-
Cardiovascular Diabetology Feb 2024Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis,... (Review)
Review
Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.
Topics: Humans; COVID-19; Post-Acute COVID-19 Syndrome; Pandemics; SARS-CoV-2; Thrombophilia; Thrombosis; Diabetes Mellitus; Endothelium
PubMed: 38378550
DOI: 10.1186/s12933-023-02097-8 -
Frontiers in Endocrinology 2023
Topics: Humans; Diabetes Mellitus; Phenotype; Cellular Senescence
PubMed: 38164496
DOI: 10.3389/fendo.2023.1345529 -
Diabetologia Jan 2024The identification of people who are at high risk of developing type 2 diabetes is a key part of population-level prevention strategies. Previous studies have evaluated...
AIMS/HYPOTHESIS
The identification of people who are at high risk of developing type 2 diabetes is a key part of population-level prevention strategies. Previous studies have evaluated the predictive utility of omics measurements, such as metabolites, proteins or polygenic scores, but have considered these separately. The improvement that combined omics biomarkers can provide over and above current clinical standard models is unclear. The aim of this study was to test the predictive performance of genome, proteome, metabolome and clinical biomarkers when added to established clinical prediction models for type 2 diabetes.
METHODS
We developed sparse interpretable prediction models in a prospective, nested type 2 diabetes case-cohort study (N=1105, incident type 2 diabetes cases=375) with 10,792 person-years of follow-up, selecting from 5759 features across the genome, proteome, metabolome and clinical biomarkers using least absolute shrinkage and selection operator (LASSO) regression. We compared the predictive performance of omics-derived predictors with a clinical model including the variables from the Cambridge Diabetes Risk Score and HbA.
RESULTS
Among single omics prediction models that did not include clinical risk factors, the top ten proteins alone achieved the highest performance (concordance index [C index]=0.82 [95% CI 0.75, 0.88]), suggesting the proteome as the most informative single omic layer in the absence of clinical information. However, the largest improvement in prediction of type 2 diabetes incidence over and above the clinical model was achieved by the top ten features across several omic layers (C index=0.87 [95% CI 0.82, 0.92], Δ C index=0.05, p=0.045). This improvement by the top ten omic features was also evident in individuals with HbA <42 mmol/mol (6.0%), the threshold for prediabetes (C index=0.84 [95% CI 0.77, 0.90], Δ C index=0.07, p=0.03), the group in whom prediction would be most useful since they are not targeted for preventative interventions by current clinical guidelines. In this subgroup, the type 2 diabetes polygenic risk score was the major contributor to the improvement in prediction, and achieved a comparable improvement in performance when added onto the clinical model alone (C index=0.83 [95% CI 0.75, 0.90], Δ C index=0.06, p=0.002). However, compared with those with prediabetes, individuals at high polygenic risk in this group had only around half the absolute risk for type 2 diabetes over a 20 year period.
CONCLUSIONS/INTERPRETATION
Omic approaches provided marginal improvements in prediction of incident type 2 diabetes. However, while a polygenic risk score does improve prediction in people with an HbA in the normoglycaemic range, the group in whom prediction would be most useful, even individuals with a high polygenic burden in that subgroup had a low absolute type 2 diabetes risk. This suggests a limited feasibility of implementing targeted population-based genetic screening for preventative interventions.
Topics: Humans; Diabetes Mellitus, Type 2; Prediabetic State; Prospective Studies; Cohort Studies; Proteome; Multiomics; Risk Factors; Biomarkers
PubMed: 37889320
DOI: 10.1007/s00125-023-06027-x -
ELife Jul 2023Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures...
Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.
Topics: Mice; Animals; Metformin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Bony Callus; Osteogenesis; Fractures, Bone; Mesenchymal Stem Cells
PubMed: 37417730
DOI: 10.7554/eLife.88310 -
Biomedicine & Pharmacotherapy =... Dec 2023The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD)...
The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D-FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7-10 animals per group). After 6 weeks, D and D-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D-FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D-FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFβ) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis.
Topics: Humans; Rats; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Pulse Wave Analysis; Rats, Wistar; Kidney; Renal Insufficiency, Chronic
PubMed: 37832406
DOI: 10.1016/j.biopha.2023.115661 -
Cardiovascular Diabetology Feb 2024Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a... (Review)
Review
Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population.
Topics: Humans; Female; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Heart Failure; Glucose
PubMed: 38347569
DOI: 10.1186/s12933-024-02136-y -
Life Sciences Sep 2023Vascular endothelial dysfunction (VED) is the onset event of cardiovascular complications in type 2 diabetes mellitus. Ginsenoside Rg1 (Rg1) can improve the...
AIMS
Vascular endothelial dysfunction (VED) is the onset event of cardiovascular complications in type 2 diabetes mellitus. Ginsenoside Rg1 (Rg1) can improve the cardiovascular system, but its mechanism in diabetic vascular endothelial dysfunction has received little attention.
MAIN METHODS
Male calpain-1-knockout and wild-type C57BL/6 J mice were intraperitoneally injected with streptozotocin and treated with Rg1 (10 and 20 mg/kg) for 8 weeks. Human aortic endothelial cells (HAECs) were incubated with high glucose (HG) and were pretreated with Rg1 (10, 20 μM), MDL-28170 (calpain-1 inhibitor), LY-333531 (PKC-β inhibitor), NAC (ROS inhibitor) and calpain-1 overexpression. Then, factors related to mitochondrial dysfunction, oxidative stress and VED were measured.
KEY FINDINGS
The administration of Rg1 and calpain-1 knockout ameliorated diabetic mitochondrial dysfunction, oxidative stress and VED and inhibited the calpain-1/ROS/PKC-β axis. LY-333531 and NAC treatment restored destructive endothelium-dependent vasodilation in mice with diabetes, while pyrogallol (ROS agonist), PMA (PKC-β agonist) or L-NAME (eNOS inhibitor) treatment abrogated the protective effect of Rg1 against diabetic endothelial dysfunction. The administration of Rg1, MDL-28170, LY-333531 and NAC improved mitochondrial dysfunction, oxidative stress and VED, whereas the overexpression of calpain-1 amplified mitochondrial dysfunction, oxidative stress and VED and further upregulated the expression of PKC-β in HAECs exposed to HG. Overexpression of calpain-1 abrogated the protective effect of Rg1 against HG-induced oxidative stress and VED.
SIGNIFICANCE
These findings reveal that Rg1 can protect against VED by suppressing the calpain-1/ROS/PKC-β axis and alleviating the development of mitochondrial dysfunction and oxidative stress.
Topics: Mice; Male; Humans; Animals; Reactive Oxygen Species; Calpain; Endothelial Cells; Diabetes Mellitus, Type 2; Endothelium, Vascular; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Vascular Diseases; Oxidative Stress
PubMed: 37482213
DOI: 10.1016/j.lfs.2023.121972 -
Cancer Reports (Hoboken, N.J.) Mar 2024The objective of this study is to investigate the influence of diabetes on breast cancer-specific survival among women with breast cancer in Aotearoa/New Zealand.
OBJECTIVES
The objective of this study is to investigate the influence of diabetes on breast cancer-specific survival among women with breast cancer in Aotearoa/New Zealand.
METHODS
This study included women diagnosed with invasive breast cancer between 2005 and 2020, with their information documented in the Te Rēhita Mate Ūtaetae-Breast Cancer Foundation National Register. Breast cancer survival curves for women with diabetes and those without diabetes were generated using the Kaplan-Meier method. The hazard ratio (HR) of breast cancer-specific mortality for women with diabetes compared to women without diabetes was estimated using the Cox proportional hazards model.
RESULTS
For women with diabetes, the 5-year and 10-year of cancer-specific survival were 87% (95% CI: 85%-88%) and 79% (95% CI: 76%-81%) compared to 89% (95% CI: 89%-90%) and 84% (95% CI: 83%-85%) for women without diabetes. The HR of cancer-specific mortality for patients with diabetes compared to those without diabetes was 0.99 (95% CI: 0.89-1.11) after adjustment for patient demographics, tumor characteristics, and treatments. Age at cancer diagnosis and cancer stage had the biggest impact on the survival difference between the two groups. When stratified by cancer stage, the cancer-specific mortality between the two groups was similar.
CONCLUSIONS
While differences in survival have been identified for women with diabetes when compared to women without diabetes, these are attributable to age and the finding that women with diabetes tend to present with more advanced disease at diagnosis. We did not find any difference in survival between the two groups due to differences in treatment.
Topics: Female; Humans; Breast Neoplasms; Diabetes Mellitus; Proportional Hazards Models; Neoplasm Staging; New Zealand
PubMed: 38507264
DOI: 10.1002/cnr2.2040 -
PloS One 2023Diabetes mellitus is a chronic metabolic health condition affecting millions globally. Diabetes is a growing concern among aging societies, with its prevalence... (Review)
Review
Diabetes mellitus is a chronic metabolic health condition affecting millions globally. Diabetes is a growing concern among aging societies, with its prevalence increasing among those aged 65 and above. Enabling disease self-management via relevant education is part of high-quality care to improve health outcomes and minimize complications for individuals living with diabetes. Successful diabetes self-management education (DSME) programs usually require tailoring for the intended audience; however, there is limited literature about the preferences of older persons in Western countries concerning DSME. As such, a broad overview of DSME for older persons was an identified need. To map the available evidence on DSME for persons aged 65 years and older in Western countries, the JBI methodology for conducting and reporting scoping reviews was used. In this scoping review, we considered all studies about DSME for older persons with T1D and T2D in Western countries where lifestyles, risks, prevention, treatment of diabetes, and approaches to self-management and DSME are similar (e.g., North America, Western and Northern Europe and Australasia). Systematic keyword and subject heading searches were conducted in 10 databases (e.g., MEDLINE, JBI EBP) to identify relevant English language papers published from 2000 to 2022. Titles and abstracts were screened to select eligible papers for full-text reading. Full-text screening was done by four independent reviewers to select studies for the final analysis. The review identified 2,397 studies, of which 1,250 full texts were screened for eligibility. Of the final 44 papers included in the review, only one included participants' understanding of DSME. The education programs differed in their context, design, delivery mode, theoretical underpinnings, and duration. Type of research designs, outcome measures used to determine the effectiveness of DSME, and knowledge gaps were also detailed. Overall, most interventions were effective and improved clinical and behavioural outcomes. Many of the programs led to improvements in clinical outcomes and participants' quality of life; however, the content needs to be adapted to older persons according to their culture, different degrees of health literacy, preference of education (e.g., individualized or group), preference of setting, degree of frailty and independence, and comorbidities. Few studies included the voices of older persons in the design, implementation, and evaluation of DSME programs. Such experiential knowledge is vital in developing educational programs to ensure alignment with this population's preferred learning styles, literacy levels, culture, and needs-such an approach could manifest more substantive, sustained results.
Topics: Humans; Aged; Aged, 80 and over; Quality of Life; Self-Management; Diabetes Mellitus; Educational Status; Health Behavior
PubMed: 37556399
DOI: 10.1371/journal.pone.0288797 -
Journal of Diabetes Research 2023
Topics: Humans; Oxidative Stress; Diabetes Mellitus, Type 2; Diabetes Mellitus; Antioxidants; Diabetes Complications
PubMed: 37546353
DOI: 10.1155/2023/9824864