RESUMO
BACKGROUND: Restoring the capacity of endothelial progenitor cells (EPCs) to promote angiogenesis is the major therapeutic strategy of diabetic peripheral artery disease. The aim of this study was to investigate the effects of GLP-1 (glucagon-like peptide 1; 32-36)-an end product of GLP-1-on angiogenesis of EPCs and T1DM (type 1 diabetes) mice, as well as its interaction with the classical GLP-1R (GLP-1 receptor) pathway and its effect on mitochondrial metabolism. METHODS: In in vivo experiments, we conducted streptozocin-induced type 1 diabetic mice as a murine model of unilateral hind limb ischemia to examine the therapeutic potential of GLP-1(32-36) on angiogenesis. We also generated Glp1r-/- mice to detect whether GLP-1R is required for angiogenic function of GLP-1(32-36). In in vitro experiments, EPCs isolated from the mouse bone marrow and human umbilical cord blood samples were used to detect GLP-1(32-36)-mediated angiogenic capability under high glucose treatment. RESULTS: We demonstrated that GLP-1(32-36) did not affect insulin secretion but could significantly rescue angiogenic function and blood perfusion in ischemic limb of streptozocin-induced T1DM mice, a function similar to its parental GLP-1. We also found that GLP-1(32-36) promotes angiogenesis in EPCs exposed to high glucose. Specifically, GLP-1(32-36) has a causal role in improving fragile mitochondrial function and metabolism via the GLP-1R-mediated pathway. We further demonstrated that GLP-1(32-36) rescued diabetic ischemic lower limbs by activating the GLP-1R-dependent eNOS (endothelial NO synthase)/cGMP/PKG (protein kinase G) pathway. CONCLUSIONS: Our study provides a novel mechanism with which GLP-1(32-36) acts in modulating metabolic reprogramming toward glycolytic flux in partnership with GLP-1R for improved angiogenesis in high glucose-exposed EPCs and T1DM murine models. We propose that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for peripheral artery disease. REGISTRATION: URL: www.ebi.ac.uk/metabolights/; Unique identifier: MTBLS9543.
Assuntos
Diabetes Mellitus Experimental , Células Progenitoras Endoteliais , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glicólise , Membro Posterior , Isquemia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica , Transdução de Sinais , Animais , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Isquemia/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Neovascularização Fisiológica/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glicólise/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Membro Posterior/irrigação sanguínea , Masculino , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/efeitos dos fármacos , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Células Cultivadas , Indutores da Angiogênese/farmacologia , Fragmentos de Peptídeos/farmacologia , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Modelos Animais de Doenças , Incretinas/farmacologia , AngiogêneseRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Nefropatias Diabéticas , Glucuronidase , Animais , Camundongos , Glicocálix/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/prevenção & controle , Heparitina Sulfato/metabolismo , Heparitina Sulfato/farmacologia , Albuminas/farmacologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/prevenção & controle , Angiopatias Diabéticas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Movimento Celular , Proliferação de Células , Músculo Liso Vascular , Miócitos de Músculo Liso , Fator de Transcrição STAT3 , Transdução de Sinais , Remodelação Vascular , Fator de Transcrição STAT3/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Animais , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Fosforilação , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/genética , Masculino , Células Cultivadas , Camundongos Knockout , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Humanos , Camundongos Endogâmicos C57BL , Produtos Finais de Glicação Avançada/metabolismoRESUMO
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.
Assuntos
Glicemia , Diabetes Mellitus Experimental , Células Endoteliais da Veia Umbilical Humana , Canais Iônicos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III , Estresse Oxidativo , Animais , Humanos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Diabetes Mellitus Experimental/metabolismo , Canais Iônicos/metabolismo , Canais Iônicos/genética , Glicemia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Mecanotransdução Celular , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/deficiência , Células Cultivadas , Proliferação de Células , Apoptose , Masculino , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/etiologia , Movimento Celular , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Camundongos , Estreptozocina , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Endotélio Vascular/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genéticaRESUMO
AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Retinopatia Diabética , Jejum , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/epidemiologia , Animais , Camundongos , Seguimentos , Retinopatia Diabética/etiologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/patologia , Prognóstico , Incidência , Biomarcadores/análise , Fatores de Risco , IdosoRESUMO
AIM: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes. MATERIALS AND METHODS: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score. RESULTS: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores. CONCLUSIONS: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes.
Assuntos
Automonitorização da Glicemia , Glicemia , Doenças de Pequenos Vasos Cerebrais , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Idoso , Estudos Transversais , Doenças de Pequenos Vasos Cerebrais/sangue , Glicemia/análise , Glicemia/metabolismo , Idoso de 80 Anos ou mais , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/etiologia , Hiperglicemia/sangue , Monitoramento Contínuo da GlicoseRESUMO
AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Reino Unido/epidemiologia , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Adulto , Fatores de Risco , Índice de Massa Corporal , Fumar/efeitos adversos , Fumar/epidemiologia , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Exercício Físico , Seguimentos , Pressão Sanguínea , IncidênciaRESUMO
AIM: The paradoxical protective association between overweight/obesity and diabetic microvascular complications (DMC), a phenomenon well-known as the obesity paradox, has been considered a non-causal association based on methodological influences. We aimed to investigate the association of generalized and abdominal obesity, as measured by body mass index (BMI) and waist circumference (WC), respectively, with DMC in patients with type 2 diabetes (T2D), using a causal inference approach. MATERIALS AND METHODS: We enrolled 1436 patients with clinically diagnosed T2D but not DMC at baseline in a community-based prospective cohort in China between 2017 and 2019 and followed them annually until 2022 with new-onset DMC recorded. Marginal structural Cox models with inverse probability weighting were constructed to determine the causal association. Subgroup analyses were performed to identify potential effect modifiers. RESULTS: We observed 360 incident DMC cases, including 109 cases of diabetic nephropathy (DN) and 277 cases of diabetic retinopathy (DR) during four follow-up visits. Multivariable-adjusted hazard ratios (95% confidence intervals) for overall DMC, DN and DR were 1.037 (1.005-1.071), 1.117 (1.062-1.175) and 1.018 (0.980-1.059) for 1 kg/m2 increase in BMI, and 1.005 (0.994-1.017), 1.034 (1.018-1.051) and 1.000 (0.987-1.014) for 1 cm increase in WC, respectively. Similar patterns were observed across the BMI and WC categories, while the positive association appeared to be more pronounced in women. CONCLUSIONS: Generalized but not abdominal obesity was associated with an increased risk for the overall DMC, whereas both obesities were causally related to DN, albeit not DR, in T2D. Routine weight management should not be neglected in diabetes care, particularly in women.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Obesidade Abdominal , Obesidade , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Idoso , China/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Índice de Massa Corporal , Circunferência da Cintura , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Fatores de Risco , Adulto , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/complicações , IncidênciaRESUMO
Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (ß = -7.215, 95% CI -11.137 to -3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (ß = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (ß = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (ß = -9.195, 95% CI -15.847 to -2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.
Assuntos
Apolipoproteína C-III , Diabetes Mellitus Tipo 2 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/genética , Retinopatia Diabética/etiologia , Glicosilação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Recent research has shown that low serum levels of magnesium are often linked to both microvascular and macrovascular complications in individuals with diabetes mellitus. Hence, monitoring of serum magnesium levels is needed in diabetic patients. Furthermore, the addition of magnesium through supplementation may present a novel therapeutic strategy for mitigating vascular complications in individuals with diabetes. OBJECTIVES: To assess the prevalence of hypomagnesemia in type 2 diabetes mellitus patients and to assess the association between hypomagnesemia and microvascular complications of diabetes mellitus in a tertiary care hospital in North Kerala. MATERIALS AND METHODS: An analytical cross-sectional study was conducted at a tertiary care hospital involving 230 diabetic patients receiving outpatient and inpatient care in the Department of Internal Medicine at Government Medical College, Kozhikode, Kerala. The study took place from January 2018 to December 2018, during which serum magnesium levels were assessed and analyzed in relation to the patients' microvascular complications and glycemic control. RESULTS: We observed that 19.13% of the participants had hypomagnesemia. This condition was found to be more common among older individuals with diabetes, as indicated by a p-value of 0.022. However, there were no significant differences in serum magnesium levels based on gender (p-value 0.18), body mass index (BMI) (p-value 0.223), or the duration of diabetes (p-value 0.36). The prevalence of diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy was higher in diabetics with hypomagnesemia than their counterparts with normal magnesium, with a p-value of 0.001, 0.001, and 0.001, respectively. There was a significant negative correlation obtained between serum magnesium and glycated hemoglobin (HbA1C) values (Pearson coefficient = -0.240 and p-value = <0.01) and fasting blood sugar (FBS) values (Pearson coefficient = -0.265 and p-value = <0.01). CONCLUSION: Hypomagnesemia is negatively correlated with HbA1C and FBS but not related to duration of diabetes and gender. The prevalence of microvascular complications was higher among the diabetics with hypomagnesemia.
Assuntos
Diabetes Mellitus Tipo 2 , Magnésio , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Magnésio/sangue , Prevalência , Deficiência de Magnésio/epidemiologia , Deficiência de Magnésio/sangue , Deficiência de Magnésio/complicações , Idoso , Índia/epidemiologia , Adulto , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/sangue , Hemoglobinas Glicadas/análiseRESUMO
OBJECTIVE: To explore the utility of heart rate variability (HRV), a noninvasive marker of cardiac autonomic activity, as a prescreening tool for the prediction of micro- and macrovascular complications in type 2 diabetes mellitus (T2DM). METHODS: Consenting type 2 diabetic patients of both genders between 30 and 70 years, without known micro- and macrovascular complications of diabetes, were enrolled. Patients with medications affecting the HRV were excluded. Prior to other screening tests, 15 minutes of resting electrocardiogram (ECG) (1 kHz) was recorded in enrolled patients, followed by an exercise stress test and assessment for nephropathy, retinopathy, and peripheral neuropathy. The patients with positive stress tests were referred for coronary angiography to confirm coronary artery disease. Based on screening test results, patients were grouped as Group I-T2DM without complications (n = 31) and Group II-T2DM with micro/macrovascular complications (n = 29), (total = 60). RESULTS: Group comparison and test for association were employed, and p-value of <0.05 was considered significant. Significantly reduced HRV (decreased standard deviation of NN interval) between groups and a strong association of HRV indices with complications of diabetes were observed. Logistic regression to classify complicated vs noncomplicated group was used, and an accuracy of 0.78 with 85% sensitivity, 74% specificity with area under the curve (AUC) of 0.83 was observed. CONCLUSION: Significantly reduced HRV, stronger association with complications, and 85% sensitivity, 74% specificity, and 78% accuracy of classification make HRV indices a promising prescreening tool to predict micro- and macrovascular complications in type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Frequência Cardíaca , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Pessoa de Meia-Idade , Masculino , Feminino , Frequência Cardíaca/fisiologia , Idoso , Adulto , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/fisiopatologia , Eletrocardiografia/métodos , Teste de Esforço/métodos , Valor Preditivo dos TestesRESUMO
Objectives: To determine how plasma fibrinogen levels impact the severity of microvascular complications in people with type 2 diabetes while focussing on the molecular mechanisms of fibrinogen's role in such complications. METHODS: The analytical, cross-sectional study was conducted from September 2022 to March 2023 at the Department of Medicine, Mardan Medical Complex and Teaching Hospital, Khyber Pakhtunkhwa, Pakistan, and comprised adult patients of either gender who had been diagnosed with type 2 diabetes and microvascular complications. Each patient was subjected to an evaluation of microvascular complications, including diabetic retinopathy, nephropathy and neuropathy, using validated diagnostic criteria and clinical examinations. Data was analysed using SPSS 26. RESULTS: Of the 174 patients 97(%) were males and 77(%) were females. Retinopathy was found in 57(32.7) patients with median age 53 years (interquartile range: 46-63 years). Nephropathy was found in 55(31.6%) subjects with median age 54 years (interquartile range: 50-61 years). Neuropathy was found in 62(35.6%) patients with median age 53 years (interquartile range: 48-58 years). Diabetic neuropathy was significantly associated with elevated plasma fibrinogen levels and various biomarkers, such as creatinine, urea, fasting blood glucose, glycated haemoglobin and estimated average glucose (p<0.05). Diabetic retinopathy was significantly linked with higher levels of fibrinogen, which manifested through symptoms, like floaters or dark spots, impaired colour vision, difficulty seeing at night, blurred or fluctuating vision and vision loss (p<0.05). Diabetic nephropathy and the progression of its severity was significantly associated with increased fibrinogen levels, as well as markers, like albuminuria, creatinine, urea, fasting blood glucose, glycated haemoglobin and estimated average glucose (p<0.05). CONCLUSIONS: Elevated plasma fibrinogen levels in patients with type 2 diabetes significantly correlated with increased microvascular complications, underscoring the importance of monitoring and managing fibrinogen levels to mitigate diabetes-associated vascular pathologies.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Neuropatias Diabéticas , Retinopatia Diabética , Fibrinogênio , Humanos , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Feminino , Pessoa de Meia-Idade , Fibrinogênio/análise , Fibrinogênio/metabolismo , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Estudos Transversais , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Paquistão/epidemiologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Biomarcadores/sangue , Glicemia/análise , Glicemia/metabolismo , Creatinina/sangueRESUMO
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.
Assuntos
Angiopatias Diabéticas , Endotélio Vascular , Humanos , Endotélio Vascular/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/patologia , Animais , Estresse Oxidativo/fisiologiaRESUMO
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.
Assuntos
Diabetes Mellitus , Angiopatias Diabéticas , Humanos , Diabetes Mellitus/diagnóstico por imagem , Angiopatias Diabéticas/diagnóstico por imagem , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/terapia , Biomarcadores , Imagem Molecular/métodosRESUMO
Advanced glycation end-products (AGEs) formation increases with metabolic disorders, leading to higher serum AGE levels in patients with progressive vascular complications. Measuring AGE levels in biological samples requires multiple pre-analytical processing steps, rendering analysis of multiple samples challenging. This study evaluated the progression of diabetic complications by analyzing AGE levels using a pre-analytical processing strategy based on a fully automated solid phase-extraction system. Serum samples from patients with diabetes, with or without macrovascular complications (Mac or non-Mac) or microvascular complications (Mic or non-Mic), were processed with the established methods. Free and total AGE levels in sera were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). In patients with diabetes, both free and total AGE levels were elevated in those with complications compared to those without complications. In Mac and Mic groups, free and total AGE levels and z-scores (the sum of normalized AGE levels) also increased. AGE z-scores were markedly higher than those of single AGE levels in distinguishing each complication. Our study demonstrated that the free AGE z-score, measured using a new analytical method without hydrolysis, correlated with the presence of vascular complications and may serve as a marker of disease complications.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Produtos Finais de Glicação Avançada , Espectrometria de Massas em Tandem , Humanos , Produtos Finais de Glicação Avançada/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Espectrometria de Massas em Tandem/métodos , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/etiologia , Cromatografia Líquida/métodos , Biomarcadores/sangueRESUMO
CONTEXT: The paucity of data on microvascular complications in patients with posttransplant diabetes (PTDM) is an obstacle to developing follow-up algorithms. OBJECTIVE: To evaluate diabetic microvascular complications in patients with long-standing PTDM. METHODS: In patients with ≥5-year history of PTDM and age-matched renal transplant recipients without PTDM (NDM), diabetic peripheral neuropathy was evaluated using the Michigan Neuropathy Screening Instrument, the CASE IV device, and in vivo corneal confocal microscopy (CCM). Cardiac autonomic neuropathy tests were performed using heart rate variability. Nephropathy screening was assessed using spot urine albumin/creatinine ratio and eGFR calculation. Diabetic retinopathy was evaluated by fundus examination and photography, and optical coherence tomography. RESULTS: This study included 41 patients with PTDM and 45 NDM patients. The median follow-up was 107.5 months in the PTDM group. Peripheral neuropathy was significantly higher in the PTDM group than in the NDM group (P = .02). In the PTDM patients with peripheral neuropathy, corneal nerve fiber density examined by CCM was significantly lower than in PTDM patients without neuropathy (P = .001). Parasympathetic involvement was observed in 58.5% of the PTDM group and 22% of the NDM group (P = .001). Sympathetic involvement was present in 65.9% of the PTDM group and 29.3% of the NDM group (P = .001). Retinopathy was observed in 19.5% of patients in the PTDM group and in none of the NDM patients (P < .001). Renal functions were similar between the study groups. CONCLUSION: Cardiac autonomic neuropathy and diabetic retinopathy can affect patients with PTDM at a high rate. Diabetic retinopathy is a threat to the vision of PTDM patients. Diabetic peripheral neuropathy can be detected early in PTDM patients by CCM.
Assuntos
Neuropatias Diabéticas , Retinopatia Diabética , Transplante de Rim , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Transplante de Rim/efeitos adversos , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/epidemiologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/epidemiologia , Adulto , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Seguimentos , Idoso , Transplantados/estatística & dados numéricos , Nefropatias Diabéticas/etiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/epidemiologiaRESUMO
Oxidative stress results from the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in quantities exceeding the potential activity of the body's antioxidant system and is one of the risk factors for the development of vascular dysfunction in diabetes and exposure to ionizing radiation. Being the secondary products of normal aerobic metabolism in living organisms, ROS and RNS act as signaling molecules that play an important role in the regulation of vital organism functions. Meanwhile, in high concentrations, these compounds are toxic and disrupt various metabolic pathways. The various stress factors (hyperglycemia, gamma-irradiation, etc.) trigger free oxygen and nitrogen radicals accumulation in cells that are capable to damage almost all cellular components including ion channels and transporters such as Na+/K+-ATPase, BKCa, and TRP channels. Vascular dysfunctions are governed by interaction of ROS and RNS. For example, the reaction of ROS with NO produces peroxynitrite (ONOO-), which not only oxidizes DNA, cellular proteins, and lipids, but also disrupts important signaling pathways that regulate the cation channel functions in the vascular endothelium. Further increasing in ROS levels and formation of ONOO- leads to reduced NO bioavailability and causes endothelial dysfunction. Thus, imbalance of ROS and RNS and their affect on membrane ion channels plays an important role in the pathogenesis of vascular dysfunction associated with various disorders.
Assuntos
Estresse Oxidativo , Espécies Reativas de Oxigênio , Humanos , Animais , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/fisiopatologia , Lesões por Radiação/etiologia , Estresse Nitrosativo/efeitos da radiação , Espécies Reativas de Nitrogênio/metabolismo , Transdução de Sinais , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/fisiopatologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Radiação IonizanteRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 1 , Angiopatias Diabéticas , Hemoglobinas Glicadas , Humanos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Masculino , Hemoglobinas Glicadas/análise , Adulto , Adolescente , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Adulto Jovem , Seguimentos , Criança , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Prognóstico , Biomarcadores/sangue , Albuminúria/epidemiologia , Fatores de Risco , Pré-Escolar , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Progressão da Doença , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. METHODS AND RESULTS: There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. CONCLUSIONS: Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Humanos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/diagnóstico , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Estudos Prospectivos , Fatores de Risco , Adulto , Incidência , Medição de Risco/métodos , Idoso , Nefropatias Diabéticas/epidemiologia , Bancos de Espécimes Biológicos , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Biobanco do Reino UnidoRESUMO
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.