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

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

The vascular complications of diabetes: a review of their management, pathogenesis, and prevention.

INTRODUCTION: This review highlights the pathogenesis of both microvascular and macrovascular complications of diabetes and how these mechanisms influence both the management and preventative strategies of these complications. The cumulative data shown in this review suggest hyperglycemic and blood pressure control remain central to this intricate process. AREAS COVERED: We reviewed the literature including retrospective, prospective trials as well as meta-analysis, and post hoc analysis of randomized trials on microvascular andmacrovascular complications. EXPERT OPINION: Further research is needed to explore the ideal intervention targets and preventative strategies needed to prevent macrovascular complications. Furthermore, as the data for trials looking at microvascular complications lengthen more long-term data will further elucidate the role that the duration of diabetes has on these complications. Additionally, trials looking to maximize hyperglycemic control with multiple agents in diabetes, such as metformin, SGL2isand GLP-1 receptor agonists are currently in process, which will have implications for rates of microvascular as well as macrovascular complications.

Dysfunctional APPL1-Mediated Epigenetic Regulation in Diabetic Vascular Injury.

BACKGROUND: APN (adiponectin) and APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) are potent vasculoprotective molecules, and their deficiency (eg, hypoadiponectinemia) contributes to diabetic vascular complications. However, the molecular mechanisms that govern their vasculoprotective genes as well as their alteration by diabetes remain unknown. METHODS: Diabetic medium-cultured rat aortic endothelial cells, mouse aortic endothelial cells from high-fat-diet animals, and diabetic human aortic endothelial cells were used for molecular/cellular investigations. The in vivo concept-prove demonstration was conducted using diabetic vascular injury and diabetic hindlimb ischemia models. RESULTS: In vivo animal experiments showed that APN replenishment caused APPL1 nuclear translocation, resulting in an interaction with HDAC (histone deacetylase) 2, which inhibited HDAC2 activity and increased H3Kac27 levels. Based on transcriptionome pathway-specific real-time polymerase chain reaction profiling and bioinformatics analysis, Angpt1 (angiopoietin 1), Ocln (occludin), and Cav1 (caveolin 1) were found to be the top 3 vasculoprotective genes suppressed by diabetes and rescued by APN in an APPL1-dependent manner. APN reverses diabetes-induced inhibition of Cav1 interaction with APPL1. APN-induced Cav1 expression was not affected by Angpt1 or Ocln deficiency, whereas APN-induced APPL1 nuclear translocation or upregulation of Angpt1/Ocln expression was abolished in the absence of Cav1 both in vivo and in vitro, suggesting Cav1 is upstream molecule of Angpt1/Ocln in response to APN administration. Chromatin immunoprecipitation-qPCR (quantitative polymerase chain reaction) demonstrated that APN caused significant enrichment of H3K27ac in Angpt1 and Ocln promoter region, an effect blocked by APPL1/Cav1 knockdown or HDAC2 overexpression. The protective effects of APN on the vascular system were attenuated by overexpression of HDAC2 and abolished by knocking out APPL1 or Cav1. The double knockdown of ANGPT1/OCLN blunted APN vascular protection both in vitro and in vivo. Furthermore, in diabetic human endothelial cells, HDAC2 activity is increased, H3 acetylation is decreased, and ANGPT1/OCLN expression is reduced, suggesting that the findings have important translational implications. CONCLUSIONS: Hypoadiponectinemia and dysregulation of APPL1-mediated epigenetic regulation are novel mechanisms leading to diabetes-induced suppression of vasculoprotective gene expression. Diabetes-induced pathological vascular remodeling may be prevented by interventions promoting APPL1 nuclear translocation and inhibiting HDAC2.

Vaccinium as Potential Therapy for Diabetes and Microvascular Complications.

Diabetes mellitus is one of the most critical global health concerns, with a fast-growing prevalence. The incidence of diabetic vascular complications is also rapidly increasing, exacerbating the burden on individuals with diabetes and the consumption of public medical resources. Despite the overall improvements in the prevention, diagnosis, and treatment of diabetic microvascular complications in recent years, safe and effective alternative or adjunctive therapies are urgently needed. The mechanisms underlying diabetic vascular complications are complex, with hyperglycemia-induced oxidative stress and inflammation being the leading causes. Therefore, glycemic control, antioxidation, and anti-inflammation are considered the main targets for the treatment of diabetes and its vascular comorbidities. Vaccinium L. (Ericaceae) is a genus of plants enriched with polyphenolic compounds in their leaves and fruits. Vaccinium and its extracts have demonstrated good bioactivity in reducing blood glucose, oxidative stress, and inflammation, making them excellent candidates for the management of diabetes and diabetic vascular complications. Here, we review recent preclinical and clinical studies on the potential effect of Vaccinium on ameliorating diabetes and diabetic complications, particularly diabetic kidney disease and diabetic retinopathy.

A multi-centre investigation of macrovascular and non-ocular microvascular complications in children and adolescents with diabetes mellitus in southern Ghana.

Objectives: To investigate the prevalence of macrovascular and non-ocular microvascular complications and the associated factors among children and adolescents with diabetes mellitus in selected hospitals in southern Ghana. Design: A cross-sectional study. Setting: The out-patient clinics of the Departments of Child Health, Medicine and Therapeutics, Family Medicine, Ophthalmology, and the National Diabetes Management and Research Centre, all at the Korle Bu Teaching Hospital, Accra, as well as from Cape-Coast Teaching Hospital in the Central Region of Ghana. Participants: Fifty-eight children and adolescents aged 4-19 years who had been diagnosed with diabetes mellitus. Main outcome measures: Macrovascular (peripheral artery disease and coronary heart disease) and non-ocular microvascular complications (neuropathy and nephropathy). Results: Data from 58 children and adolescents with diabetes were analysed. The mean age of participants was 14.6±2.6 years, and a female preponderance was observed (45, 77.6%). The prevalence of macrovascular and non-ocular microvascular complications was 27.6% and 8.6%, respectively. Long duration of diabetes diagnosis (p=0.044) and low triglycerides (p=0.009) were associated with microvascular complications, while high triglycerides (p=0.032), lower HDL cholesterol (p=0.046), and abnormal body mass index (p=0.020) were associated with macrovascular complications. Conclusions: Macrovascular and non-ocular microvascular complications are common among children and adolescents with diabetes in southern Ghana and are associated with a long duration of diabetes diagnosis, abnormal body mass index, low HDL cholesterol, and triglyceride levels. Therefore, the early institution of regular screening for diabetes-related complications to allow early detection and appropriate management is recommended. Funding: University of Ghana Research Fund.

Protective effect of the curcumin-baicalein combination against macrovascular changes in diabetic angiopathy.

Endothelial dysfunction is an early pathological event in diabetic angiopathy which is the most common complication of diabetes. This study aims to investigate individual and combined actions of Curcumin (Cur) and Baicalein (Bai) in protecting vascular function. The cellular protective effects of Cur, Bai and Cur+Bai (1:1, w/w) were tested in H2O2 (2.5 mM) impaired EA. hy926 cells. Wistar rats were treated with vehicle control as the control group, Goto-Kakizaki rats (n=5 each group) were treated with vehicle control (model group), Cur (150 mg/kg), Bai (150 mg/kg), or Cur+Bai (75 mg/kg Cur + 75 mg/kg Bai, OG) for 4 weeks after a four-week high-fat diet to investigate the changes on blood vessel against diabetic angiopathy. Our results showed that Cur+Bai synergistically restored the endothelial cell survival and exhibited greater effects on lowering the fasting blood glucose and blood lipids in rats comparing to individual compounds. Cur+Bai repaired the blood vessel structure in the aortic arch and mid thoracic aorta. The network pharmacology analysis showed that Nrf2 and MAPK/JNK kinase were highly relevant to the multi-targeted action of Cur+Bai which has been confirmed in the in vitro and in vivo studies. In conclusion, Cur+Bai demonstrated an enhanced activity in attenuating endothelial dysfunction against oxidative damage and effectively protected vascular function in diabetic angiopathy rats.

Diabetes Physical Examination.

The physical examination of the patient with diabetes may have revealed findings that confirm the diagnosis, classify the type of diabetes, and begin to evaluate for the macro- and microvascular complications of diabetes and significant comorbid conditions. While screening for the diagnosis of diabetes occurs with assessment for abnormal blood glucose, given the high rates of morbidity and mortality associated with diabetes, utilization of the physical examination plays a key role in identifying patients at risk for the complications of diabetes. The discussion of elements of the physical examination relevant to the patient with diabetes, both type 1 and type 2, will be discussed in this article.

Endogenous Protective Factors and Potential Therapeutic Agents for Diabetes-Associated Atherosclerosis.

The complications of macrovascular atherosclerosis are the leading cause of disability and mortality in patients with diabetes. It is generally believed that the pathogenesis of diabetic vascular complications is initiated by the imbalance between injury and endogenous protective factors. Multiple endogenous protective factors secreted by endothelium, liver, skeletal muscle and other tissues are recognized of their importance in combating injury factors and maintaining the homeostasis of vasculatures in diabetes. Among them, glucagon-like peptide-1 based drugs were clinically proven to be effective and recommended as the first-line medicine for the treatment of type 2 diabetic patients with high risks or established arteriosclerotic cardiovascular disease (CVD). Some molecules such as irisin and lipoxins have recently been perceived as new protective factors on diabetic atherosclerosis, while the protective role of HDL has been reinterpreted since the failure of several clinical trials to raise HDL therapy on cardiovascular events. The current review aims to summarize systemic endogenous protective factors for diabetes-associated atherosclerosis and discuss their mechanisms and potential therapeutic strategy or their analogues. In particular, we focus on the existing barriers or obstacles that need to be overcome in developing new therapeutic approaches for macrovascular complications of diabetes.

Factores asociados al control óptimo simultáneo de la diabetes, hipertensión arterial e hipercolesterolemia en la población diabética. Estudio BPC diabetes / Factors associated with the optimum simultaneous control of diabetes, arterial hypertension and hypercholesterolemia in the diabetic population. BPC Diabetes study

Objetivos: Conocer el grado de control óptimo simultáneo de la diabetes (DM), hipertensión arterial (HTA) e hipercolesterolemia y determinar los factores asociados. Material y métodos: Estudio descriptivo transversal en pacientes diabéticos de 18 o más de edad, seleccionados consecutivamente en consultas de medicina de familia (MF). Los datos de los pacientes se obtuvieron mediante acceso a la historia informatizada, registrándose variables clínicas y analíticas de interés. Se consideró buen control metabólico una HbA1c < 7%, buen control de la presión arterial (PA) valores < 140/80 mmHg y buen control de colesterol LDL (c-LDL) valores < 100 mg/dL. Se realizó análisis bivariante y se calcularon odds ratio (OD) en un modelo de regresión logística. El estudio fue aprobado por el CEIm del Hospital Clínico San Carlos (Madrid). Resultados: Se incluyó a 1.420 pacientes (55,8% varones), con una edad media (DE) de 70,6 (10,8) años. El 75,9% eran hipertensos y el 69,1% dislipémicos. Los valores de HbA1c fueron de 6,9 (1,2) %, PA sistólica 135,0 (16,8) mmHg, PA diastólica 75,9 (10,6) mmHg y LDL-colesterol 93,7 (32,8) mg/dL. El buen control metabólico de la DM se alcanzó en el 63% (intervalo de confianza [IC] 95%: 60,4-65,5), el buen control de la HTA en el 42,6% (IC 95%: 40,0-45,2) y el buen control de colesterol LDL en el 61,1% (IC 95%: 58,4-63,7) de los pacientes. El buen control de los tres factores de riesgo cardiovascular (FRCV) simultáneamente se alcanzó en el 16,1% (IC 95%: 14,2-18,1). Se observó una asociación positiva e independiente (p < 0,05) entre el buen control simultáneo de los FRCV con la edad (OR: 1.017) y los antecedentes personales de enfermedad cardiovascular (OR: 1.596). Conclusiones: Los resultados de nuestro estudio indican que una proporción pequeña, menos de dos de cada 10 pacientes cumplen los objetivos de buen control recomendados por las guías de práctica clínica (AU)

Objectives: To know the degree of simultaneous optimal control of diabetes (DM), high blood pressure (BP) and hypercholesterolemia and determine the associated factors. Material and method: Cross-sectional descriptive study in diabetic patients 18 years aged or older selected consecutively in primary care centers (PC). Patient data were obtained through access to electronical clinical history. Clinical and analytical variables of interest were registered. Good metabolic control was considered as HbA1c < 7%, good blood pressure control (PA) as values < 140/80 mmHg and good LDL cholesterol control (c-LDL) as values < 100 mg/dL. Bivariate analysis was performed and odds ratio were calculated in a logistic regression model. The study was approved by the San Carlos Clinical Hospital's Clinical Research Ethics Committee (CREC), in Madrid. Results: 1420 patients (55.8% male), with an average (SD) age of 70.6 (10.8) years were included. 75.9% were hypertensive patients, and 69.1% dyslipemic. HbA1c values were 6.9 (1.2) %, sistolic BP 135.0 (16.8) mmHg, diastolic BP 75.9 (10.6) mmHg and LDL-cholesterol 93.7 (32.8) mg/dL. Good metabolic control of DM was achieved at 63.0% (95% CI: 60.4–65.5), good control of HTA at 42.6% (95% CI: 40.0–45.2) and good LDL cholesterol control in 61.1% (95% IC: 58.4–63.7) of patients. Good simultaneous control of the three cardiovascular risk factors (CVRF) was reached at 16.1% (95% CI: 14.2–18.1). A positive and independent association (p<0.05) was observed between good simultaneous control of CVRF with age (OR: 1.017) and with personal history of cardiovascular disease (OR: 1.596). Conclusions: The results of our study indicate that a small proportion, less than two out of 10 patients, meet the good control goals recommended by clinical practice guidelines. We found important differences between patients with and without cardiovascular disease (AU)

Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials.

As the worldwide prevalence of diabetes and obesity continues to rise, so does the risk of debilitating cardiovascular complications. Given the significant association between diabetes and cardiovascular risk, the actions of glucose-lowering therapies within the cardiovascular system must be clearly defined. Incretin hormones, including GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide), are gut hormones secreted in response to nutrient intake that maintain glycemic control by regulating insulin and glucagon release. GLP-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase 4 inhibitors (DPP-4is) represent two drug classes used for the treatment of type 2 diabetes mellitus (T2DM) that improve glucose regulation through stimulating the actions of gut-derived incretin hormones or inhibiting their degradation, respectively. Despite both classes acting to potentiate the incretin response, the potential cardioprotective benefits afforded by GLP-1Ras have not been recapitulated in cardiovascular outcome trials (CVOTs) evaluating DPP-4is. This review provides insights through discussion of clinical and preclinical studies to illuminate the physiological mechanisms that may underlie and reconcile observations from GLP-1Ra and DPP-4i CVOTs. Furthermore, critical knowledge gaps and areas for further investigation will be emphasized to guide future studies and, ultimately, facilitate improved clinical management of cardiovascular disease in T2DM.

The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). OBJECTIVES: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. METHODS: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. RESULTS: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002). CONCLUSIONS: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

Benefits and Risks Associated With Aspirin Use in Patients With Diabetes for the Primary Prevention of Cardiovascular Events and Mortality: A Meta-Analysis.

Purpose: A meta-analysis was conducted to assess the benefits and risks of aspirin for the primary prevention of cardiovascular disease and all-cause mortality events in adults with diabetes. Methods: An extensive and systematic search was conducted in MEDLINE (via PubMed), Cinahl (via Ebsco), Scopus, and Web of Sciences from 1988 to December 2020. A detailed literature search was conducted using aspirin, cardiovascular disease (CVD), diabetes, and efficacy to identify trials of patients with diabetes who received aspirin for primary prevention of CVD. Demographic details with the primary outcome of events and bleeding outcomes were analyzed. The Cochrane Collaboration's risk of bias tool was used to assess the methodological quality of the included studies. Random-effects meta-analysis was used to calculate the pooled odds ratio for outcomes of cardiovascular events, death, and adverse events. Findings: A total of 8 studies were included with 32,024 patients with diabetes; 16,001 allocated to aspirin, and 16,023 allocated to the control group. There was no difference between aspirin and control groups with respect to all-cause mortality, cardiovascular mortality, or bleeding events. However, MACE was significantly lower in the aspirin group. Implications: Although aspirin has no significant risk on primary endpoints of cardiovascular events and bleeding outcomes in patients with diabetes compared to control, major adverse cardiovascular events (MACE) were significantly lower in the aspirin group. Further research on the use of aspirin alone or in combination with other antiplatelet drugs is required in patients with diabetes to supplement currently available research. Systematic Review Registration: identifier [XU#/IRB/2020/1005].

Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging.

Vascular aging is characterized by alterations in the constitutive properties and biological functions of the blood vessel wall. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are indispensability elements in the inner layer and the medial layer of the blood vessel wall, respectively. Dipeptidyl peptidase-4 (DPP4) inhibitors, as a hypoglycemic agent, play a protective role in reversing vascular aging regardless of their effects in meliorating glycemic control in humans and animal models of type 2 diabetes mellitus (T2DM) through complex cellular mechanisms, including improving EC dysfunction, promoting EC proliferation and migration, alleviating EC senescence, obstructing EC apoptosis, suppressing the proliferation and migration of VSMCs, increasing circulating endothelial progenitor cell (EPC) levels, and preventing the infiltration of mononuclear macrophages. All of these showed that DPP4 inhibitors may exert a positive effect against vascular aging, thereby preventing vascular aging-related diseases. In the current review, we will summarize the cellular mechanism of DPP4 inhibitors regulating vascular aging; moreover, we also intend to compile the roles and the promising therapeutic application of DPP4 inhibitors in vascular aging-related diseases.

The Protective Effect of Metformin on Abdominal Aortic Aneurysm: A Systematic Review and Meta-Analysis.

Background: Type 2 diabetes mellitus (T2DM) patients have a lower risk of abdominal aortic aneurysm (AAA) and its comorbidities, which might be associated with the usage of metformin. The objective of the study was to evaluate the role of metformin in the process of AAA development. Method: PubMed, Embase and Cochrane Library were searched up to May 15th, 2021. We implemented several methods including the risk of bias graph, GRADE system and funnel plot to assess the quality and possible bias of this study. Subgroup analysis and sensitivity analysis were applied to address quality differences and validate the robustness of the final results. Result: Ten articles were enrolled after screening 151 articles searched from databases. The pooled results showed that, compared with T2DM patients without metformin, metformin prescription was associated with a slower annual growth rate of the aneurysm (mean difference (MD) -0.67 cm [95% confidence interval (CI) -1.20 ~ -0.15 cm]). Besides, metformin exposure was associated with a lower frequency of AAA events (odds ratio (OR) 0.61 [95% CI 0.41-0.92]). Conclusion: Metformin alleviated both annual expansion rate and aneurysm rupture frequency in AAA patients with T2DM. Systematic Review Registration: PROSPERO, identifier https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=217859 (CRD42020217859).

Optimal glycaemic and blood pressure but not lipid targets are related to a lower prevalence of diabetic microvascular complications.

BACKGROUND: Diabetic microvascular complications are a major cause of morbidity and are related to glycaemic control and cardiovascular risk factors. AIMS: We sought to determine the association of microvascular complications in relation to control of glycemia, blood pressure and lipids in T2DM patients attending secondary care in Qatar. METHODS: This is a cross-sectional study undertaken in patients with T2DM attending Qatar's National Diabetes Centres. Patients underwent assessment of glycemia, blood pressure and lipids and prevalence of diabetic peripheral neuropathy (DPN), retinopathy and microalbuminuria. RESULTS: We included 1114 subjects aged 52.1 ± 11.3 years with a duration of diabetes 10.0 ± 7.6 years and had a prevalence of 25.8% for DPN, 34.3% for painful DPN, 36.8% for microalbuminuria and 25.1% for retinopathy. Patients who achieved an HbA1c ≤ 7.0% compared to >7% had a significantly lower prevalence of DPN (P < 0.01), painful DPN (P < 0.01), retinopathy (P < 0.01) and microalbuminuria (P < 0.007). Patients who achieved a systolic BP ≤ 140 mmHg compared to >140 mmHg had a significantly lower prevalence of DPN (P < 0.001), painful DPN (P < 0.001), retinopathy (P < 0.001) and microalbuminuria (P < 0.001). Patients who achieved an LDL ≤2.6 mmol/l compared to >2.6 mmol/l had a significantly higher prevalence of DPN (P < 0.03), but no difference in other outcomes. There was no difference in microvascular complications between those who achieved a HDL-C ≥ 1.02 mmol/l, and among those who achieved triglycerides ≤1.7 mmol/l. CONCLUSIONS: Optimal control of glycemia and blood pressure, but not lipids is associated with a lower prevalence of diabetic microvascular complications.

Effects of three types of bariatric interventions on myocardial infarct size and vascular function in rats with type 2 diabetes mellitus.

AIMS: The effects of three types of bariatric interventions on myocardial infarct size were tested in the rat model of type 2 diabetes mellitus (T2DM). We also evaluated the effects of bariatric surgery on no-reflow phenomenon and vascular dysfunction caused by T2DM. MAIN METHODS: Rats with T2DM were assigned into groups: without surgery, sham-operated, ileal transposition, Roux-en-Y gastric bypass, and sleeve gastrectomy. Oral glucose tolerance, glucagon-like peptide-1, and insulin levels were measured. Six weeks after surgery, the animals were subjected to myocardial ischemia-reperfusion followed by histochemical determination of infarct size (IS), no-reflow zone, and blood stasis area size. Vascular dysfunction was characterized using wire myography. KEY FINDINGS: All bariatric surgery types caused significant reductions in animal body weight and resulted in T2DM compensation. All bariatric interventions partially normalized glucagon-like peptide-1 responses attenuated by T2DM. IS was significantly smaller in animals with T2DM. Bariatric surgery provided no additional IS limitation compared with T2DM alone. Bariatric surgeries reversed T2DM-induced enhanced contractile responses of the mesenteric artery to 5-hydroxytryptamine. Sleeve gastrectomy normalized decreased nitric oxide synthase contribution to the endothelium-dependent vasodilatation in T2DM. SIGNIFICANCE: T2DM resulted in a reduction of infarct size and no-reflow zone size. Bariatric surgery provided no additional infarct-limiting effect, but it normalized T2DM-induced augmented vascular contractility and reversed decreased contribution of nitric oxide to endothelium-dependent vasodilatation typical of T2DM. All taken together, we suggest that this type of surgery may have a beneficial effect on T2DM-induced cardiovascular diseases.

A Comprehensive Cardiovascular-Renal-Metabolic Risk Reduction Approach to Patients with Type 2 Diabetes Mellitus.

Despite decades of research into risk-reduction strategies, cardiovascular disease and renal disease remain leading causes of morbidity and mortality among patients with type 2 diabetes mellitus. Given the tight clustering of cardiovascular and renal disease with the metabolic abnormalities of type 2 diabetes mellitus, we can think of these conditions together as cardiovascular-renal-metabolic disease states. A holistic view of cardiovascular-renal-metabolic disease states is critical to provide integrated patient-centered care to individuals with these disease states. Here, we explore the cardiovascular and renal risks associated with type 2 diabetes mellitus and highlight the importance of reducing cardiovascular-renal-metabolic disease risk in a comprehensive manner. We advocate a cross-disciplinary, team-based model to manage cardiovascular-renal-metabolic disease risk among patients with type 2 diabetes mellitus.

Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction.

AIMS/HYPOTHESIS: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage. METHODS: The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis. RESULTS: IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression. CONCLUSIONS/INTERPRETATION: Taken together, activation of SIRT1 signalling by IF or through pharmacological activation represents an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimens and prevention of microvascular and bone marrow dysfunction in diabetes.