Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Early increase in HbA1c trajectory predicts development of severe microangiopathy in patients with type 1 diabetes: the VISS study.

INTRODUCTION: To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. RESEARCH DESIGN AND METHODS: In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). RESULTS: After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. CONCLUSIONS: The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR.

Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.

BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.

l-thyroxine attenuates extracellular Hsp90α-induced vascular endothelial calcification in diabetes mellitus, as revealed by parallel metabolic profiles.

BACKGROUND AND AIMS: Diabetic atherosclerotic vascular disease is characterized by extensive vascular calcification. However, an elevated blood glucose level alone does not explain this pathogenesis. We investigated the metabolic markers underlying diabetic atherosclerosis and whether extracellular Hsp90α (eHsp90α) triggers vascular endothelial calcification in this particular metabolic environment. METHODS: A parallel human/animal model metabolomics approach was used. We analyzed 40 serum samples collected from 24 patients with atherosclerosis and from the STZ-induced ApoE-/- mouse model. A multivariate statistical analysis of the data was performed, and mouse aortic tissue was collected for the assessment of plaque formation. In vitro, the effects of eHsp90α on endothelial cell calcification were assessed by serum analysis, Western blotting and immunoelectron microscopy. RESULTS: Diabetic ApoE-/- mice showed more severe plaque lesions and calcification damage. Stearamide, oleamide, l-thyroxine, l-homocitrulline and l-citrulline are biomarkers of diabetic ASVD; l-thyroxine was downregulated in both groups, and the thyroid sensitivity index was correlated with serum Hsp90α concentration. In vitro studies showed that eHsp90α increased Runx2 expression in endothelial cells through the LRP1 receptor. l-thyroxine reduced the increase in Runx2 levels caused by eHsp90α and affected the distribution and expression of LRP1 through hydrogen bonding with glutamine at position 1054 in the extracellular segment of LRP1. CONCLUSIONS: This study provides a mechanistic link between characteristic serum metabolites and diabetic atherosclerosis and thus offers new insight into the role of extracellular Hsp90α in promoting vascular calcification.

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications.

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.

BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling.

BACKGROUND: Diabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation. METHODS: In this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre; BAG3FL/FL mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction. RESULTS: In diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs. CONCLUSIONS: BAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diabetes. This provides a new orientation for the prevention and treatment of diabetic vascular remodeling.

Association of the systemic immuno-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic microvascular complications.

Background: The systemic immuno-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used and have been shown to be predictive indicators of various diseases. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) are the most prominent and common microvascular complications, which have seriously negative impacts on patients, families, and society. Exploring the associations with these three indicators and diabetic microvascular complications are the main purpose. Methods: There were 1058 individuals with type 2 diabetes mellitus (T2DM) in this retrospective cross-sectional study. SII, NLR, and PLR were calculated. The diseases were diagnosed by endocrinologists. Logistic regression and subgroup analysis were applied to evaluate the association between SII, NLP, and PLR and diabetic microvascular complications. Results: SII, NLR, and PLR were significantly associated with the risk of DN [odds ratios (ORs): 1.52, 1.71, and 1.60, respectively] and DR [ORs: 1.57, 1.79, and 1.55, respectively] by multivariate logistic regression. When NLR ≥2.66, the OR was significantly higher for the risk of DPN (OR: 1.985, 95% confidence interval: 1.29-3.05). Subgroup analysis showed no significant positive associations across different demographics and comorbidities, including sex, age, hypertension, HbA1c (glycated hemoglobin), and dyslipidemia. Conclusion: This study found a positive relationship between NLR and DN, DR, and DPN. In contrast, SII and PLR were found to be only associated with DN and DR. Therefore, for the diagnosis of diabetic microvascular complications, SII, NLR and PLR are highly valuable.

Transglutaminase 2 in diabetes mellitus: Unraveling its multifaceted role and therapeutic implications for vascular complications.

Diabetes, a severe metabolic disease characterized by chronic hypoglycemia, poses debilitating and life-threatening risks of microvascular and macrovascular complications, including blindness, kidney failure, heart attacks, and limb amputation. Addressing these complications is paramount, urging the development of interventions targeting diabetes-associated vascular dysfunctions. To effectively combat diabetes, a comprehensive understanding of the pathological mechanisms underlying complications and identification of precise therapeutic targets are imperative. Transglutaminase 2 (TGase2) is a multifunctional enzyme implicated in the pathogenesis of diverse diseases such as neurodegenerative disorders, fibrosis, and inflammatory conditions. TGase2 has recently emerged as a key player in both the pathogenesis and therapeutic intervention of diabetic complications. This review highlights TGase2 as a therapeutic target for diabetic complications and explores TGase2 inhibition as a promising therapeutic approach in their treatment.

Long-term exposure to ambient air pollution and risk of microvascular complications among patients with type 2 diabetes: a prospective study.

BACKGROUND: Patients with type 2 diabetes (T2D) may disproportionately suffer the adverse cardiovascular effects of air pollution, but relevant evidence on microvascular outcome is lacking. We aimed to examine the association between air pollution exposure and the risk of microvascular complications among patients with T2D. METHODS: This prospective study included 17 995 participants with T2D who were free of macro- and micro-vascular complications at baseline from the UK Biobank. Annual average concentrations of particulate matter (PM) with diameters <2.5 µm (PM2.5), <10 µm (PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx) were assessed using land use regression models. Cox proportional hazards regression was used to estimate the associations of air pollution exposure with incident diabetic microvascular complications. The joint effects of the air pollutant mixture were examined using quantile-based g-computation in a survival setting. RESULTS: In single-pollutant models, the adjusted hazard ratios (95% confidence intervals) for composite diabetic microvascular complications per interquartile range increase in PM2.5, PM10, NO2 and NOx were 1.09 (1.04-1.14), 1.06 (1.01-1.11), 1.07 (1.02-1.12) and 1.04 (1.00-1.08), respectively. Similar significant results were found for diabetic nephropathy and diabetic neuropathy, but not for diabetic retinopathy. The associations of certain air pollutants with composite microvascular complications and diabetic nephropathy were present even at concentrations below the World Health Organization limit values. Multi-pollutant analyses demonstrated that PM2.5 contributed most to the elevated risk associated with the air pollutant mixture. In addition, we found no interactions between air pollution and metabolic risk factor control on the risk of diabetic microvascular complications. CONCLUSIONS: Long-term individual and joint exposure to PM2.5, PM10, NO2 and NOx, even at low levels, was associated with an increased risk of diabetic microvascular complications, with PM2.5 potentially being the main contributor.

Aberrant splicing of CaV1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia.

Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The CaV1.2 calcium channel is one primary pathway for Ca2+ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular CaV1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K+-induced arterial constriction and CaV1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K+-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and CaV1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, CaV1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of CaV1.2 channels in VSMCs and MAs. Notably, GS increases K+-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates CaV1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.

Microvascular disease, modifiable risk factor profiles and incident arrhythmias in type 2 diabetes.

BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.

The association between variability of risk factors and complications in type 2 diabetes mellitus: a retrospective study.

The variability in diabetes risk factors, such as uric acid and lipids, may influence the development of complications. This study aimed to investigate the influence of such variability on the occurrence of diabetic complications. A retrospective analysis of electronic medical records was conducted with type 2 diabetic patients who received treatment at a tertiary care hospital in Chengdu, Sichuan Province, between 2013 and 2022. The risk factor variability is presented as the standard deviation (SD). The associations between the variability and complications were examined using a binary logistic regression model. The study included 369 patients with type 2 diabetes. The findings revealed that outpatient special disease management served as a protective factor against the development of complications [OR = 0.53, 95% confidence interval (CI) (0.29-0.10)], particularly for the prevention of diabetic peripheral neuropathy [OR = 0.51, 95% CI (0.30-0.86)]. Variability in total cholesterol (TC-SD) was found to be a risk factor for the development of complications [OR = 2.42, 95% CI (1.18-4.97)] and acted as a risk factor for diabetic peripheral vasculopathy [OR = 2.50, 95% CI (1.25-5.02)]. TC-SD is a risk factor for the occurrence of diabetic peripheral neuropathy and diabetic peripheral vasculopathy, whereas outpatient special disease management functions as a protective factor against complications and diabetic peripheral neuropathy. Thus, in addition to glycaemic control, the regulation of lipid levels should be emphasized, particularly among patients without outpatient special disease management, to delay the onset of complications.

Roles of Sirt1 and its modulators in diabetic microangiopathy: A review.

Diabetic vascular complications include diabetic macroangiopathy and diabetic microangiopathy. Diabetic microangiopathy is characterised by impaired microvascular endothelial function, basement membrane thickening, and microthrombosis, which may promote renal, ocular, cardiac, and peripheral system damage in diabetic patients. Therefore, new preventive and therapeutic strategies are urgently required. Sirt1, a member of the nicotinamide adenine dinucleotide-dependent histone deacetylase class III family, regulates different organ growth and development, oxidative stress, mitochondrial function, metabolism, inflammation, and aging. Sirt1 is downregulated in vascular injury and microangiopathy. Moreover, its expression and distribution in different organs correlate with age and play critical regulatory roles in oxidative stress and inflammation. This review introduces the background of diabetic microangiopathy and the main functions of Sirt1. Then, the relationship between Sirt1 and different diabetic microangiopathies and the regulatory roles mediated by different cells are described. Finally, we summarize the modulators that target Sirt1 to ameliorate diabetic microangiopathy as an essential preventive and therapeutic measure for diabetic microangiopathy. In conclusion, targeting Sirt1 may be a new therapeutic strategy for diabetic microangiopathy.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Efficacy of 1-hour postload plasma glucose as a suitable measurement in predicting type 2 diabetes and diabetes-related complications: A post hoc analysis of the 30-year follow-up of the Da Qing IGT and Diabetes Study.

AIM: To evaluate whether 1-hour plasma glucose (1hPG) can be a comparable measurement to 2-hour plasma glucose (2hPG) in identifying individuals at high risk of developing diabetes. METHODS: A total of 1026 non-diabetic subjects in the Da Qing IGT and Diabetes Study were included and classified according to baseline postload 1hPG. The participants were followed up and assessed at 6-, 20- and 30year follow-up for outcomes including diabetes, all-cause and cardiovascular mortality, cardiovascular disease (CVD) events, and microvascular disease. We then conducted a proportional hazards analysis in this post hoc study to determine the risks of developing type 2 diabetes and its complications in a '1hPG-normal' group (1hPG <8.6 mmol/L) and a '1hPG-high' group (≥8.6 mmol/L). The predictive values of 1hPG and 2hPG were evaluated using a time-dependent receiver-operating characteristic (ROC) curve. RESULTS: Compared with the 1hPG-normal group, the 1hPG-high group had increased risk of diabetes (hazard ratio [HR] 4.45, 95% CI 3.43-5.79), all-cause mortality (HR 1.46, 95% CI 1.07-2.01), CVD mortality (HR 1.84, 95% CI 1.16-2.95), CVD events (HR 1.39, 95% CI 1.03-1.86) and microvascular disease (HR 1.70, 95% CI: 1.03-2.79) after adjusting for confounders. 1hPG exhibited a higher area under the ROC curve (AUC) for predicting diabetes than 2hPG during the long-term follow-up (AUC [1hPG vs. 2hPG]: 10 years: 0.86 vs. 0.84, p = 0.08; 20 years: 0.88 vs. 0.87, p = 0.04; 30 years: 0.85 vs. 0.82, p = 0.009). CONCLUSIONS: Elevated 1hPG level (≥8.6 mmol/L) was associated with increased risk of developing type 2 diabetes and its long-term complications, and could be considered as a suitable measurement for identifying individuals at high risk of type 2 diabetes.

Toward Ultrasound Molecular Imaging of Endothelial Dysfunction in Diabetes: Targets, Strategies, and Challenges.

Diabetes vasculopathy is a significant complication of diabetes mellitus (DM), and early identification and timely intervention can effectively slow the progression. Accumulating studies have shown that diabetes causes vascular complications directly or indirectly through a variety of mechanisms. Direct imaging of the endothelial molecular changes not only identifies the early stage of diabetes vasculopathy but also sheds light on the precise treatment. Targeted ultrasound contrast agent (UCA)-based ultrasound molecular imaging (UMI) can noninvasively detect the expression status of molecular biomarkers overexpressed in the vasculature, thereby being a potential strategy for the diagnosis and treatment response evaluation of DM. Amounts of efforts have been focused on identification of the molecular targets expressed in the vasculature, manufacturing strategies of the targeted UCA, and the clinical translation for the diagnosis and evaluation of therapeutic efficacy in both micro- and macrovasculopathy in DM. This review summarizes the latest research progress on endothelium-targeted UCA and discusses their promising future and challenges in diabetes vasculopathy theranostics.

Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes.

BACKGROUND: Diabetes mellitus is a chronic disease which is detrimental to cardiovascular health, often leading to secondary microvascular complications, with huge global health implications. Therapeutic interventions that can be applied to multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (DKD) are characterised by early microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, respectively. The heparan sulphate cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microvascular complications, but the common underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined. METHODS: In this study, two mouse models of heparan sulphate depletion (enzymatic removal and genetic ablation by endothelial specific Exotosin-1 knock down) were utilized to investigate the impact of endothelial cell surface (i.e., endothelial glycocalyx) heparan sulphate loss on microvascular barrier function. Endothelial glycocalyx changes were measured using fluorescence microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluorescein angiography in the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2D, db/db) mouse model was used to determine the therapeutic potential of preventing heparan sulphate damage using treatment with a novel heparanase inhibitor, OVZ/HS-1638. Endothelial glycocalyx changes were measured as above, and microvascular barrier function assessed by albumin extravasation in the eye and a glomerular permeability assay in the kidney. RESULTS: In both models of heparan sulphate depletion, endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permeability was increased. T2D mice treated with OVZ/HS-1638 had improved endothelial glycocalyx measurements compared to vehicle treated T2D mice and were simultaneously protected from microvascular permeability changes associated with DR and DKD. CONCLUSION: We demonstrate that endothelial glycocalyx heparan sulphate plays a common mechanistic role in microvascular barrier function in the eye and kidney. Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor OVZ/HS-1638, effectively prevents microvascular permeability changes associated with DR and DKD, demonstrating a novel systemic approach to address diabetic microvascular complications.

Glycaemic control and macrovascular and microvascular outcomes: A systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes.

AIM: We aimed to determine the macrovascular and microvascular outcomes of intensive versus standard glucose-lowering strategies in type 2 diabetes (T2D) and investigate the relationships between these outcomes and trial arm glycated haemoglobin (HbA1c) reduction. MATERIALS AND METHODS: In this systematic review and meta-analysis, we identified relevant trials from MEDLINE, Embase, the Cochrane Library, and bibliographies up to August 2023. Macrovascular and microvascular outcomes, along with safety outcomes, were evaluated. Pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and meta-regression was employed to analyse the relationships between outcomes and HbA1c reduction. RESULTS: We included 11 unique RCTs involving 51 469 patients with T2D (intensive therapy, N = 26 691; standard therapy, N = 24 778). Intensive versus standard therapy reduced the risk of non-fatal myocardial infarction (MI) (HR 0.84; 95% CI 0.75-0.94) with no difference in the risk of major adverse cardiovascular events (HR 0.97; 95% CI 0.92-1.03) and other adverse cardiovascular outcomes. Intensive versus standard therapy reduced the risk of retinopathy (HR 0.85; 0.78-0.93), nephropathy (HR 0.71; 0.58-0.87) and composite microvascular outcomes (HR 0.88; 0.77-1.00). Meta-regression analyses showed modest evidence of inverse linear relationships between HbA1c reduction and the outcomes of major adverse cardiovascular events, non-fatal MI, stroke and retinopathy, but these were not statistically significant. CONCLUSIONS: In people with T2D, intensive glucose control was associated with a reduced risk of non-fatal MI and several microvascular outcomes, particularly retinopathy and nephropathy. The lack of an effect of intensive glucose-lowering on most macrovascular outcomes calls for a more comprehensive approach to managing cardiovascular risk factors alongside glycaemic control.