Risk Of Macrovascular Disease Research Articles

Identifying novel small molecule integrin agonists to mimic the favourable effects of the RGD domain of IGFBP-1 to treat cardiometabolic disease

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): British Heart Foundation (BHF) 4-Year PhD Programme Background Insulin-like growth factor binding protein (IGFBP)-1 has previously been shown to be associated with reduced type 2 diabetes (T2D) progression and preferable cardiovascular profiles in patients. Our laboratory previously demonstrated that IGFBP-1 is an insulin sensitiser in mouse models, in addition to having favourable vascular effects, independently of IGFs. IGFBP-1 has an Arg-Gly-Asp (RGD) domain which is thought to facilitate the direct interaction with the heterodimeric cell-surface receptor, integrin α5β1, inducing downstream cell signalling. We then showed the positive effects of IGFBP-1 could be mimicked with an RGD-containing linear peptide, GRGDTP, however this peptide is not a suitable therapeutic as it is rapidly metabolised in vivo. To our knowledge, RGD-based therapeutics have not been explored for cardiometabolic disease. Purpose There are currently few therapeutics which have been specifically designed to address both insulin resistance and the high risk of macrovascular disease in T2D. Therefore, exploring RGD-based integrin agonists will be essential in developing new insulin sensitising therapeutics which prevent cardiovascular complications. Methods The ROCS high speed ligand-based virtual screening tool was used to screen commercially available small molecule libraries mimicking the chemical structure of the RGD sequence of IGFBP-1. Additionally, we performed in silico modelling to predict the binding interactions of these molecules with the integrin α5β1 headpiece to select candidates. We then used a LIVE/DEAD cell viability assay to initially profile any cytotoxic effects of our selected compounds in integrin-expressing human umbilical vein endothelial cells (HUVECs) and C2C12 skeletal muscle myotubes. We further assessed the effects of compounds on relevant HUVEC functions using a high-throughput wound closure assay. Results The structure of the RGD domain of IGFBP-1 can be mimicked with small molecules containing amino acid moieties. These molecules are predicted to bind with micromolar affinity to the integrin, promoting beneficial interactions for integrin agonism. We selected 17 structurally diverse small molecules with the best predicted binding interactions. Initial in vitro profiling demonstrates that the molecules are not cytotoxic. In preliminary analyses, three of the selected compounds show a trend towards inhibition of HUVEC migration and proliferation, while six show a trend towards increased migration and proliferation. Conclusion The RGD domain of IGFBP-1 can be mimicked with novel small molecules, of which we have selected 17 ligands. Our compounds do not affect cell viability in relevant cell types, so can be further profiled. Our initial findings indicate that the compounds have different functional effects on HUVECs which allows us to prioritise hits having favourable effects in the context of T2D, such as enhancing angiogenic properties of endothelial cells.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

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). 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. 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. 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.

EPIDEMIOLOGY OF PREDIABETES AND IT’S DIAGNOSIS AND TREATMENT: A REVIEW

A state of hyperglycemia known as prediabetes is characterized by glycemic indices that are above normal but still below the diabetes threshold. Pre-diabetes remains significantly connected with a yearly conversion rate of 5% to 10% to diabetes, even with differences in the diagnostic criteria among international professional organizations. Observational research suggests a potential link between prediabetes and diabetic sequelae, including small fiber neuropathy, early retinopathy, early nephropathy, and an increased risk of macrovascular disease. Numerous studies showing the value of lifestyle changes in avoiding diabetes have shown a relative risk reduction of 40%–70% in those with prediabetes. Although there is growing evidence that pharmaceutical therapy alternatives other than metformin are beneficial in preventing diabetes in individuals with prediabetes, their use is limited due to adverse effects. The health outcomes of childhood prediabetes have not been the subject of any rigorous evaluations. Pharmacotherapy for prediabetes may have uncertain consequences on a child's growth and pubertal development. High-risk individuals are advised to undergo secondary intervention with metformin pharmacotherapy; nevertheless, the eventual goal of therapy, the long-term cost-effectiveness of such interventions, and the advantages of early intervention are not well understood. In kids with prediabetes, pharmacotherapy needs to be used carefully. Prediabetes is the term for blood glucose levels that are higher than usual but not entirely above the diabetic threshold. In this at-risk status, diabetes is considered to be highly likely to develop. Even though prediabetes is usually an asymptomatic condition, it is always present before the beginning of diabetes. As hyperglycemia is a continuum, prediabetes cannot be ruled out as a completely benign illness. In this review, we discussed the difficulties in diagnosing prediabetes, the potential adverse health consequences that come with it, the available treatments for prediabetes, and the reasons behind using them.

The evolution of type 2 diabetes management: glycemic control and beyond with SGLT-2 inhibitors and GLP-1 receptor agonists.

Diabetes mellitus (DM) is one of the most prevalent diseases encountered by the primary care physician on a daily basis. Complications associated with DM can include nephropathy, neuropathy, and retinopathy ("microvascular complications"), along with cardiovascular disease (CVD), which can include myocardial infarction (MI) and strokes ("macrovascular complications"). In the 1990s, landmark clinical trials demonstrated that intensive glycemic control can reduce the risk of developing microvascular complications, but reduction in macrovascular complications with intensive glycemic control was not clearly demonstrated. At this point, intensive glycemic control became the standard of care (SOC). In the 2000s, additional trials evaluating the effect of intensive glycemic control in patients with type 2 diabetes mellitus (T2D) and established CVD, or risk factors for CVD, subsequently failed to identify a macrovascular benefit from intensive glycemic control, and one of the trials was terminated early because of an increase in the risk of mortality observed among patients assigned to receive intensive glycemic control. These results led to less strict glycemic targets being recommended in older patients, particularly those with established CVD. In 2007, everything changed after a report surfaced suggesting that rosiglitazone was associated with a significant increase in the risk of MI, as well as an increase in the risk of cardiovascular death that was of borderline significance. As a result, in 2008, the FDA mandated that all new diabetes medications must exclude an unacceptable level of risk for atherosclerotic cardiovascular disease (ASCVD) prior to drug approval, and thus undergo additional cardiovascular safety trials. Accordingly, through these trials, some of the newer agents, particularly sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), were demonstrated to reduce the risk of major adverse cardiovascular events (MACEs), independent of their effect on glycemic control. These findings subsequently led to further trials to evaluate the effects of some of these therapies on the risk of chronic kidney disease (CKD) progression, as well as adverse heart failure-related outcomes. SGLT-2 inhibitors have been demonstrated to reduce the risk of CKD progression, as well as a reduction in the risk of cardiovascular death or hospitalization secondary to heart failure in patients with both reduced ejection and preserved ejection fractions. A trial evaluating the effects of GLP-1RA on CKD outcomes is ongoing. The aim of this narrative review article, compiled by identifying relevant studies via the utilization of PubMed, is to provide a broad overview over the various clinical trials and analyses that have led to current diabetes management guidelines, and ultimately, help guide primary care physicians in selecting therapies that will not only improve glycemic control and reduce the risk of microvascular complications, but also reduce the risk of macrovascular disease in their patients with T2D.

Cardiovascular and microvascular outcomes according to vitamin D level and genetic variants among individuals with prediabetes: a prospective study

BackgroundWhether serum vitamin D mediate vascular diseases in prediabetic populations remains unclear. This study aimed to determine the associations between circulating 25-hydroxyvitamin D [25(OH)D] levels and vitamin D receptor (VDR) polymorphisms with the risk of macrovascular complications, including myocardial infarction and stroke, and microvascular complications such as diabetic nephropathy and retinopathy, among adults with prediabetes.MethodsParticipants with prediabetes in UK Biobank were included (N = 56,387). Multivariable dose–response and Cox proportion models were used to explore the relationship of serum 25(OH)D status and the risks of vascular complications. The interaction of VDR polymorphisms with serum 25(OH)D level on risks of vascular events was also assessed.ResultsDuring a median follow-up of 12 years, higher levels of 25(OH)D were significantly and nonlinearly associated with a lower risk of macrovascular diseases among prediabetic individuals. The adjusted hazard ratios (95% confidential interval) of serum 25(OH)D levels of ≥ 75.0 nmol/L versus < 25 nmol/L were 0.75 (0.63–0.88) for myocardial infarction, 0.74 (0.55–1.00) for stroke, 1.02 (0.60–1.74) for diabetic nephropathy, and 1.30 (0.92–1.84) for diabetic retinopathy, respectively. The rs2228570 (FokI) polymorphisms significantly interacted with 25(OH)D on incident myocardial infarction (P-interaction = 0.042) and stroke (P-interaction = 0.033). The individuals with serum 25(OH)D level of 50.0–74.9 nmol/L and rs2228570 (FokI) homozygotes had the lowest risks of vascular complications.ConclusionsLower serum 25(OH)D levels are significantly and nonlinearly associated with an increased risk of cardiocerebrovascular diseases in prediabetic individuals, with VDR polymorphisms of rs2228570 (FokI) modify such associations. Monitoring a safe 25(OH)D concentration is suggested to prevent the vascular complications for prediabetes.

Association between depression and macrovascular disease: a mini review.

Depression and macrovascular diseases are globally recognized as significant disorders that pose a substantial socioeconomic burden because of their associated disability and mortality. In addition, comorbidities between depression and macrovascular diseases have been widely reported in clinical settings. Patients afflicted with coronary artery disease, cerebrovascular disease or peripheral artery disease exhibit an elevated propensity for depressive symptoms. These symptoms, in turn, augment the risk of macrovascular diseases, thereby reflecting a bidirectional relationship. This review examines the physiological and pathological mechanisms behind comorbidity while also examining the intricate connection between depression and macrovascular diseases. The present mechanisms are significantly impacted by atypical activity in the hypothalamic-pituitary-adrenal axis. Elevated levels of cortisol and other hormones may disrupt normal endothelial cell function, resulting in vascular narrowing. At the same time, proinflammatory cytokines like interleukin-1 and C-reactive protein have been shown to disrupt the normal function of neurons and microglia by affecting blood-brain barrier permeability in the brain, exacerbating depressive symptoms. In addition, platelet hyperactivation or aggregation, endothelial dysfunction, and autonomic nervous system dysfunction are important comorbidity mechanisms. Collectively, these mechanisms provide a plausible physiological basis for the interplay between these two diseases. Interdisciplinary collaboration is crucial for future research aiming to reveal the pathogenesis of comorbidity and develop customised prevention and treatment strategies.

A Review on Diabetic Peripheral Neuropathy

Diabetes has become considered one of the most common health-care crisis of the 21st century. Diabetes increases the risk of various microvascular and macrovascular diseases. Diabetic neuropathy is one of the microvascular complications that can affect as many as 50% of patients with diabetes. It is generally agreed that the toxic consequences of hyperglycemia play a significant part in the emergence of this problem, but several other hypothesis also have been proposed. Diabetes can lead to variety of neuropathic problems, both acute and chronic, that can impact the peripheral nerve at every level from the root to the distal axon. Major international clinical recommendations for the therapy of Diabetic peripheral neuropathy [DPN] offer many symptomatic therapies. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants are among the first-line treatments. Opioids and topical medications like capsaicin cream and lidocaine patches are among the further treatments. The main focus of this review is recommendations for the management of DPN. Keywords: Diabetes, DPN, Hyperglycemia, Antidepressants, Anticonvulsants

PSUN326 An Interim Analysis of Healthcare Professionals’ Gaps in Incretin Knowledge Before and After Education

Abstract Background Patients with type 2 diabetes (T2D) who have poor glycemic control are at increased risk for macrovascular and microvascular disease. The growing body of cardiovascular (CV) and renal outcomes data for newer agents such as glucagon-like peptide 1 (GLP-1) receptor agonists has shifted management approaches toward therapies that provide extra glycemic benefits in addition to glucose-lowering ability. The rapidly evolving role of these new agents and new data on the potential role of a glucose-dependent insulinotropic polypeptide (GIP) agonist/GLP-1 agonist combination agent may create confusion among healthcare professionals (HCPs) treating patients with T2D. Greater competence is needed on the actions and clinical applications of current and emerging incretin-based therapies. Therefore, Clinical Care Options (CCO) created a series of online-based microlearning modules on the topic of incretin therapy in patients with T2D and cardiometabolic comorbidities for HCPs. This ongoing program, which was supported by an unrestricted medical education grant, is providing us with rich outcomes data that characterizes HCPs’ learning and current knowledge gaps regarding the use of incretins in patients with T2D. Aim The goal of this analysis was to determine the interim educational impact as well as remaining knowledge gaps among HCPs following education on incretin therapies. This information could inform future medical education that closes knowledge gaps and arms HCPs with the tools to effectively manage patients with T2D. Methods CCO produced an online educational program on incretin therapies, released in August 2021. We used pre/post questions to mine data on HCPs’ gaps. Questions measuring HCPs’ knowledge and competence were asked at baseline ("pre") and then repeated after the education was delivered ("post"). To uncover key educational gaps, we identified questions with the lowest correct responses at baseline as well as persistence of incorrect responses post education. Interim Results HCP Demographics N = 9837; MD: 61%; RPh: 10%; NP/PA: 12%; RN: 5%; other HCP: 5%, non-HCP: 8% Baseline and Remaining Gaps Incretin-based questions with topics including GLP-1 effects on glucose homeostasis, metabolic effects of GIP/GLP-1 coagonists, and the A1C-lowering ability of tirzepatide all scored &amp;lt;50% at baseline. Following education, the GLP-1 effect on glucose homeostasis increased only slightly from 36% to 40%, and the metabolic effects of GIP/GLP-1 coagonists increased from 19% to 54%, indicating that HCPs still struggle with understanding the effects of these agents. Conclusions This analysis demonstrates that HCPs who care for patients with T2D have significant knowledge gaps in the effects of newer incretin agents. As guidelines are placing more emphasis on the use of newer incretin agents as first-line therapy, HCPs must have the knowledge and competence of their actions to initiate incretin therapy in the primary care setting. Comparison to a similar program with an alternative format may provide further insight. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Part Six: Antidiabetic Medication Benefits Beyond Glucose Lowering in Older People.

Older people with type 2 diabetes are at an increased risk for macrovascular (damage to arteries that can lead to myocardial infarction or stroke) and microvascular (damage to small blood vessels including retinopathy and nephropathy) disease. Since 2008, newly approved antidiabetic medications have been required to show cardiovascular safety as part of the US Food and Drug Administration approval process. Since this time, new data have emerged regarding the differences between agents in terms of reducing diabetes-related complications. Older people often are at risk for or currently have one or more diabetes-related complication. When managing antidiabetic medication in older people, it is imperative to consider the risk versus benefit of each medication and to use agents that have proven benefits.

Retinal Artery Occlusion as an Early Indicator of Macrovascular Complications in Diabetes

BackgroundA characteristic of the retinal circulation is that arterial occlusion is embolic or secondary to vasculitis but rarely or never due to in situ atherosclerosis. Therefore, retinal artery occlusion suggests the presence of cardiac or large-vessel disease outside the eye. This cohort study examined the general risk of macrovascular disease in individuals with diabetes, with or without retinal artery occlusion. MethodsWe retrieved data on 992 subjects with incident retinal artery occlusion and preexisting diabetes, registered in Denmark between January 1, 2000, and December 31, 2018. Each retinal artery occlusion subject was matched for age, sex, and diabetes duration, with 5 control subjects with diabetes but without retinal artery occlusion. We performed survival analyses to compare the risk of extraocular macrovascular disease between the 2 groups in a 5-year follow-up. ResultsAfter 1 year, the incidence of macrovascular disease in subjects with retinal artery occlusion was approximately 21 per 100 person-years (95% confidence interval [CI]: 18.11-24.29), compared to 6.25 per 100 patient-years (95% CI: 5.57-7.00) in those without retinal artery occlusion. After 5 years, the cumulative incidences of macrovascular disease were 51.2% (95% CI: 47.9-54.7%) and 29.4% (95% CI: 28.0-30.8%) in patients with diabetes with or without retinal artery occlusion, respectively. Hazard rate ratios were 3.36 (95% CI: 2.79-4.05) after 1 year and 2.27 (95% CI: 2.04-2.53) after 5 years. ConclusionAmong individuals with diabetes, those diagnosed with retinal artery occlusion had a higher general risk of macrovascular complications for at least 5 years after the occlusion event compared with those without retinal artery occlusion.

Hypovitaminosis D in patients with type 2 diabetes: risk factors and association with glycemic control and established microvascular complications

Several studies reported than vitamin D deficiency increases the risk of macrovascular and microvascular disease in patients with type 2 diabetes (T2DM). We investigated the plasma levels of 25OHD in adult patients T2DM, risk factors for 25OHD deficiency and the relationship between 25OHD, glycemic control and chronic complications of T2DM. A cross-sectional study was carried out, in which 25OHD levels were evaluated in adult patients (over 18 years) with T2DM. Correlation analyses were performed to evaluate the interdependence of the 25OHD with other continuous variables. A receiver operating characteristic analysis was also performed to identify cutoff values for diagnosing vitamin D deficiency. Logistic regression was performed to identify the independent association between vitamin D deficiency and the variables associated with lower 25OHD. 208 patients were analyzed. The mean age of the patients was 62 years. The 25OHD level was 19 ng/ml (IQR 13.28-24.43), 59.78% had vitamin D deficiency, and 10.33% had severe deficiency. Glycemia, HbA1c, and BMI were negatively correlated with 25OHD. Cutoff point for vitamin D deficiency was 33.39 kg/m2 for body mass index (BMI), 123 mg/dl for glycemia, and 6.65% for HbA1c. In multivariate logistic regression, BMI>33.39 kg/m2, glycemia >123.5 mg/dl, and albuminuria presented higher odds of vitamin D deficiency. Vitamin D deficiency was highly prevalent among patients with T2DM. Low levels were related to higher fasting plasma glucose, higher BMI, and diabetic nephropathy.

Risk of Macrovascular and Microvascular Disease in Diabetes Diagnosed Using Oral Glucose Tolerance Test With and Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort Study.

Background:It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease.Methods:Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min−1·1.73 m−2) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants.Results:Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12–2.10] and 1.85 [95% CI, 1.50–2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09–2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22–2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99–1.07) similar to that of the diabetes-free population.Conclusions:More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial

BackgroundMetformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo.MethodsThis study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease.ResultsThis study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [− 8.4% (− 18.6, 3.2), p = 0.150, and − 4.6% (− 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [− 1.6% (− 2.9, − 0.2), p = 0.021] but not troponin I concentrations [− 1.5% (− 4.2, 1.2), p = 0.263].ConclusionsIn this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury.Trial registration ClinicalTrials.gov identifier NCT00375388.

Cre/CysC ratio may predict muscle composition and is associated with glucose disposal ability and macrovascular disease in patients with type 2 diabetes

IntroductionSince the ratio of creatinine to cystatin C (Cre/CysC) can reflect muscle volume, it has been proven to be a predictor of sarcopenia in patients with or without diabetes. Here,...

ADIPOCYTE FATTY ACID BINDING PROTEIN (A-FABP) AS A NOVEL BIOCHEMICAL MARKER OF DIABETIC RETINOPATHY

Introduction: Diabetes mellitus is acomplex metabolic disorder associated with increased risk of microvascular and macrovascular disease characterized by chronic hyperglycaemia resulting from defect in insulin secretion, insulin action, or both. Diabetic retinopathy (DR) causes visual impairment as a result of long term accumulated damaged to the small blood vessels in the retina.Adipocyte fatty acid binding protein(AFABP), been suggested as a third adipokine, in addition to leptin and adiponectin. AFABP might have a role in the proliferation of endothelial cells, as well as in angiogenesis. A-FABP levels were determined in subjects witout diabetes mellitus, with type 2 diabetes mellitus without DR and with DR at admission in order to investigate a possible association of A-FABP to the increased risk of incidence of DR. Material and methods: This study was done on non-diabetic (n=25) and Type 2 diabetes subjectswith(n=25) and without retinopathy (n=25) who visited HAHC hospital. Blood glucose (fasting and post prandial), glycated hemoglobin(HbA1c), urea, creatinine, uric acid, total protein, serum albumin,serum electrolytes (sodium, potassiumand chloride), totalcholesterol,triglyceride, high density lipoprotein(HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and and AFABP were measured . Result: The mean values of blood glucose (fasting and post prandial),HbA1C,urea, creatinine , TG, LDL VLDL and AFABP were higher in diabetic subjectswith diabetic retinopathy in comparison to diabetic subjects without retinopathy and subjects without diabetes mellitus and were highly significant statistically.(p&lt;0.01). The mean value of HDL was lower in diabetic subjects with diabetic retinopathy in comparison to diabetic subjects without retinopathy and subjects without diabetes mellitus and was highly significant statistically. Conclusion:The study helps in associating AFABP as an early biochemical marker for identifying onset of diabetic retinopathy in subjects with diabetes mellitus at an early stage.

Characterization of cholesterol efflux capacity in diabetic and non-diabetic patients with coronary artery disease: comparison between acute coronary syndrome and stable coronary artery disease

Abstract Introduction Type 2 diabetic patients more likely exhibit a lower high-density lipoprotein (HDL) level. Given a greater glycation and oxidative stress in diabetic subjects, these atherogenic characteristics could cause dysfunctional HDL including a reduced cholesterol efflux capacity (CEC), which may account for an increased risk of diabetic macrovascular disease including acute coronary syndrome (ACS). However, it remains to be fully elucidated characteristics of HDL-mediated CEC in type 2 diabetic patients, in association with clinical presentation of coronary artery disease (CAD). Purpose To characterize CEC in CAD subjects with type 2 diabetes mellitus. Methods The current study prospectively analyzed 87 statin-naive patients with CAD. CEC was measured by using the collected apolipoprotein B-depleted serum. Liquid scintillation counting (Perkin-Elmer Analytical Sciences, MA, US) was used to quantify the efflux of radioactive cholesterol from J774 cells. Clinical characteristics and CEC were compared in diabetic and non-diabetic subjects. Results The averaged HbA1c in diabetic patients was 6.7±1.2, and 66.7% of them achieved HbA1c &amp;lt;7.0%. Diabetic subjects more likely exhibited a history of hypertension and dyslipidemia, and multi-vessel disease (Table). Moreover, a lower CEC level was observed in diabetic patients, accompanied by a lower HDL-C and apolipoprotein A-I levels with a higher level of triglyceride (Table). HDL-C (r=0.62, p-value&amp;lt;0.01) and Apolipoprotein A-I (r=0.70, p-value &amp;lt;0.01) were associated with CEC, whereas there was no significant difference in CEC between subjects with HbA1c &amp;lt;7.0% vs. ≥7.0% (0.74±0.07 vs. 0.78±0.08, p=0.22). On multivariate analysis, type 2 diabetes mellitus was an independent contributor to CEC &amp;lt;0.79 (median) (HR=2.75, 95% CI: 1.11–6.82, p=0.03). Interestingly in particular, CEC was substantially lower in diabetic patients with ACS compared to those with stable CAD (Figure). By contrast, clinical presentation of CAD did not affect CEC in non-diabetic subjects (Figure). Conclusions A lower CEC level was observed in subjects with type 2 diabetes mellitus. In particular, this HDL functionality was profoundly diminished in those presenting ACS. Our findings suggest functionality of HDL as a potential therapeutic target in diabetic patients experiencing ACS. Funding Acknowledgement Type of funding sources: None. Table 1Figure 1

Extracellular vesicles-incorporated microRNA signature as biomarker and diagnosis of prediabetes state and its complications.

Extracellular vesicles (EVs) are small anuclear vesicles, delimited by a lipid bilayer, released by almost all cell types, carrying functionally active biological molecules that can be transferred to the neighbouring or distant cells, inducing phenotypical and functional changes, relevant in various physio-pathological conditions. The microRNAs are the most significant active components transported by EVs, with crucial role in intercellular communication and significant effects on recipient cells. They may also server as novel valuable biomarkers for the diagnosis of metabolic disorders. Moreover, EVs are supposed to mediate type 2 diabetes mellitus (T2DM) risk and its progress. The T2DM development is preceded by prediabetes, a state that is associated with early forms of nephropathy and neuropathy, chronic kidney disease, diabetic retinopathy, and increased risk of macrovascular disease. Although the interest of scientists was focused not only on the pathogenesis of diabetes, but also on the early diagnosis, little is known about EVs-incorporated microRNA involvement in prediabetes state and its microvascular and macrovascular complications. Here, we survey the biogenesis, classification, content, biological functions and the most popular primary isolation methods of EVs, review the EVs-associated microRNA profiling connexion with early stages of diabetes and discuss the role of EVs containing specific microRNAs in prediabetes complications.

The Cre/CysC Ratio Can Predict Muscle Composition and is Associated with Glucose Disposal Ability and Macrovascular Disease in Patients with Type 2 Diabetes

Aims: The ratio of creatinine to cystatin C (Cre/CysC) has been proven to be a predictor of sarcopenia in patients with or without diabetes. Here, we investigated the predictive value of Cre/CysC in skeletal muscle composition and its correlations with glucose disposal ability and diabetic complications in patients with type 2 diabetes. Methods: The skeletal muscle index (SMI) and mean skeletal muscle attenuation (MMA) values of 193 patients with type 2 diabetes were obtained through analyses of CT images at the lumbar 3 level. Results: Serum Cre/CysC was significantly correlated with both the SMI (r =0.375, P < 0.001) and MMA (r = 0.378, P < 0.001). Multiple stepwise linear regression analysis demonstrated that Cre/CysC was the only biochemical predictor of the SMI [β = 0.48, (95% Cl, 0.02 to 0.94) and MMA [β= 0.57, (95% Cl, 0.14 to 1.01). In the complications analysis, Cre/CysC was negatively correlated with cardiovascular disease (r = -0.190, P = 0.008) and lower extremity arterial disease (r = -0.209, P = 0.004). Moreover, in the 100 g steamed bun test, Cre/CysC was significantly correlated with glucose levels at 60 min (r = -0.162, P = 0.045), 120 min (r = -0.287, P < 0.001) and 180 min (r = -0.313, P < 0.001). Conclusion: Cre/CysC is a valuable predictor of skeletal muscle composition in type 2 diabetes. Patients with higher levels of Cre/CysC may have a better ability to dispose of postprandial glucose and lower risk of macrovascular disease. Funding: The present study was supported by the Doctoral foundation of Affiliated Hospital of Jining Medical University (2020-BS-008). Declaration of Interest: The authors declare that they have no competing interests.

The risk of micro and macrovascular disease in Egyptian patients with diabetes and peripheral arterial disease

ABSTRACT Aim: The aim of this study was to assess the prevalence of micro- and macrovascular disease in Egyptian patients with diabetes mellitus (DM) and peripheral arterial disease (PAD). Methods: The study included 161 Egyptian patients with DM and PAD (91.3% had type 2 DM and 67.1% were females). Mean diabetes duration was 14.2 ± 5.2 years. Full history, clinical and fundus examination as well as laboratory investigations were done. PAD was diagnosed through assessment of ankle/brachial index (ABI) by Doppler ultrasonography. Results: ABI was <0.9 in 33.5% and >1.3 in 66.5% of patients. A significant positive correlation was found between abnormal ABI and diabetes duration, ischemic heart disease (IHD), diabetic retinopathy and neuropathy, foot ulcers, elevated blood pressure (BP), creatinine, urine albumin/creatinine ratio (ACR) and triglycerides and a significant negative correlation with HDL. Multivariate regression analysis revealed that the independent predictors for PAD in patients with ABI< 0.9 were neuropathy, creatinine, triglyceride, LDL, urine ACR and low HDL, and in patients with ABI >1.3 were IHD, neuropathy, elevated diastolic BP and triglyceride. Conclusion: The risk of micro- and macrovascular disease is high in Egyptian patients with diabetes and PAD. Early diagnosis and good control of risk factors could reduce PAD progression.

Left Ventricular Dysfunction in Prediabetic Patients: A review article

Background: Prediabetes is a common condition that indicates a state between normal glucose metabolism and diabetes. This is considered a dangerous condition because of the high risk of developing diabetes. A recent study in Europe shows that visually impaired fasting increases glucose and impaired glucose tolerance. prevalence of impaired fasting glucose (IFG) levels range from approximately 3%to 5% in the 20 -44 age group and approximately 20% to 30% in the 65-74 age group. Evidence suggesting a link between the risk of neuropathy, nephropathy, early retinopathy, and macrovascular disease and prediabetes. Prediabetes is associated with a 20% increased risk of cardiovascular disease compared to normoglycemic individuals. Several studies have established systolic and diastolic left ventricular dysfunction in prediabetic patients. We aimed to highlight left ventricular dysfunction in Prediabetic patients and to describe the possible underlying mechanisms of this association. Conclusion : There is a significant association between left ventricular systolic and diastolic dysfunction and prediabetes. The defects underlying prediabetes which include insulin resistance, metabolic syndrome, dyslipidemia, and inflammation, have been implicated to predispose diabetic patients to increased risk of developing ventricular dysfunction.