence of IHCA, irrespective of the presence of diabetes.

Visit-to-visit blood pressure variability is a factor for a series of cardiovascular diseases in hypertensive patients. Hypertension is a common complication of patients with type 2 diabetes mellitus. Our research demonstrated that blood pressure variability is more important than systolic blood pressure to be associated with the occurrence of coronary artery disease and stroke. However, the importance of visit-to-visit blood pressure variability was easily overlooked. The results aimed to inform the health professionals the significance of stability blood pressure variability in the blood pressure management for patients with type 2 diabetes.

Diabetes mellitus (DM) promotes atherosclerosis, leading to increased risk for cardiovascular morbidity and mortality. Diabetics represent a challenging subset of patients undergoing percutaneous coronary intervention (PCI) or who have experienced an acute coronary syndrome (ACS), a subset characterized by higher rates of recurrent ischemic events compared with non-diabetics. These events are caused by both patient-related accelerated atherosclerotic disease progression and worse stent-related adverse clinical outcomes translating into a higher risk for repeat revascularization. In addition, DM is paradoxically associated with an increased risk of major bleeding following PCI or an ACS. Secondary prevention therapies following PCI or an ACS in diabetic patients are therefore of paramount importance. This mini review focuses on the currently available evidence regarding short- and long-term secondary prevention treatments for diabetic patients undergoing PCI or who have experienced an ACS.

High glucose-induced dysfunction of endothelial cells is a critical and initiating factor in the genesis of diabetic vascular complications. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention. It has been reported that it exhibits protective effects on high glucose-induced osteoblast dysfunction, but little was known on diabetic vascular complications. In this work, we aim to clarify the role of LMHFV on high glucose-induced endothelial dysfunction and hypothesized that the protective effects functioned through adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. We cultured primary murine aortic endothelial cells (MAECs) in normal or HG medium, respectively, before exposing to LMHFV. The tube formation, paracellular permeability assay, and aortic ring sprouting assay showed that the high glucose injured-function of MAECs was improved after LMHFV treatment. The intracellular ROS generation analysis, mitochondrial complex I activities measurement, ATP measurement and mitochondrial membrane potential (MMP), and mitochondrial ROS generation analysis of MAECs indicated that mitochondrial function was restored by LMHFV loading in a high glucose environment. Mechanically, western blot assays showed that AMPK phosphorylation was promoted and mTOR was inhibited in LMHFV-induced endothelial function restoration. After the administration of the AMPK inhibitor, Compound C, these protective effects resulting from LMHFV are reversed. These findings suggest that LMHFV plays a significant role in protecting endothelial cells' function and mitochondrial function in high glucose-induced injured MAECs via AMPK/mTOR signalling.

This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats.

Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo.

Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % → 5 %).

Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol.

Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

Despite advancements in therapeutic agents for diabetic chronic wounds, challenges such as suboptimal bioavailability, intricate disease milieus, and inadequate delivery efficacy have impeded treatment outcomes. Here, ultrasound-responsive hydrogel incorporated with heparin-binding domain (HBD) peptide nanoparticles is developed to promote diabetic wound healing. HBD peptide, derived from von Willebrand Factor with angiogenic activity, are first engineered to self-assemble into nanoparticles with enhanced biostability and bioavailability. Ultrasound responsive cargo release and hydrogel collapses are first verified through breakage of crosslinking. In addition, desired antioxidant and antibacterial activity of such hydrogel is observed. Moreover, the degradation of hydrogel under ultrasound stimulation into smaller fragments facilitated the deeper wound penetration of ≈400 µm depth. Complete wound closure is observed from diabetic mice with chronic wounds after being treated with the proposed hydrogel. In detail, in vivo studies revealed that hydrogels loaded with HBD peptide nanoparticles increased the levels of angiogenesis-related growth factors (VEGF-A, CD31, and α-SMA) to effectively accelerate wound repair. Overall, this study demonstrates that ultrasound-responsive HBD peptide hydrogel provides a synergistic therapeutic strategy for external biofilm elimination and internal effective delivery for diabetic wounds with biofilm infection.

Individuals with type 2 diabetes and increased albuminuria, a well-established marker of microvascular complications, are at a higher risk for cardiovascular disease (CVD) and premature mortality. Therefore, a better understanding of the underlying pathophysiology is needed to improve risk stratification and tailor prevention and intervention.

We conducted a cross-sectional study including 463 individuals with type 2 diabetes, various degrees of albuminuria and without CVD. We analysed the association between albuminuria and markers of endothelial function (thrombomodulin and syndecan-1), thrombin generation (thrombin-antithrombin complex, prothrombin fragment 1 + 2), fibrinogen, platelet function (activation using soluble plasma selectin and aggregation using Multiplate® Analyzer) using regression models.

In the study cohort 33 % were women, the mean ± SD age was 65 ± 9 years, and median [IQR] diabetes duration was 15 [9-20] years. In total, 344 (74 %) individuals had normal albuminuria, 87 (19 %) moderately- and 32 (7 %) severely increased albuminuria levels. Higher markers of endothelial function and fibrinogen were independently associated with higher albuminuria levels (p < 0.01). No association between albuminuria and markers of thrombin generation and platelet was demonstrated.

We demonstrated an independent association between albuminuria and markers of endothelial function and fibrinogen in individuals with type 2 diabetes and no history of CVD.

To investigate the role of glucagon-like peptide 1 (GLP-1) in myocardial perfusion, focusing on its effects on coronary microcirculation and cardiovascular outcomes.

Review of foundational research and large-scale clinical trials, including Cardiovascular Outcome Trials (CVOTs), examining the cardiovascular effects of GLP-1. Systematic analysis of trial data to assess the impact of GLP-1 therapy on myocardial infarction, composite cardiovascular events, and stroke incidence.

GLP-1 therapy was found to significantly reduce myocardial infarction and composite cardiovascular events. Additionally, GLP-1 receptor agonists were observed to reduce stroke incidence, suggesting systemic effects on panvascular diseases. While direct protective effects on coronary microvasculature have been less studied, growing evidence supports GLP-1's role in comprehensive myocardial perfusion.

GLP-1 is a promising therapeutic agent for improving myocardial perfusion and reducing cardiovascular events. Its protection is likely associated with comprehensive improvements in myocardial perfusion, including effects on coronary microcirculation. Further research is needed to fully elucidate its mechanisms of action and potential clinical applications.

To investigate the predictive value of the central arterial waveform for intradialytic blood pressure (BP) change, a total of 152 hemodialysis patients (mean age 68 years) on a thrice-weekly hemodialysis schedule were enrolled, and at both the first and second session of the week, BP and central arterial waveform were measured every 30 min during hemodialysis. In both sessions, a 1-standard deviation increase in baseline subendocardial viability ratio (SEVR), an index of subendocardial perfusion, as well as in baseline systolic BP (SBP) was an independent predictor of maximum SBP decrease ≥ 30 mmHg during hemodialysis. When divided into four groups based on the respective median level of SEVR in the SBP ≥ median and SBP < median groups, intradialytic SBP change was different among the subgroups. Multiple logistic regression analysis revealed that, compared with the SBP < median; low SEVR group, the SBP < median; high SEVR group had lower risk, and the SBP ≥ median; low SEVR group had higher risk of SBP decrease ≥ 30 mmHg, but the risk did not differ from that in the SBP ≥ median; high SEVR group. Predialysis subendocardial perfusion evaluated by SEVR was associated with the maximum intradialytic BP decrease, and evaluation of the central arterial waveform could be used as complementary screening for intradialytic BP change.

Changes in microcirculation lead to the progression of organ pathology in diabetes. Although neuroimmune interactions contribute to a variety of conditions, it is still unclear whether abnormal neural activities affect microcirculation related to diabetes. Using laser speckle contrast imaging, we examined the skin of patients with type 2 diabetes and found that their microvascular perfusion was significantly compromised. This phenomenon was replicated in a high-fat diet-driven murine model of type 2 diabetes-like disease. In this setting, although both macrophages and mast cells were enriched in the skin, only mast cells and associated degranulation were critically required for the microvascular impairment. Sensory neurons exhibited enhanced TRPV1 activities, which triggered mast cells to degranulate and compromise skin microcirculation. Chemical and genetic ablation of TRPV1+ nociceptors robustly improved skin microcirculation status. Substance P (SP) is a neuropeptide and was elevated in the skin and sensory neurons in the context of type 2 diabetes. Exogenous administration of SP resulted in impaired skin microcirculation, whereas neuronal knockdown of SP dramatically prevented mast cell degranulation and consequently improved skin microcirculation. Overall, our findings indicate a neuron-mast cell axis underlying skin microcirculation disturbance in diabetes and shed light on neuroimmune therapeutics for diabetes-related complications.

Peripheral artery disease (PAD) is a common disease associated with atherosclerosis, leading to significant mortality and morbidity worldwide. Our study focuses on the association between insulin resistance (IR) and PAD, specifically investigating the triglyceride-glucose index (TyG) as a potential surrogate marker of IR in the context of PAD by pooling the existing studies on this topic.

Online databases, including PubMed, Embase, Scopus, and the Web of Science, were searched to find the studies comparing the TyG index in PAD vs. control, reporting the TyG index among PAD severities, and assessing the association of increase in TyG with PAD prevalence. Random-effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for TyG level comparison and to calculate pooled odds ratio (ORs) for a 1-unit increase in TyG and higher vs. lower quartile/tertile of TyG association with PAD.

In the final review, 22 studies comprising 73,168 cases were included. Random-effect meta-analysis showed that patients with PAD had significantly higher levels of the TyG index compared with controls (SMD 0.76, 95%CI 0.65-0.88, P < 0.001). Also, higher severities of PAD were associated with higher TyG levels (SMD 0.48, 95%CI 0.22-0.74, P = 0.0003). Additionally, a 1-unit increase in TyG was associated with a 60% increase in odds of PAD (OR 1.60, 95%CI 1.41-1.80, P < 0.001). Finally, the highest quartile (Q4) of TyG had significantly higher odds of PAD compared to Q1 (OR 1.94, 95%CI 1.49-2.54, P < 0.001).

Our meta-analysis has identified a significant association between TyG levels and PAD and its severity. These findings not only contribute to our understanding of the role of IR in PAD pathology but also offer clinicians an exact index for evaluating PAD risk and its complications. This could potentially lead to more effective prevention and management strategies in the future.

Diabetes is a significant global public health issue with implications for vascular endothelial cells (ECs) dysfunction and the subsequent development and advancement of diabetes complications. This study aims to compare the cellular and molecular properties of the aorta in normal and streptozotocin (STZ)-induced diabetic mice, with a focus on elucidating potential mechanism underlying EC dysfunction. Here, we performed a single-cell RNA sequencing survey of 32,573 cells from the aorta of normal and STZ-induced diabetic mice. We found a compendium of 10 distinct cell types, mainly ECs, smooth muscle cells, fibroblast, pericyte, immune cells, and stromal cells. As the diabetes condition progressed, we observed a subpopulation of aortic ECs that exhibited significantly elevated expression of complement (C) molecule C1qa compared with their healthy counterparts. This increased expression of C1qa was found to induce reactive oxygen species (ROS) production, facilitate EC migration and increased permeability, and impair the vasodilation within the aortic segment of mice. Furthermore, AAV-Tie2-shRNA-C1qa was administered into diabetic mice by tail vein injection, showing that inhibition of C1qa in the endothelium led to a reduction in ROS production, decreased vascular permeability, and improved vasodilation. Collectively, these findings highlight the crucial involvement of C1qa in endothelial dysfunction associated with diabetes.

The systemic immune-inflammation index (SII) is a novel inflammatory marker used to assess the immune-inflammatory status of the human body. The systemic immune inflammation has an interplay and mutual relationship with neurological disorders. Serum neurofilament light chain (sNfL) is widely regarded as a potential biomarker for various neurological diseases. The study aimed to examine the association between SII and sNfL.

This cross-sectional investigation was conducted in a population with complete data on SII and sNfL from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). The SII was calculated by dividing the product of platelet count and neutrophil count by the lymphocyte count. Multivariate linear regression models and smooth curves were used to explore the linear connection between SII and sNfL. Sensitivity analyses, interaction tests, and diabetes subgroup smoothing curve fitting were also performed.

A total of 2,025 participants were included in our present research. SII showed a significant positive association with the natural logarithm-transformed sNfL (ln-sNfL) in crude model [0.17 (0.07, 0.28)], partially adjusted model [0.13 (0.03, 0.22)], and fully adjusted model [0.12 (0.02, 0.22)]. In all participants, the positive association between SII and ln-sNfL served as a linear relationship, as indicated by a smooth curve. Interaction tests showed that age, gender, BMI, hypertension, and diabetes did not have a significant impact on this positive association (p for interaction >0.05). The subgroup analysis of diabetes was conducted using smooth curve fitting. It was found that compared to the group without diabetes and the group in a pre-diabetic state, the effect was more pronounced in the group with diabetes.

Our findings suggest that there is a positive association between SII and sNfL. Furthermore, in comparison to individuals without diabetes and those in a pre-diabetic state, the positive association between SII and sNfL was more pronounced in individuals with diabetes. Further large-scale prospective studies are needed to confirm the association between SII and sNfL.

Evidence on the prevalence of foot problems among people with diabetes in India at a national level is lacking. Hence, this study was aimed to assess the burden of high-risk (HR) feet in people with diabetes across India.

A cross-sectional national-level project 'Save the Feet and Keep Walking' campaign was conducted by the Research Society for the Study of Diabetes in India (RSSDI) from July 10, 2022 to August 10, 2022. A modified version of 3 min foot examination was used to assess the foot problems. Around 10 000 doctors with RSSDI membership were trained online to conduct foot screening and provided a standardised monofilament for detection of loss of protective sensation. People with diabetes aged >18 years who visited the clinics during the study period were examined for foot problems. Data were collected online using the semi-structured questionnaire. A total of 33 259 participants with complete information were included for the final analysis. The foot at risk was categorised based on International Working Group on the Diabetic Foot guidelines 2023.

Nearly 75% of the participants were aged above 45 years. Around 49% had diabetes duration >5 years and uncontrolled diabetes (hemoglobin A1c >8%). Presence of history of foot ulcer (20%), lower limb amputation (15.3%), foot deformities (24.5%) and absence of diminished dorsal pedis and posterior tibial pulses (26.4%) was noted in the study participants. Around 25.2% of them had HR feet and highly prevalent among males. Diabetic kidney and retinal complications were present in 70% and 75.5% of people with HR feet. Presence of heel fissures (OR (95% CI) 4.6 (4.2 to 5.1)) and callus or corns (OR (95% CI) 3.6 (3.3 to 4.0)) were significantly associated with HR feet.

One-fourth of people with diabetes were found to have HR feet in India. The findings are suggestive of regular screening of people with diabetes for foot problems and strengthening of primary healthcare.

The presence of calcified nodule (CN) is a significant characteristic of atherothrombosis in acute coronary syndrome (ACS). However, its characteristics continue to be understudied. This review aimed to further investigate these characteristics. This study found that CN was a distinctive feature of an atheromatous plaque, representing 6.3% of ACS. CN was more common in NSTE-ACS than in STEMI patients (9.4% vs. 6.6%). CN was also chiefly observed in the left anterior descendant artery (48%), followed by the right coronary (40.4%) and left circumflex (14.5%) arteries. Higher prevalence of hypertension (78.8%), diabetes mellitus (50.8%), multivessel disease (71.7%), and kidney disease (26.43%) were noted in CN compared to non-CN patients. CN-associated ACS also 6-fold increased the risk of target lesion revascularization compared to those without CN.

Changes in arterial wall viscosity (AWW) and stiffness during type 2 diabetes (T2D) have been little investigated. We explored changes in carotid AWV considering change in arterial stiffness and loading conditions, in patients with T2D.

This cross-sectional, monocentric study compared 19 middle-aged patients with T2D to 30 non-diabetic (ND) controls. The absolute viscosity (WV) was determined as the area of the pressure-lumen cross-sectional area (P-LCSA) loop obtained by carotid tonometry and contralateral echo-tracking. The relative viscosity was determined as the ratio between WV and the elastic energy stored within the arterial wall (WV/WE). Carotid geometry, midwall stress, distensibility and elastic modulus were also compared between groups.

T2D patients were older and more frequently had hypertension. Internal diameter, mean central and pulse blood pressure were higher in T2D patients but midwall stress was similar compared to ND controls. WV and WV/WE were higher in T2D patients when compared with ND controls (23 [16-41] vs. 11 [7-18] mm Hg.mm2, p=0.007 and 21% [17-25] vs. 12% [8-17], p < 0.001 respectively) even after adjustment on confounding factors. Carotid arterial stiffness was higher in T2D patients, but after adjustment this difference was only observed for the highest levels of midwall stress.

Carotid AWV and stiffness are increased in T2D patients but only AWV is significantly increased after considering loading conditions. Whether this increase in energy dissipation within the arterial wall contributes to alter cardiovascular coupling in T2D remains to be established.

Partial and full PPAR-γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-γ, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR-γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 μg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-γ, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR-γ agonists and adiponectin receptors.

We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 μM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 μM), or the Ca2+-sensitive K+ channel inhibitor paxilline (10 μM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 μM) and XE991 (10 μM), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 μM) and cyclopiazonic acid (10 μM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 μM) and KT5720 (1 μM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K+ (ATP-sensitive K+, inwardly rectifying K+, and Ca2+-sensitive K+) channels, cGMP/PKG-associated signaling, and the endothelium.

Polyvascular disease has a significant global burden and is associated with increased risk of major adverse cardiac events with each additional vascular territory involved. The purpose of this review is to highlight the risk factors, associated outcomes, emerging genetic markers, and evidence for screening and treatment of polyvascular disease.

Polyvascular disease is the presence of atherosclerosis in two or more vascular beds. It has a significant global burden, with a prevalence of 30-70% in patients with known atherosclerosis. Patients with polyvascular disease experience elevated rates of cardiovascular death, myocardial infarction and stroke, especially among high-risk subgroups like those with type 2 diabetes mellitus and there is a step-wise increased risk of adverse outcomes with each additional vascular territory involved. Genetic analyses demonstrate that some individuals may carry a genetic predisposition, while others exhibit higher levels of atherogenic lipoproteins and inflammatory markers. Routine screening for asymptomatic disease is not currently recommended by major cardiovascular societies unless patients are high-risk. While there are no established protocols for escalating treatment, existing guidelines advocate for lipid-lowering therapy. Additionally, recent studies have demonstrated benefit from antithrombotic agents, such as P2Y12 inhibitors and low-dose anticoagulation, but the optimal timing and dosage of these agents has not been established, and the ischemic benefit must be balanced against the increased risk of bleeding in the polyvascular population. Due to the high prevalence and risks associated with polyvascular disease, early identification and treatment intensification are crucial to reduce disease progression. Future research is needed to develop screening protocols and determine the optimal timing and dosing of therapy to prevent ischemic events.

Cardiovascular disease (CVD) is the leading cause of death in people with diabetes. Compared with European Americans, African Americans have more favorable lipid profiles, as indicated by higher high-density lipoprotein cholesterol, lower triglycerides, and less dense low-density lipoprotein particles. The less atherogenic lipid profile translates to lower incidence and prevalence of CVD in African Americans with diabetes, despite higher rates of hypertension and obesity. However, African Americans with CVD experience worse clinical outcomes, including higher mortality, compared with European Americans. This mini-review summarizes the epidemiology, pathophysiology, mechanisms, and management of CVD in people with diabetes, focusing on possible factors underlying the "African American CVD paradox" (lower CVD incidence/prevalence but worse outcomes). Although the reasons for the disparities in CVD outcomes remain to be fully elucidated, we present a critical appraisal of the roles of suboptimal control of risk factors, inequities in care delivery, several biological factors, and psychosocial stress. We identify gaps in current knowledge and propose areas for future investigation.

Major adverse cardiovascular event (MACE) outcomes associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies remain unclear in patients with type 2 diabetes and newly diagnosed diabetic foot complications (DFCs). This study examined the impact of SGLT2i and GLP-1 RA use on the rates of MACEs and amputations in patients with type 2 diabetes and without cardiovascular disease.

Data from the Taiwan National Health Insurance Research Database (2004-2017) were analyzed, focusing on patients with type 2 diabetes without previous MACE and newly diagnosed DFCs. The primary outcome was the first MACE occurrence, and the secondary outcomes included MACE components, all-cause mortality, and lower extremity amputation (LEA) rates.

SGLT2i users showed a significant decrease in the MACE (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.88) and hospitalization for heart failure (HR, 0.54; 95% CI, 0.35-0.83) rates compared with dipeptidyl peptidase-4 inhibitor users. The amputation rates were also lower in SGLT2i users without LEA at the first DFC diagnosis (HR, 0.28; 95% CI, 0.10-0.75) and did not increase in those with a history of peripheral artery disease or LEA. No significant differences were observed between dipeptidyl peptidase-4 inhibitor and GLP-1 RA users in terms of the primary or secondary outcomes.

In patients with type 2 diabetes initially diagnosed with DFC, SGLT2i are effective in significantly reducing the hospitalization for heart failure and MACE rates. SGLT2i lower the amputation rates, especially in patients who have not previously had a LEA, than the dipeptidyl peptidase-4 inhibitor therapy.

Few studies have explored long-term trends and risk factors for peripheral arterial complications in type 2 diabetes compared to the general population. Our research focuses on identifying optimal risk factors, their significance, risk associated with multifactorial risk factor control, and trends for these complications in diabetic patients versus general controls.

This study included persons with type 2 diabetes mellitus entered into the Swedish National Diabetes Register 2001-2019 and controls matched for age-, sex- and county of residence. Outcomes comprised of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity arterial disease and diabetes foot disease. Standardized incidence rates and Cox regression were used for analyses.

The study comprises 655,250 persons with type 2 diabetes mellitus; average age 64.2; 43.8% women. Among persons with type 2 diabetes mellitus, the incidence rates per 100,000 person years for each non-coronary peripheral arterial complication event changed between 2001 and 2019 as follows: extracranial large artery disease 170.0-84.9; aortic aneurysm 40.6-69.2; aortic dissection 9.3 to 5.6; lower extremity artery disease from 338.8 to 190.8; and diabetic foot disease from 309.8 to 226.8. Baseline hemoglobin A1c (HbA1c), systolic blood pressure (SBP), smoking status and lipid levels were independently associated with all outcomes in the type 2 diabetes mellitus cohort. Within the cohort with type 2 diabetes mellitus, the risk for extracranial large artery disease and lower extremity artery disease increased in a stepwise fashion for each risk factor not within target. Excess risk for non-coronary peripheral arterial complications in the entire cohort for persons with type 2 diabetes mellitus, compared to matched controls, were as follows: extracranial large artery disease adjusted hazard ratio (HR) 1.69 (95% confidence interval (CI), 1.65-1.73), aortic aneurysm HR 0.89 (95% CI, 0.87-0.92), aortic dissection HR 0.51 (95% CI, 0.46-0.57) and lower extremity artery disease HR 2.59 (95% CI, 2.55-2.64).

The incidence of non-coronary peripheral arterial complications has declined significantly among persons with type 2 diabetes mellitus, with the exception of aortic aneurysm. HbA1c, smoking and blood pressure demonstrated greatest relative contribution for outcomes and lower levels of cardiometabolic risk factors are associated with reduced relative risk of outcomes.

Swedish Governmental and the County support of research and education of doctors, the Swedish Heart-Lung Foundation and Åke-Wibergs grant.

Diabetes mellitus is a metabolic disorder denoted by chronic hyperglycemia that drives maladaptive structural changes and functional damage to the vasculature. Attenuation of this pathological remodeling of blood vessels remains an unmet target owing to paucity of information on the metabolic signatures of this process. Ca2+/calmodulin-dependent kinase II (CaMKII) is expressed in the vasculature and is implicated in the control of blood vessels homeostasis. Recently, CaMKII has attracted a special attention in view of its chronic upregulated activity in diabetic tissues, yet its role in the diabetic vasculature remains under investigation.This review highlights the physiological and pathological actions of CaMKII in the diabetic vasculature, with focus on the control of the dialogue between endothelial (EC) and vascular smooth muscle cells (VSMC). Activation of CaMKII enhances EC and VSMC proliferation and migration, and increases the production of extracellular matrix which leads to maladaptive remodeling of vessels. This is manifested by activation of genes/proteins implicated in the control of the cell cycle, cytoskeleton organization, proliferation, migration, and inflammation. Endothelial dysfunction is paralleled by impaired nitric oxide signaling, which is also influenced by CaMKII signaling (activation/oxidation). The efficiency of CaMKII inhibitors is currently being tested in animal models, with a focus on the genetic pathways involved in the regulation of CaMKII expression (microRNAs and single nucleotide polymorphisms). Interestingly, studies highlight an interaction between the anti-diabetic drugs and CaMKII expression/activity which requires further investigation. Together, the studies reviewed herein may guide pharmacological approaches to improve health-related outcomes in patients with diabetes.

This multicenter cross-sectional study was performed on two groups of adults (nondiabetes and type 2 diabetes) of various ages, sexes, and body mass index (BMI). CIMT for each side was measured at three segments using high-resolution ultrasound, and the mean of both sides was determined. Comparison was made between each group, and the association of CIMT with each of age, sex, BMI, serum vitamin D status, smoking, and physical activity status was studied. The chi-square test was used to compare categorical data, and binary logistic regression was utilized to ascertain the relationship between CIMT and the study variables.

A significant difference was observed between the CIMT of the diabetes and nondiabetes group, average CIMT was 0.82 ± 0.23 mm vs. 1.12 ± 0.24 mm for the nondiabetes and diabetes group, respectively, with P value <0.005. No significant correlation was observed between serum vitamin D level and CIMT neither in the study group as a whole nor in either subgroup; however, a significant association was observed between CIMT with each of age, sex, BMI, smoking, and physical activity status.

Ultrasound is a sensitive tool for CIMT evaluation. Diabetes has a 5.4-fold higher risk of having high CIMT. Serum vitamin D level showed no significant influence on CIMT. Smoking, BMI, and physical activity are among the modifiable risk factors with significant influence on CIMT.

Metabolic diseases and their complications impose health and economic burdens worldwide. Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment, such as hyperglycemia or hyperlipidemia, thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments. The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease. Multiple molecular mechanisms collectively participate in metabolic memory management, resulting in different cellular alterations as well as tissue and organ dysfunctions, culminating in disease progression and even affecting offspring. The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management. Here, we retrace the history of relevant research on metabolic memory and summarize its salient characteristics. We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular, cellular, and organ levels, with emphasis on the impact of epigenetic modulations. Finally, we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.

Changes in the anterior segment of the eye due to type 2 diabetes mellitus (T2DM) are not well-characterized, in part due to the lack of a reliable animal model. This study evaluates changes in the anterior segment, including crystalline lens health, corneal endothelial cell density, aqueous humor metabolites, and ciliary body vasculature, in a rat model of T2DM compared with human eyes. Male Sprague-Dawley rats were fed a high-fat diet (45% fat) or normal diet, and rats fed the high-fat diet were injected with streptozotocin i.p. to generate a model of T2DM. Cataract formation and corneal endothelial cell density were assessed using microscopic analysis. Diabetes-related rat aqueous humor alterations were assessed using metabolomics screening. Transmission electron microscopy was used to assess qualitative ultrastructural changes ciliary process microvessels at the site of aqueous formation in the eyes of diabetic rats and humans. Eyes from the diabetic rats demonstrated cataracts, lower corneal endothelial cell densities, altered aqueous metabolites, and ciliary body ultrastructural changes, including vascular endothelial cell activation, pericyte degeneration, perivascular edema, and basement membrane reduplication. These findings recapitulated diabetic changes in human eyes. These results support the use of this model for studying ocular manifestations of T2DM and support a hypothesis postulating blood-aqueous barrier breakdown and vascular leakage at the ciliary body as a mechanism for diabetic anterior segment pathology.

Environmental exposure, medical diagnostic and therapeutic applications, and industrial utilization of radionuclides have prompted a growing focus on the risks associated with low-dose radiation (< 100 mGy). Current evidence suggests that such radiation can induce epigenetic changes. Nevertheless, whether exposure to low-dose radiation can disrupt endothelial cell function at the molecular level is unclear. Because endothelial cells play crucial roles in cardiovascular health and disease, we aimed to investigate whether low-dose radiation could lead to differential DNA methylation patterns at the genomic level in endothelial cell (EC) lines.

We screened for changes in DNA methylation patterns in primary human aortic (HAECs) and coronary artery endothelial cells following exposure to low-dose ionizing radiation. Using a subset of genes altered via DNA methylation by low-dose irradiation, we performed gene ontology (GO) analysis to predict the possible biological network mediating the effect of low-dose radiation. In addition, we performed comprehensive validation using methylation and gene expression analyses, and ChIP assay to identify useful biomarkers among candidate genes for use in detecting low-dose radiation exposure in human primary normal ECs.

Low-dose radiation is sufficient to induce global DNA methylation alterations in normal EC lines. GO analysis demonstrated that these hyper- or hypo-methylated genes were linked to diverse biological pathways. Our findings indicated a robust correlation between promoter hypermethylation and transcriptional downregulation of four genes (PGRMC1, UNC119B, RERE, and FNDC3B) in response to low-dose ionizing radiation in HAECs.

Based on these findings, the identified genes can serve as potential DNA methylation biomarkers for the assessment of cardiovascular risk upon exposure to low-dose radiation.

Hyperglycemia, lipotoxicity, and insulin resistance are known to increase the secretion of extracellular matrix from cardiac fibroblasts as well as the activation of paracrine signaling from cardiomyocytes, immune cells, and vascular cells, which release fibroblast-activating mediators. However, their influences on vascular smooth muscle cells (vSMCs) have not been well examined. This study aimed to investigate whether contractile vascular vSMCs could develop a more synthetic phenotype in response to hyperglycemia. The results showed that contractile and synthetic vSMCs consumed high glucose in different ways. Lactate/GPR81 promotes the synthetic phenotype in vSMCs in response to high glucose levels. The stimulation of high glucose was associated with a significant increase in fibroblast-like features: synthetic vSMC marker expression, collagen 1 production, proliferation, and migration. GPR81 expression is higher in blood vessels in diabetic patients and in the high-glucose, high-lipid diet mouse. The results demonstrate that vSMCs assume a more synthetic phenotype when cultured in the presence of high glucose and, consequently, that the high glucose could trigger a vSMC-dependent cardiovascular disease mechanism in diabetes via lactate/GPR81.

The heat-related health burden is expected to persist and worsen in the coming years due to an aging global population and climate change. Defining the breadth and depth of our understanding of age-related changes in thermoregulation can identify underlying causes and strategies to protect vulnerable individuals from heat. We conducted the first systematic quantitative literature review to provide context to the historical experimental research of healthy older adults - compared to younger adults or unhealthy age matched cases - during exogenous heat strain, focusing on factors that influence thermoregulatory function (e.g. co-morbidities). We identified 4,455 articles, with 147 meeting eligibility criteria. Most studies were conducted in the US (39%), Canada (29%), or Japan (12%), with 71% of the 3,411 participants being male. About 71% of the studies compared younger and older adults, while 34% compared two groups of older adults with and without factors influencing thermoregulation. Key factors included age combined with another factor (23%), underlying biological mechanisms (18%), age independently (15%), influencing health conditions (15%), adaptation potential (12%), environmental conditions (9%), and therapeutic/pharmacological interventions (7%). Our results suggest that controlled experimental research should focus on the age-related changes in thermoregulation in the very old, females, those with overlooked chronic heat-sensitive health conditions (e.g. pulmonary, renal, mental disorders), the impact of multimorbidity, prolonged and cumulative effects of extreme heat, evidence-based policy of control measures (e.g. personal cooling strategies), pharmaceutical interactions, and interventions stimulating protective physiological adaptation. These controlled studies will inform the directions and use of limited resources in ecologically valid fieldwork studies.

The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.