Diabetes-associated Cardiovascular Disease Research Articles

Puerarin mitigated LPS-ATP or HG-primed endothelial cells damage and diabetes-associated cardiovascular disease via ROS-NLRP3 signalling.

The occurrence and development of diabetic vascular diseases are closely linked to inflammation-induced endothelial dysfunction. Puerarin (Pue), the primary component of Pueraria lobata, possesses potent anti-inflammatory properties. However, its vasoprotective role remains elusive. Therefore, we investigated whether Pue can effectively protect against vascular damage induced by diabetes. In the study, Pue ameliorated lipopolysaccharide-adenosine triphosphate (LPS-ATP) or HG-primed cytotoxicity and apoptosis, while inhibited reactive oxygen species (ROS)-mediated NLR family pyrin domain containing 3 (NLRP3) inflammasome in HUVECs, as evidenced by significantly decreased ROS level, NOX4, Caspase-1 activity and expression of NLRP3, GSDMD, cleaved caspase-1, IL-1β and IL-18. Meanwhile, ROS inducer CoCI2 efficiently weakened the effects of Pue against LPS-ATP-primed pyroptosis. In addition, NLRP3 knockdown notably enhanced Pue's ability to suppress pyroptosis in LPS-ATP-primed HUVECs, whereas overexpression of NLRP3 reversed the inhibitory effects of Pue. Furthermore, Pue inhibited the expression of ROS and NLRP3 inflammasome-associated proteins on the aorta in type 2 diabetes mellitus rats. Our findings indicated that Pue might ameliorate LPS-ATP or HG-primed damage in HUVECs by inactivating the ROS-NLRP3 signalling pathway.

Early-Onset Hypertension and Sex-Specific Residual Risk for Cardiovascular Disease in Type 2 Diabetes.

To investigate whether the sex disparities in type 2 diabetes-associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03-1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the excess in diabetes-related CVD risk for women but may benefit from intensive BP control.

Cardio Metabolic Outcomes of Glimepiride with Metformin Combinations Therapy in Diabetes-Associated Cardiovascular Disease

Cardio Metabolic Outcomes of Glimepiride with Metformin Combinations Therapy in Diabetes-Associated Cardiovascular Disease

Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights.

Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.

Sex comparisons in the association of prediabetes and type 2 diabetes with cognitive function, depression, and quality of life: The Maastricht study.

There are sex differences in the excess risk of diabetes-associated cardiovascular disease. However, it is not clear whether these sex differences exist with regard to other complications like mental health aspects. Therefore, we investigated sex differences in the association of prediabetes and type 2 diabetes (T2D) with cognitive function, depression, and quality of life (QoL). In a population-based cross-sectional cohort study (n = 7639; age 40-75 years, 50% women, 25% T2D), we estimated sex-specific associations, and differences therein, of prediabetes and T2D (reference: normal glucose metabolism) with measures of cognitive function, depression, and physical and mental QoL. Sex differences were analysed using multiple regression models with interaction terms. In general, T2D, but not prediabetes, was associated with higher odds of cognitive impairment, major depressive disorder, and poorer QoL. The odds ratio (OR) of cognitive impairment associated with T2D was 1.29 (95% CI: 0.96-1.72) for women and 1.39 (1.10-1.75) for men. The OR of major depressive disorder associated with T2D was 1.19 (0.69-2.04) for women and 1.68 (1.02-2.75) for men. The mean difference of the physical QoL score (ranging from 0 to 100, with 100 indicating the best possible QoL) associated with T2D was -2.09 (-2.92 to -1.25) for women and -1.81 (-2.48 to -1.13) for men. The mean difference of the mental QoL score associated with T2D was -0.90 (-1.79 to -0.02) for women and -0.52 (-1.23 to 0.20) for men. There was no clear pattern of sex differences in the associations of either prediabetes or T2D with measures of cognitive function, depression, or QoL. In general, T2D was associated with worse cognitive function, depression, and poorer QoL. The strength of these associations was similar among women and men.

Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes.

Cardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease.

Sex and gender-specific aspects in prediabetes and diabetes mellitus-clinical recommendations (Update 2023)

Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are amajor challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect pathophysiology, screening, diagnostic and treatment strategies of diseases as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at ayounger age and at alower body mass index (BMI) compared to women but women feature adramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with ahigher increase in vascular complications in women but ahigher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with ahigher number of vascular risk factors, such as inflammatory parameters, unfavourable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have amuch higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed ahigher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with arisk reduction of nearly 40%. Nevertheless, along-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. Ahistory of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels and decreased estrogen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA1c, blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration.

The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease.

Both type 1 and type 2 diabetes are associated with an increased risk of atherosclerotic cardiovascular disease (CVD). Research based on human-first or bedside-to-bench approaches has provided new insights into likely mechanisms behind this increased risk. Although both forms of diabetes are associated with hyperglycemia, it is becoming increasingly clear that altered lipoprotein metabolism also plays a critical role in predicting CVD risk in people with diabetes. This review examines recent findings indicating that increased levels of circulating remnant lipoproteins could be a missing link between diabetes and CVD. Although CVD risk associated with diabetes is clearly multifactorial in nature, these findings suggest that we should increase efforts in evaluating whether remnant lipoproteins or the proteins that govern their metabolism are biomarkers of incident CVD in people living with diabetes and whether reducing remnant lipoproteins will prevent the increased CVD risk associated with diabetes.

SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes.

IntroductionCardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications.MethodsType 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.).ResultsDAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment.ConclusionsThese data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

HDL Improves Cholesterol and Glucose Homeostasis and Reduces Atherosclerosis in Diabetes-Associated Atherosclerosis.

Background and Aims Apolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe−/−) mice results in diabetes-accelerated atherosclerosis in response to a “Western” diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail−/−Apoe−/− mice. Methods and Results Trail−/−Apoe−/− and Apoe−/− mice on a “Western” diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail−/−Apoe−/− but not in Apoe−/− mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail−/−Apoe−/− mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail−/−Apoe−/− but not in Apoe−/− mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL's mechanism of action.

Nanomedicine for the treatment of diabetes-associated cardiovascular diseases and fibrosis.

Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy.

β-Hydroxybutyrate inhibits histone deacetylase 3 to promote claudin-5 generation and attenuate cardiac microvascular hyperpermeability in diabetes.

Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. We found that 10weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability. Graphical abstract.

Up-regulation of FoxO1 contributes to adverse vascular remodelling in type 1 diabetic rats.

Vascular complications from diabetes often result in poor outcomes for patients, even after optimized interventions. Forkhead box protein O1 (FoxO1) is a key regulator of cellular metabolism and plays an important role in vessel formation and maturation. Alterations of FoxO1 occur in the cardiovascular system in diabetes, yet the role of FoxO1 in diabetic vascular complications is poorly understood. In Streptozotocin (STZ)‐induced type 1 diabetic rats, FoxO1 expression was up‐regulated in carotid arteries at 8 weeks of diabetes that was accompanied with adverse vascular remodelling characterized as increased wall thickness, carotid medial cross‐sectional area, media‐to‐lumen ratio and decreased carotid artery lumen area. This adverse vascular remodelling induced by hyperglycaemia in diabetic rats required FoxO1 activation as pharmacological inhibition of FoxO1 with 50mg/kg AS1842856 (AS) reversed vascular remodelling in type 1 diabetic rats. The adverse vascular remodelling in type 1 diabetes mellitus (T1DM) occurred concomitantly with increases in pro‐inflammatory factors, adhesion factors, apoptosis, NOD‐like receptor family protein‐3 inflammasome activation and the phenotypic switch of arterial smooth muscle cells, which were all reversed by AS. In addition, FoxO1 inhibition counteracted the down‐regulation of its upstream mediator PDK1 in T1DM. PDK1 activator reduced FoxO1 nuclear translocation, which serves as the basis for subsequent transcriptional regulation during hyperglycaemia. Taken together, our data suggest that FoxO1 is a critical trigger for type 1 diabetes‐induced vascular remodelling in rats, and inhibition of FoxO1 thus offers a potential therapeutic option for diabetes‐associated cardiovascular diseases.

Identification of Susceptibility Modules and Genes for Cardiovascular Disease in Diabetic Patients Using WGCNA Analysis.

Objective To identify susceptibility modules and genes for cardiovascular disease in diabetic patients using weighted gene coexpression network analysis (WGCNA). Methods The raw data of GSE13760 were downloaded from the Gene Expression Omnibus (GEO) website. Genes with a false discovery rate < 0.05 and a log2 fold change ≥ 0.5 were included in the analysis. WGCNA was used to build a gene coexpression network, screen important modules, and filter the hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the genes in modules with clinical interest. Genes with a significance over 0.2 and a module membership over 0.8 were used as hub genes. Subsequently, we screened these hub genes in the published genome-wide SNP data of cardiovascular disease. The overlapped genes were defined as key genes. Results Fourteen gene coexpression modules were constructed via WGCNA analysis. Module greenyellow was mostly significantly correlated with diabetes. The GO analysis showed that genes in the module greenyellow were mainly enriched in extracellular matrix organization, extracellular exosome, and calcium ion binding. The KEGG analysis showed that the genes in the module greenyellow were mainly enriched in antigen processing and presentation, phagosome. Fifteen genes were identified as hub genes. Finally, HLA-DRB1, LRP1, and MMP2 were identified as key genes. Conclusion This was the first study that used the WGCNA method to construct a coexpression network to explore diabetes-associated susceptibility modules and genes for cardiovascular disease. Our study identified a module and several key genes that acted as essential components in the etiology of diabetes-associated cardiovascular disease, which may enhance our fundamental knowledge of the molecular mechanisms underlying this disease.

SUN-570 The Crosstalk Between Central Leptin and PPARbeta/delta Protects the Heart Against Oxidative Stress Damage and the Development of Hypertrophy

Cardiovascular disease is a common cause of morbidity and mortality in obese people with type 2 diabetes, which is often associated with increased levels of leptin. While many studies hint at the existence of important roles for both hyperleptinemia and leptin resistance in obesity and diabetes-associated cardiovascular disease, others support that leptin has cardioprotective effects. Leptin action comprises direct effects on cardiac tissue and indirect effects mediated via the sympathetic nervous system. Since the molecular underpinnings of leptin-regulated pathways in cardiac tissue in normoleptinemic animals remain less well defined, we addressed the effects of central leptin infusion on cardiac function and remodeling analyzing FOXO1/3 and mTORC1 pathways, paying special attention to PPARβ/δ as a key leptin signal regulator. We found that central leptin regulated dynamically the network between PPARβ/δ, FOXOs, and mTORC1 in cardiac tissue, through antioxidant, thermogenic and autophagy programs. Intracerebroventricular (ICV) leptin infusion (0.2µg/day) for 7 days in male 3-months-old Wistar rats induced protection from hypertrophy without increasing TBARS and protein carbonylation nor ROS/RSN cardiac levels. These effects were further supported by both increased of Sod2 and Ucp1 expression and reduced Tnf-α. Atrophy-related ubiquitin ligase Atrogin-1, accompanied by Beclin-1 and LC3II, gene products of the autophagic pathway response, were all upregulated by central leptin. In addition, mTORC1 activity and OXPHOS protein levels were decreased without affecting cellular function. Moreover, the content of carbonylated proteins did not increase upon the central leptin treatment, suggesting a key role of leptin in preventing cardiac oxidative stress. Finally, the pharmacological inhibition of PPARβ/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3 and Atrogin-1 in the heart mediated by icv leptin infusion. Together these data support that PPARβ/δ may act as a mediator of central leptin effects on cardiac cellular reprogramming through the activation of FOXO1/3 and the inactivation of mTORC1 pathways, and the upregulation of Atrogin-1 and the genes involved in energy uncoupling.

Integrins α4β1 and αVβ3 are Reduced in Endothelial Progenitor Cells from Diabetic Dyslipidemic Mice and May Represent New Targets for Therapy in Aortic Valve Disease

Diabetes reduces the number and induces dysfunction in circulating endothelial progenitor cells (EPCs) by mechanisms that are still uncovered. This study aims to evaluate the number, viability, phenotype, and function of EPCs in dyslipidemic mice with early diabetes mellitus and EPC infiltration in the aortic valve in order to identify possible therapeutic targets in diabetes-associated cardiovascular disease. A streptozotocin-induced diabetic apolipoprotein E knock-out (ApoE−/−) mouse model was used to identify the early and progressive changes, at 4 or 7 days on atherogenic diet after the last streptozotocin or citrate buffer injection. Blood and aortic valves from diabetic or nondiabetic ApoE−/− animals were collected. EPCs were identified as CD34 and vascular endothelial growth factor receptor 2 positive monocytes, and the expression levels of α4β1, αVβ3, αVβ5, β1, αLβ2, α5 integrins, and C-X-C chemokine receptor type 4 chemokine receptor on EPC surface were assessed by flow cytometry. The number of CD34 positive cells in the aortic valve, previously found to be recruited progenitor cells, was measured by fluorescence microscopy. Our results show that aortic valves from mice fed 7 days with atherogenic diet presented a significantly higher number of CD34 positive cells compared with mice fed only 4 days with the same diet, and diabetes reversed this finding. We also show a reduction of circulatory EPC numbers in diabetic mice caused by cell senescence and lower mobilization. Dyslipidemia induced EPC death through apoptosis regardless of the presence of diabetes, as shown by the higher percent of propidium iodide positive cells and higher cleaved caspase-3 levels. EPCs from diabetic mice expressed α4β1 and αVβ3 integrins at a lower level, while the rest of the integrins tested were unaffected by diabetes or diet. In conclusion, reduced EPC number and expression of α4β1 and αVβ3 integrins on EPCs at 4 and 7 days after diabetes induction in atherosclerosis-prone mice have resulted in lower recruitment of EPCs in the aortic valve.

The Role of Bone Morphogenetic Proteins in Diabetic Complications.

The prevalence of diabetes has reached epidemic proportions and is placing a significant burden on healthcare systems globally. Diabetes has a detrimental impact on many organs in the human body, including accelerating the development of micro- and macrovascular complications. Current therapeutic options to treat diabetic complications have their limitations. Importantly, many slow but fail to reverse the progression of diabetic complications. Bone morphogenetic proteins (BMPs) are a highly conserved subgroup of the transforming growth factor β (TGFβ) superfamily, signaling via serine/threonine kinase receptors, that have recently been implicated in glucose homeostasis and insulin resistance in the setting of diabetes. Downstream of the receptors, the signal can be transduced via the canonical Smad-dependent pathway or the noncanonical Smad-independent pathways. BMPs are essential in organ development, tissue homeostasis, and, as expected, disease pathogenesis. In fact, deletion of BMPs can be embryonically lethal or result in severe organ abnormalities. This review outlines the BMP signaling pathway and its relevance to diabetic complications, namely, diabetic nephropathy, diabetes-associated cardiovascular diseases, and diabetic retinopathy. Understanding the complexities of BMP signaling and particularly its tissue-, cellular-, and time-dependent actions will help delineate the underlying pathogenesis of the disease and may ultimately be harnessed in the treatment of diabetes-induced complications. This would replicate progress made in numerous other diseases, including cancer and atherosclerosis.

Sex and gender-specific aspects in prediabetes and diabetes mellitus-clinical recommendations (Update 2019)

Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are amajor challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect screening, diagnostic and treatment strategies as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at a younger age and at a lower body mass index (BMI) compared to women but women feature adramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with a higher increase in vascular complications in women but a higher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with ahigher number of vascular risk factors, such as inflammatory parameters, unfavorable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have a much higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed a higher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with arisk reduction of nearly 40%. Nevertheless, along-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. Ahistory of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA1c, blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration.

Liraglutide inhibited AGEs induced coronary smooth muscle cell phenotypic transition through inhibiting the NF-κB signal pathway

Vascular smooth muscle cell (VSMC) phenotype transition is involved in diabetes-associated cardiovascular diseases. The mechanism of VSMCs phenotypic transition in T2DM was still unclear. Rat coronary artery SMCs were pretreated with liraglutide alone, liraglutide and H89(a PKA inhibitor), neutralizing anti-RAGE antibody or the antioxidant pyrrolidine dithiocarbamate (PDTC; a nuclear factor-κB (NF-κB) inhibitor), followed by treatment with AGE. The morphological change of the SMCs was observed. We also observed the α-actin positive myofilaments and F-actin distribution in SMC through immunofluorescence microscopy. Smooth muscle myosin heavy chain 11(MYH11), α-smooth muscle actin (α-SMA) and myocardin protein expression were detected by Western blot. Collagen I productionS and NF-κB nuclear translocation were also investigated. AGEs induced a transition of SMC from contractile to synthetic phenotype, which was associated with decreased SMC differentiation markers such as α-SMA, MYH11 and myocardin by activating the NF-κB pathway. AGE also increased collagen I production and secretion by SMCs. Liraglutide inhibited AGEs induced SM phenotypic transition and down-regulation of α-SMA, MYH11 and myocardin. Liraglutide also inhibited AGEs induced NF-κB pathway activation and collagen I production. Pretreatment with liraglutide and H89 together did not exhibit this inhibitory effect as mentioned above. Blockade of RAGE in SMCs with neutralizing antibody inhibited AGEs induced phenotypic transition of SMC, and up-regulated α-SMA and MYH11 expression. Liraglutide inhibited AGE induced SMC phenotypic transition, increased SMC contractile markers expression, and decreased collagen production through down-regulation of myocardin, inhibition of NF-κB pathway, and activation of PKA signaling pathway.

Metabolic Karma-The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture.

Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.