elastin and Diabetes-Mellitus--Type-2

The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans--hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy) are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined.

Topics: Basement Membrane; Cardiovascular System; Collagen; Diabetes Mellitus, Type 2; Elastin; Endothelium, Vascular; Extracellular Matrix; Glycoproteins; Humans; Integrins; Matrix Metalloproteinases; Metabolic Syndrome; Pericytes; Protein Kinase C

In type 2 diabetes mellitus (T2DM), elevated glucose level impairs the biochemistry of the skin which may result in alteration of its mechanical and structural properties. The several aspects of structural and mechanical changes in skin due to T2DM remain poorly understood. To fill these research gaps, we developed a non-obese T2DM rat (Sprague Dawley (SD)) model for investigating the effect of T2DM on the in vivo strain stress state, mechanical and structural properties of skin. In vivo strain and mechanical anisotropy of healthy and T2DM skin were measured using the digital imaging correlation (DIC) technique and DIC coupled bulge experiment, respectively. Fluorescence microscopy and histology were used to assess the collagen and elastin fibers microstructure whereas nanoscale structure was captured through atomic force microscopy (AFM). Based on the microstructural observations, skin was modeled as a multilayer membrane where in and out of plane distribution of collagen fibers and planar distribution of elastin fibers were cast in constitutive model. Further, the state of in vivo stresses of healthy and T2DM were measured using model parameters and in vivo strain in the constitutive model. The results showed that T2DM causes significant loss in in vivo stresses (p < 0.01) and increase in anisotropy (p < 0.001) of skin. These changes were found in good correlation with T2DM associated alteration in skin microstructure. Statistical analysis emphasized that increase in blood glucose concentration (HbA1c) was the main cause of impaired biomechanical properties of skin. The presented data in this study can help to understand the skin pathology and to simulate the skin related clinical procedures. STATEMENT OF SIGNIFICANCE: Our study is significant as it presents findings related to the effect of T2DM on the physiologic stress strain, structural and mechanical response of SD rat skin. In this study, we developed a non-obese T2DM SD rat model which mimics the phenotype of Asian type 2 diabetics (non-obese). Several structural and mechanical characterization techniques were explored for multiscale characterization of healthy and T2DM skin. Further, based on microstructural information, we presented the constitutive models that incorporate the real microstructure of skin. The presented results can be helpful to simulate the realistic mechanical response of skin during various clinical trials.

Topics: Animals; Biomechanical Phenomena; Collagen; Diabetes Mellitus, Type 2; Elastin; Rats; Rats, Sprague-Dawley; Stress, Mechanical

Topics: Biomarkers; Case-Control Studies; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Risk Assessment

Proteins containing advanced glycation end products are highly immunogenic and anti-advanced glycation end products antibodies (anti-AGEs antibodies) are found in the sera of diabetics.. Enzyme-linked immunosorbent assay (ELISA) was used for measuring levels of anti-advanced glycation end products antibodies in sera of 93 patients with type 2 diabetes mellitus and arterial hypertension (mean age 61.4±11.3 years, diabetes duration 9.88±3.12 years; hypertension duration 9.28±4.98). These values were compared to serum anti-AGEs antibodies in 42 age and sex matched controls. Diabetics were divided in two groups according to presence or absence of microangiopathy, group 1 (n=67) and group 2 (n=26), respectively.. Serum levels of anti-AGEs antibodies in patients with type 2 diabetes mellitus and arterial hypertension were statistically significantly higher than those in the control group (1.39±0.39 vs. 1.05±0.32), (p<0.05). Group 1 showed significantly higher levels of anti-AGEs antibodies than those of healthy controls (1.53±0.14 vs. 1.05±0.32), (p<0.01). Anti-AGEs antibodies levels were higher in patients with microvascular complications than these in patients without complications. Anti-AGEs antibodies correlate with diastolic blood pressure (r=0.26, p=0.05) and body mass index (r=0.37, p=0.03). We found significantly higher percentage of positive patients for anti-AGEs antibodies (mean+2SD) in group 1 than in group 2.. Determining the levels of serum anti-AGEs antibodies can help physicians make early diagnosis and prognosis of the severity of late diabetic complications in hypertensive patients.

Topics: Aged; Albuminuria; Autoantibodies; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Elastin; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged

The clinical utility of many peptide and protein drugs is limited by their short in-vivo half-life. To address this limitation, we report a new class of polypeptide-based materials that have a long plasma circulation time. The design of these polypeptides is motivated by the hypothesis that incorporating a zwitterionic sequence, within an intrinsically disordered polypeptide motif, would impart "stealth" behavior to the polypeptide and increase its plasma residence time, a behavior akin to that of synthetic stealth polymers. We designed these zwitterionic polypeptides (ZIPPs) with a repetitive (VPX

Topics: Amino Acid Sequence; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Delivery Systems; Elastin; Glucagon-Like Peptide 1; Intrinsically Disordered Proteins; Male; Mice, Inbred C57BL; Peptides; Tissue Distribution

Exenatide (Ex) is a 39-amino acid peptide of glucagon-like peptide-1 (GLP-1) receptor agonist that was approved by the FDA in 2005 as a Type II diabetes treatment. It shows a 53% homology with GLP-1 but has an extended half-life (ca. 2.4 h) relative to GLP-1 (ca. 2-3 min). In this study, to further extend its in vivo half-life, we constructed a fusion protein (Ex-(EBP)

Topics: Animals; Diabetes Mellitus, Type 2; Elastin; Exenatide; Glucose Tolerance Test; Half-Life; Humans; Male; Mice; Peptides; Recombinant Fusion Proteins; Saccharomyces cerevisiae

Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.

Topics: Animals; Biomarkers; Body Mass Index; Cells, Cultured; Cohort Studies; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Progression; Elastin; Extracellular Matrix; Female; Gene Expression Regulation; Humans; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Peptide Fragments; Proof of Concept Study; Receptors, Cell Surface; Signal Transduction

Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin-related proteins correlate to signs of CVD in patients with T2DM.. Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index.. T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure.. Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Elastin; Female; Humans; Male; Matrix Metalloproteinase 2; Middle Aged; Protein-Lysine 6-Oxidase; Proteolysis; Regression Analysis

Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown.. Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis.. Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.

Topics: Aged; Black People; Cardiovascular Diseases; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type III; Diabetes Mellitus, Type 2; Elastin; Female; Gene Regulatory Networks; Genetic Loci; Genome-Wide Association Study; Hispanic or Latino; Humans; Middle Aged; Polymorphism, Single Nucleotide; Protein Interaction Maps; Risk Factors; White People

Little is known about the impact of type 2 diabetes mellitus (DM) on coronary arteriole remodeling. The aim of this study was to determine the mechanisms that underlie coronary arteriole structural remodeling in type 2 diabetic (db/db) mice. Passive structural properties of septal coronary arterioles isolated from 12- to 16-week-old diabetic db/db and control mice were assessed by pressure myography. Coronary arterioles from 12-week-old db/db mice were structurally similar to age-matched controls. By 16 weeks of age, coronary wall thickness was increased in db/db arterioles (p < 0.01), while luminal diameter was reduced (control: 118 ± 5 μm; db/db: 102 ± 4 μm, p < 0.05), augmenting the wall-to-lumen ratio by 58% (control: 5.9 ± 0.6; db/db: 9.5 ± 0.4, p < 0.001). Inward hypertrophic remodeling was accompanied by a 56% decrease in incremental elastic modulus (p < 0.05, indicating decreased vessel coronary wall stiffness) and a ~30% reduction in coronary flow reserve (CFR) in diabetic mice. Interestingly, aortic pulse wave velocity and femoral artery incremental elastic modulus were increased (p < 0.05) in db/db mice, indicating macrovascular stiffness. Molecular tissue analysis revealed increased elastin-to-collagen ratio in diabetic coronaries when compared to control and a decrease in the same ratio in the diabetic aortas. These data show that coronary arterioles isolated from type 2 diabetic mice undergo inward hypertrophic remodeling associated with decreased stiffness and increased elastin-to-collagen ratio which results in a decreased CFR. This study suggests that coronary microvessels undergo a different pattern of remodeling from macrovessels in type 2 DM.

Topics: Animals; Arterioles; Collagen Type I; Coronary Vessels; Diabetes Mellitus, Type 2; Elasticity; Elastin; Male; Mice; Mice, Mutant Strains; Reverse Transcriptase Polymerase Chain Reaction

The number of men with type II diabetes-associated erectile dysfunction (ED) continues to grow rapidly; however, the majority of basic science studies has examined mechanisms of ED in animal models of type I diabetes. In this study, we first establish an in vivo mouse model of type II diabetic ED using the leptin receptor mutated db/db and wild-type control BKS mouse. Furthermore, we hypothesized that dual mechanistic impairments contribute to the impaired erectile function in the type II diabetic mouse, altered vasoreactivity, and venoocclusive disorder. In vivo erectile function was measured as intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP) following electrical stimulation of the cavernosal nerve. Venoocclusion was assessed by the maintenance of elevated in vivo ICP following intracorporal saline infusion. Vasoreactivity of isolated cavernosum in response to contractile and dilatory stimulation was examined in vitro by myography. Collagen and elastin content were evaluated by quantification of hydroxyproline and desmosine, respectively, as well as by quantitative PCR and histological analysis of isolated cavernosum. Erectile function was significantly decreased in db/db vs. BKS mice in a manner consistent with impairments in venoocclusive ability and decreased inflow. Heightened vasoconstriction and attenuated dilation in cavernosum of db/db vs. BKS mice suggest an overall lowered relaxation ability and thus impaired filling of the cavernosal spaces. A decrease in desmosine and hydroxyproline as well as lowered mRNA levels for tropoelastin, fibrillin-1, and alpha1(I) collagen were detected. These vasoreactive and sinusoidal matrix alterations may alter tissue compliance dispensability, preventing the normal expansion necessary for erection.

Topics: Acetylcholine; Animals; Blood Glucose; Blood Pressure; Body Weight; Collagen; Desmosine; Diabetes Mellitus, Type 2; Disease Models, Animal; Elastin; Electric Stimulation; Erectile Dysfunction; Extracellular Matrix; Hydroxyproline; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myography; Organ Size; Penis; Phenylephrine; Polymerase Chain Reaction; Receptors, Leptin; Regional Blood Flow; RNA, Messenger; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Veins

Diabetes is an independent risk factor for the development of neointimal hyperplasia and subsequent vein graft failure after coronary or peripheral artery bypass grafting. We evaluate a new mouse model of surgical vein grafting to investigate the mechanisms of neointimal formation in the setting of type 2 diabetes.. Surgical vein grafts were created by inserting vein segments from age-matched C57BL/KsJ wild-type mice into the infra-renal aorta of lepr(db/db) diabetic and C57BL/KsJ wild-type mice. Mice were euthanized &4 weeks later, and vein grafts were analyzed using morphometric and immunohistochemical techniques. A significant increase in neointimal formation was noted in lepr(db/db) mice (139+/-64 versus 109+/-62 mm2; P=0.008) after 4 weeks. This difference was mainly secondary to an increase in collagen formation within the lesion in the vein grafts from lepr(db/db) mice (0.53+/-0.4 versus 0.44+/-0.05; P<0.001), whereas only slight increases (P=not significant) in alpha actin-stained smooth muscle cells were noted in the lepr(db/db) mice.. We established a new physiologically relevant model of surgical vein grafting in mice. In this report, type 2 diabetes was associated with significant increase in extracellular matrix deposition in addition to increased smooth muscle cell deposition. This new model may allow mechanistic studies of cellular and molecular pathways of increased neointimal formation in the setting of diabetes.

Topics: Actins; Animals; Aorta, Abdominal; Bioprosthesis; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Collagen; Diabetes Mellitus, Type 2; Disease Models, Animal; Elastin; Extracellular Matrix; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Smooth, Vascular; Receptors, Cell Surface; Receptors, Leptin; Transplantation, Heterotopic; Tunica Intima; Vena Cava, Inferior

Diabetes is a risk factor for the development of cardiovascular diseases associated with impaired angiogenesis or increased endothelial cell apoptosis.. Here it is shown that angiogenic repair of ischemic hindlimbs was impaired in Lepr(db/db) mice, a leptin receptor-deficient model of diabetes, compared with wild-type (WT) C57BL/6 mice, as evaluated by laser Doppler flow and capillary density analyses. To identify molecular targets associated with this disease process, hindlimb cDNA expression profiles were created from adductor muscle of Lepr(db/db) and WT mice before and after hindlimb ischemia using Affymetrix GeneChip Mouse Expression Set microarrays. The expression patterns of numerous angiogenesis-related proteins were altered in Lepr(db/db) versus WT mice after ischemic injury. These transcripts included neuropilin-1, vascular endothelial growth factor-A, placental growth factor, elastin, and matrix metalloproteinases implicated in blood vessel growth and maintenance of vessel wall integrity.. These data illustrate that impaired ischemia-induced neovascularization in type 2 diabetes is associated with the dysregulation of a complex angiogenesis-regulatory network.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Elastin; Gene Expression Profiling; Hindlimb; Ischemia; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microcirculation; Muscle, Skeletal; Neovascularization, Physiologic; Neuropilin-1; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic