scholarly journals The BET protein inhibitor apabetalone (RVX-208) restores angiogenic response in type 1 and type 2 diabetes by transcriptional regulation of thrombospondin-1

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Mohammed ◽  
M A Mattia ◽  
G K Gergely ◽  
G S Gaia ◽  
S A Ambrosini ◽  
...  

Abstract Background Peripheral artery disease (PAD) is highly prevalent in people with type 2 diabetes and associates with chronic limb ischemia and poor prognosis. Understanding the mechanisms of impaired blood vessel growth in diabetic patients is of paramount importance to develop new angiogenic therapies in this setting. Dysregulation of epigenetic mechanisms of gene transcription in vascular cells contributes to cardiovascular disease development but is currently not targeted by therapies. Apabetalone (RVX-208) – an FDA approved small molecule inhibitor of the epigenetic readers bromodomain and extra-terminal (BET) proteins – has recently shown to modulate transcriptional programs implicated in vascular inflammation and atherosclerosis. Purpose To investigate RVX-208 effects in modulating angiogenic response and post-ischemic vascularization in diabetes. Methods Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 20 mM) for 48 hours in presence of RVX-208 (20μM) or vehicle (DMSO). Scratch and tube formation assays were performed to investigate the impact of RVX-208 on angiogenic properties of HAECs. T1D mice (streptozotocin-induced diabetes) and T2D mice (Lepdb/db) were orally treated with apabetalone or vehicle for 5 days. Hindlimb ischemia was induced in T1D mice & blood flow recovery analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Sprouting and matrigel plug assays were performed in Lepdb/db mice. Gastrocnemius muscle samples from patients with and without T2D were employed to translate our experimental findings. Results HG impaired HAECs migration and tube formation as compared to NG, whereas treatment with RVX-208 rescued HG-induced impairment of angiogenic properties. Real time PCR arrays in HG-treated HAECs showed that RVX-208 treatment prevents the dysregulation of genes implicated in endothelial migration, sprouting and inflammation, namely the anti-angiogenic molecule thrombospondin (THBS1), VEGF-A, IL-1β, IL-6, VCAM-1, and CXCL1. Of interest, both gene silencing of BET protein (BRD4) or its pharmacological inhibition by RVX-208 reduced THBS1 expression while restoring VEGFA levels in HG-treated HAECs. ChIP assays showed the enrichment of both BRD4 and the active chromatin mark H3K27Ac on THBS1 promoter. Mechanistic experiments uncovered the inhibitory role of THBS1 on VEGFA signalling, as also confirmed by STRING analysis. Treatment of T1D mice with RVX-208 improved blood flow reperfusion and vascular density at 14 days as compared to vehicle-treated animals. Moreover, RVX-208 restored endothelial sprouting in T2D-Lepdb/db mice. Of clinical relevance, THBS1 was upregulated while VEGFA expression was reduced in gastrocnemius muscle specimens from T2D patients with PAD as compared to non-diabetic controls. Conclusion In vivo targeting of BET-proteins by RVX-208 may represents a novel therapeutic approach to boost post-ischemic neovascularization in diabetes. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.A Mohammed ◽  
S Costantino ◽  
A Akhmedov ◽  
G Karsai ◽  
S Ambrosini ◽  
...  

Abstract Background Despite advances in revascularization strategies, type 2 diabetic (T2D) patients with peripheral artery disease (PAD) continue to have a high risk of limb amputation. Modulation of blood vessel growth holds great promise for the treatment of PAD patients. Epigenetic modifications, namely histone post-translational modifications, have shown to regulate transcriptional programs implicated in the pathogenesis of cardiovascular disease. Aim To investigate the role of chromatin changes in regulating post-ischemic vascularization in experimental diabetes as well as in patients with T2D. Methods Experiments were performed in primary human aortic endothelial cells (HAECs), double-mutant leptin deficient mice (Lepdb/db) carrying a genetic deletion of the methyltransferase SETD7 (Setd7−/−Lepdb/db) as well as in gastrocnemius muscle samples from T2D patients with PAD and age-matched non-diabetic controls. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). Pharmacological blockade of SETD7 was performed by using the selective inhibitor (R)-PFI-2. Scratch and tube formation assays were performed to investigate the impact of SETD7 on angiogenic response. Results RNA-seq in high glucose-treated HAECs revealed a profound upregulation of the methyltransferase SETD7 (fold change 2.8, p<0.001), an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and Chromatin Immunoprecipitation (ChIP) assays showed that SETD7-dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G). Increased SEMA-3G transcript was associated with enhanced secretion from HAECs. Co-immunofluorescence experiments showed that SEMA-3G blunts the angiogenic response by competing with VEGF receptors VEGFR/Neuropillin2. Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. SETD7 and SEMA-3G were significantly upregulated in endothelial cells from Lepdb/db mice, whereas SEMA-3G transcription was blunted in Setd7−/−Lepdb/db animals. Consistently, endothelial sprouting was defective in aortas from Lepdb/db as compared to WT mice, whereas Setd7−/−Lepdb/db mice displayed a preserved angiogenic response. Of clinical relevance, SETD7/SEMA-3G axis was upregulated in gastrocnemius muscle specimens from T2D patients with PAD as compared with non-diabetic controls. Conclusion In HAECs, genetically modified mice and T2D patients we show that SETD7-dependent chromatin changes regulate SEMA-3G transcription and angiogenic response. Pharmacological inhibition of SETD7 may represent a novel epigenetic therapy to boost neovascularization in T2D patients with PAD. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Zurich/Universitätsspital Zürich


Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 2123
Author(s):  
Daniela Pollakova ◽  
Aikaterini Andreadi ◽  
Francesca Pacifici ◽  
David Della-Morte ◽  
Davide Lauro ◽  
...  

A protective effect of vegan diets on health outcomes has been observed in previous studies, but its impact on diabetes is still debated. The aim of this review is to assess the relationship between vegan diets and the risk for type 2 diabetes (T2D) along with its effect on glycemic control and diabetes-related complications. In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta–Analyses) guidelines, Pubmed and Cochrane library databases were systematically searched for all relevant studies. Seven observational and eight randomized controlled (RCTs) studies were included. The methodological quality of studies was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies and the Cochrane Risk of Bias Tool for RCTs. We found that a vegan diet is associated with lower T2D prevalence or incidence and in T2D patients decreases high glucose values and improves glucose homeostasis, as reported from the majority of included studies. This approach seems to be comparable to other recommended healthful eating models, but as it may have potential adverse effects associated with the long-term exclusion of some nutrients, appropriate nutritional planning and surveillance are recommended, particularly in specific groups of diabetic patients such as frail elderly, adolescents, and pregnant or breastfeeding women.


2021 ◽  
Vol 24 (1) ◽  
pp. 32-44
Author(s):  
T. A. Zelenina ◽  
V. V. Salukhov ◽  
A. B. Zemlianoi ◽  
S. G. Zheleznjak ◽  
O. A. Klitsenko

BACKGROUND: Diabetic autonomic neuropathy is the reason for early morbidity and mortality on diabetic patients. The pathology not only cardiac innervation but microvascular is presented.AIMS: We estimated the parameters of skin microvascular blood flow in accordance with cardiovascular autonomic neuropathy (CAN) staging in diabetic patients. We also assessed other risk factors of CAN in patients with diabetes.MATERIALS AND METHODS: We included 76 patients with type 2 diabetes in the study (24 patients with resent-onset diabetes and/or diabetes without microvascular complications, 26 with diabetic sensorimotor neuropathy (SMN) and 26 with SMN and previous history of diabetic foot amputation). The SMN was diagnosed on the basis of patients complaints, anamnesis and data of clinical neurological examinations. CAN was detected using several cardiovascular autonomic reflex tests (CART) as a gold standard of diagnosis: the tilt-table test, a deepbreathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction. According to the Toronto Diabetic Neuropathy Expert Group Recommendation all patients was separated on the groups: CAN 0 (all CARTs were normal), CAN 1 (possible/early CAN — one abnormal CART was presented), CAN 2 (definite/confirmed CAN –at least two abnormal CARTs were found), CAN 3 (severe/advanced CAN — in the cases of orthostatic hypotension in addition to CARTs abnormalities). Microvascular blood flow of skin at the nail roller of fingers skin was valuated at rest as well as in functional cold test by the method of High-frequency Ultrasonic Dopplerography using the “Minimax Doppler K” device (LLC JV “Minimax”, St. Petersburg, Russia).RESULTS: CAN 1 was found in 8% diabetic patients without microvascular complications, 42 and 21% patients with SMN and diabetic foot amputations respectively. CAN 2 was diagnosed in 27% patients with SMN and 58% patients history of diabetic foot amputations. CAN 3 in 8% and 19% cases in patients with SMN and history of diabetic foot amputations respectively. The parameters of microvascular blood flow at rest were significantly decreased in patients with confirmed/severe CAN in comparison with early staging of CAN and patients without CAN (Vm=2.5±0.66 sm/sec vs. 4.4±0.54 sm/sec and 5.1±1.01 sm/sec respectively; p=0.0033). The abnormal result of cold test was detected in 94% patients with confirmed/ severe CAN and 26% patients with CAN 1.CONCLUSIONS: This investigation has demonstrated in a cohort with type 2 diabetes patients with/without SMN and with/ without history of previously foot amputations that decrease the Vm (the variable of microvascular blood flow assessed by High-frequency Ultrasonic Dopplerography) lower than 2.4 sm/sec is associated with 6.4 times increased likelihood of confirmed/severe CAN as well as positive cold test result. That the patients with positive cold test results were 28.6 times more likely have confirmed/severe CAN.


Author(s):  
S. Pavithra ◽  
S. Lavanya ◽  
P. Vaishnavi ◽  
A. Rakesh Rosario ◽  
Priyadharshini A ◽  
...  

COVID-19 is a pathogenic virus that caused a pandemic outbreak in December 2019. The impact of this virus may be severe in the patients having co-morbidities like diabetes, hypertension, Chronic Kidney Disease, cardiovascular disease, etc. Aim and Objectives: This study Aims in Assessing the impact of COVID-19 on Diabetic and Hypertensive patients as well as COVID-19 patients without any co-morbidities. Objective of this is to evaluate the association between COVID-19 and its risk factors (diabetes and hypertension) and to evaluate whether the severity of the symptoms in COVID-19 patients is due to comorbidities or past medications. Methodology: A Retrospective study was conducted in SRM Hospital (Medical Records Department) for a period of 3 Months with the study population 670 at the age group of 25, known case of Diabetes and Hypertension. Cases of Pregnant women are excluded from the study. The patients were grouped into 4 categories 1) control group (patient without any co-morbidities) 2) diabetic patients 3) Hypertensive patient 4) Diabetic+Hypertension patient and studied their prescribing pattern by collecting the past medication history. Results and Discussion: There is a significant decrease in a lymphocyte in covid-19 Type 2 diabetic patients in our study. These results suggest that different mechanism exists for hypertension and diabetes mellitus as risk factors for covid-19. It is also known that these patients have impaired immune response to many infections [30]. In our retrospective study, we collected 670 covid-19 cases. It consists of 12.5% of diabetic patients and 6.6% of hypertensive patients. This study compared COVID-19 patients without any comorbidity (neither Type 2 diabetes mellitus nor hypertension) with covid- 19 patients with comorbidities (Type 2 diabetes mellitus and hypertension). COVID-19 patients with T2DM have an increased level of D-dimer compared to non-T2DM patients. Conclusion: Diabetic and hypertensive patients affected with COVID-19 are low in our study. Out of the total study population, only 12.5% are diabetic, 6.56% are hypertensive, and 9.25% were both diabetic and hypertensive. But when comparing in terms of severity, hypertensive and diabetic patients have severe effects than the control patients. In simpler terms, not every person who has diabetes and hypertension are affected with COVID-19, but those who were affected by COVID-19 showed more severity than the patients who don't have any comorbidities


2020 ◽  
Author(s):  
Robert Mutagwanya ◽  
Christine Magala Nyago ◽  
Fredrick Nelson Nakwagala

Abstract Background: Consumption of a varied diet reduces the risk of developing a deficiency or excess of any one nutrient. One of the three corner stones of diabetes management is diet and therefore, dietary diversity is key among diabetes patients. Objective: The objective of this study was to establish the impact of nutrition education on the dietary diversity scores (DDS) among type 2 diabetes patients. Methods: Kant et al method was used for scoring dietary diversity. Data were analyzed using the statistical package for social sciences (SPSS version 21). Pair sample t-test was used to compare total DDS after and before nutrition education. P< 0.05 was considered as statistically significant.Subjects: One hundred type 2 diabetic patients were randomly selected and divided into two groups of intervention and control (50 patients in each group) to participate in the study. Data were collected using a pre-tested questionnaire before and after intervention every after one month for a period of four months of intervention.Results: The average age of patients who participated in the study was 48 (40–51) years. Most of the patients were females (65.39%), compared to males (34.01%). At the end of the study period of four months, DDS in the control group decreased from 40.08% to 38.49% (p=0.064) while in the intervention group, DDS increased from 35.30 % to 54.20% (p<0.001). Conclusion: Dietary diversity increased after nutrition education among type 2 diabetes patients.Trial registration: The study was registered and approved on 17th April 2013 by the Research and Ethics committee of Mulago Hospital and Institutional Review Board of Mulago hospital (Protocol MREC 113).


PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254980
Author(s):  
Tsuneaki Omae ◽  
Youngseok Song ◽  
Takafumi Yoshioka ◽  
Tomofumi Tani ◽  
Akitoshi Yoshida

This study aimed to evaluate whether long-term insulin treatment is associated with abnormalities in retinal circulation in type 2 diabetic patients. We evaluated 19 eyes of nondiabetic individuals and 68 eyes of type 2 diabetic patients. The eyes of diabetic patients were classified into two groups according to the presence or absence of long-term insulin therapy. We used a Doppler optical coherence tomography flowmeter to measure diameter, velocity, and blood flow in the major temporal retinal artery. The pulsatility ratio (PR) and resistance index (RI), indices of vascular rigidity, were calculated from the blood velocity profile. PR and RI were significantly elevated in type 2 diabetic patients compared with nondiabetic subjects (P < 0.05). In type 2 diabetes patients, PR and RI were significantly higher in patients receiving long-term insulin treatment than in those without (P < 0.01). There was a significant difference in velocity (P < 0.05), but not diameter and blood flow, between nondiabetic subjects and type 2 diabetes patients. No significant difference in diameter, velocity, or blood flow was observed between the groups with and without long-term insulin treatment. Long-term insulin treatment can affect PR and RI, which might be associated with vascular rigidity of the retinal artery in patients with type 2 diabetes.


Author(s):  
Jeung-Hee Kim ◽  
Weon-Young Lee ◽  
Song Soo Lim ◽  
Young Taek Kim ◽  
Yeon-Pyo Hong

Previous studies have analyzed the impact of diabetes mellitus on labor market participation by men and women, but gender difference between type 2 diabetes mellitus (T2DM) and employment has not been the focus. This study aims to explore gender differences between T2DM and employment status. Data from the Korea Health Panel Study, 2013–2015 were analyzed by distinguishingT2DM and non-diabetes (N = 11,216). The empirical model was established and the generalized two-stage least squares (2SLS) was estimated, controlling for endogeneity. A family history of diabetes, as an instrumental variable, was related to an individual’s genetic predisposition to develop diabetes. The estimated results for the 2SLS showed the interaction effects between T2DM and employment. T2DM had a statistically significant and negative effect on employment for women only. The comparison with non-diabetes showed that women with T2DM had a lower probability of employment by 51.9% (p < 0.05). Exposing gender bias in employment suggests that healthcare policies and disease management programs for diabetic patients should adopt gender-specific remedies.


2002 ◽  
Vol 283 (2) ◽  
pp. H557-H561 ◽  
Author(s):  
Miyoko Komatsu ◽  
Takahiko Kawagishi ◽  
Masanori Emoto ◽  
Tetsuo Shoji ◽  
Atsuko Yamada ◽  
...  

The association between endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphism and vascular endothelial function has not been clarified. We investigated the impact of ecNOS gene polymorphism on endothelial function in 95 patients with Type 2 diabetes (ecNOS genotype: 4b/b, n= 62; 4b/a, n = 30; 4a/a, n = 3). Flow-mediated (endothelium dependent, FMD) and nitroglycerin-induced (endothelium independent, NTG) vasodilations of the right brachial artery were studied using a phase-locked echotracking system. There were no significant differences in clinical characteristics among the ecNOS genotypes. The FMD was significantly lower in the patients with ecNOS4a allele than in those without ecNOS4a allele ( P< 0.05). Multiple regression analysis showed that ecNOS4a allele and mean blood pressure were significant independent determinants for reduced FMD in all patients ( R2 = 0.122, P = 0.0025). The ecNOS4a allele was an independent determinant for reduced FMD in smokers but not in nonsmokers. These results suggest that ecNOS4a allele is a genetic risk factor for endothelial dysfunction in diabetic patients, especially in smokers.


2020 ◽  
Author(s):  
Inass Hassan Ahmad ◽  
Mervat El Shahat El Wakeel ◽  
Sally Said Abd Elhamed ◽  
Marwa Abdelmonim Mohammed ◽  
Basma Elnagger ◽  
...  

Abstract Background In the present study, our goal was to assess the impact of type 2 diabetes mellites (T2DM) on osteoporosis markers (sclerostin and CTRP3) among postmenopausal women, and whether sclerostin and CTRP3 can be used as early biomarkers of osteoporosis/osteopenia in T2DM patients. Methods In a comparative, observation, study, a total of 30 postmenopausal women with osteoporosis/osteopenia and T2DM were included, as well as 30 non-diabetic women with osteoporosis/osteopenia. Thirty age and sex-matched healthy women were included as control groups. The enzyme-linked immunosorbent assay (ELISA) was used to assess the serum levels of sclerostin and CTRP3. Results A total of 90 women were included in the present study (30 patients per group). The serum CTRP3 was significantly lower in the DM-OST (3.45 ± 3.5 ng/dL) and OST (9.15 ± 3.65 ng/dL) groups than the control group (16.80 ± 0.55 ng/dL; p < 0.001); likewise, the serum sclerostin was higher in the DM-OST (109.95 ± 28.96 pmol/L) and OST (51.52 ± 23.18 pmol/L) than the control group (11.22 ± 1.21 pmol/L; p < 0.001). Notably, the serum CTRP3 was significantly lower and sclerostin was significantly higher in the DM-OST group than the OST group (p < 0.001)). In the DM + OST and OST groups, the serum CTRP3 correlated positively with BMD of lumbar spines, left femur, and left forearm. Serum CTRP3 was associated with lower risk of osteoporosis (OR) and diabetes (OR) in postmenopausal women. In addition, the serum sclerostin was associated with higher risk of osteoporosis (OR) and diabetes (OR) in postmenopausal women. Conclusion The present study provides a novel evidence about the impact of T2DM on osteoporosis biomarkers, serum CTRP3 and sclerostin. The results indicated that women with combined T2DM and osteoporosis/osteopenia exhibited more dysregulation in both biomarkers than women with osteoporosis/osteopenia. alone. Thus, serum CTRP3 and sclerostin can be used as biomarkers for early detection of osteoporosis in diabetic patients.


2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Jawaher Masmoudi ◽  
Rahma Damak ◽  
Hela Zouari ◽  
Uta Ouali ◽  
Anouar Mechri ◽  
...  

Objectives. To estimate the prevalence of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) in a population aged over sixty years with type 2 diabetes and to study the impact of anxiety and depression on glycemic balance and disease outcome.Results. The prevalence of anxiety and depression in the 62 subjects included in the study was, respectively, 40.3% and 22.6%. We found a relationship between these disorders and complicated diabetes. The subjects having an imperfectly balanced diabetes had a higher average anxiety score than those having a good glycemic control ( versus ; ). No relationship was found between diabetes balance and depression.Conclusion. Association between anxiety and depressive disorders and diabetes is frequent and worsens patients’ outcome, in terms of diabetes imbalance as well as in terms of diabetic complications. Our study shows that there is need for physicians to detect, confirm, and treat anxiety and depressive disorders in elderly diabetic patients.


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