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Nature Dec 2023People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown....
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Chromatin; Dendritic Cells; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Glucose; Histones; Hyperglycemia; Lung; T-Lymphocytes; Virus Diseases; Viruses; Disease Models, Animal; Humans
PubMed: 38093014
DOI: 10.1038/s41586-023-06803-0 -
Frontiers in Endocrinology 2023Worldwide, diabetes and its complications have seriously affected people's quality of life and become a serious public health problem. C-peptide is not only an indicator... (Review)
Review
Worldwide, diabetes and its complications have seriously affected people's quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic β-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance.
Topics: Animals; Humans; C-Peptide; Quality of Life; Diabetes Complications; Diabetes Mellitus
PubMed: 37745697
DOI: 10.3389/fendo.2023.1256093 -
Cardiovascular Diabetology Sep 2023Peripheral artery disease (PAD) is a major health problem with increased cardiovascular mortality, morbidity and disabling critical limb threatening ischemia (CLTI) and... (Review)
Review
Peripheral artery disease (PAD) is a major health problem with increased cardiovascular mortality, morbidity and disabling critical limb threatening ischemia (CLTI) and amputation. Diabetes mellitus (DM) and cigarette smoke are the main risk factors for the development of PAD. Although diabetes related PAD shows an accelerated course with worse outcome regarding complications, mortality and amputations compared with non-diabetic patients, current medical treatment does not make this distinction and includes standard antiplatelet and lipid lowering drugs for all patients with PAD. In this review we discuss the pathophysiologic mechanisms of PAD, with focus on differences in thrombo-inflammatory processes between diabetes-related and smoking-related PAD, and hypothesize on possible mechanisms for the progressive course of PAD in DM. Furthermore, we comment on current medical treatment and speculate on alternative medical drug options for patients with PAD and DM.
Topics: Humans; Peripheral Arterial Disease; Diabetic Angiopathies; Diabetic Neuropathies; Inflammation; Smoking; Diabetes Mellitus
PubMed: 37735399
DOI: 10.1186/s12933-023-01990-6 -
Frontiers in Endocrinology 2024Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes. The potential targets of renin-angiotensin-aldosterone system (RAAS) inhibitors for the...
Network pharmacology combined with Mendelian randomization analysis to identify the key targets of renin-angiotensin-aldosterone system inhibitors in the treatment of diabetic nephropathy.
BACKGROUND
Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes. The potential targets of renin-angiotensin-aldosterone system (RAAS) inhibitors for the treatment of DN need to be explored.
METHODS
The GSE96804 and GSE1009 datasets, 729 RAAS inhibitors-related targets and 6,039 DN-related genes were derived from the public database and overlapped with the differentially expressed genes (DN vs. normal) in GSE96804 to obtain the candidate targets. Next, key targets were screened via the Mendelian randomization analysis and expression analysis. The diagnostic nomogram was constructed and assessed in GSE96804. Additionally, enrichment analysis was conducted and a 'core active ingredient-key target-disease pathway' network was established. Finally, molecular docking was performed.
RESULTS
In total, 60 candidate targets were derived, in which and were screened as the key targets and had a causal association with DN as the protective factors ( < 0.05, OR < 1). Further, a nomogram exhibited pretty prediction efficiency. It is indicated that Benadryl hydrochloride might play a role in the DN by affecting the pathways of 'cytokine cytokine receptor interaction', etc. targeting the . Moreover, might be involved in 'ECM receptor interaction', etc. for the effect of NSAID, captopril, chlordiazepoxide on DN. Molecular docking analysis showed a good binding ability of benadryl hydrochloride and , NSAID and . , , and are causally associated with acute kidney injury.
CONCLUSION
and were identified as key targets for RAAS inhibitors in the treatment of DN, which might provide some clinical significance in helping to diagnose and treat DN. Among the targets of RAAS inhibitors, PTGS2, ITGA4 and ANPEP have a causal relationship with acute kidney injury, which is worthy of further clinical research.
Topics: Humans; Diabetic Nephropathies; Renin-Angiotensin System; Molecular Docking Simulation; Mendelian Randomization Analysis; Network Pharmacology; Cyclooxygenase 2; Acute Kidney Injury; Anti-Inflammatory Agents, Non-Steroidal; Diphenhydramine; Diabetes Mellitus
PubMed: 38332893
DOI: 10.3389/fendo.2024.1354950 -
Medicine Oct 2023Diabetes mellitus is a complex chronic metabolic disease characterized by hyperglycemia and various complications. According to the different pathophysiological... (Review)
Review
Diabetes mellitus is a complex chronic metabolic disease characterized by hyperglycemia and various complications. According to the different pathophysiological mechanisms, these complications can be classified as microvascular or macrovascular complications, which have long-term negative effects on vital organs such as the eyes, kidneys, heart, and brain, and lead to increased patient mortality. Diabetes mellitus is a major global health issue, and its incidence and prevalence have increased significantly in recent years. Moreover, the incidence is expected to continue to rise as more people adopt a Western lifestyle and diet. Thus, it is essential to understand the epidemiology, pathogenesis, risk factors, and treatment of vascular complications to aid patients in managing the disease effectively. This paper provides a comprehensive review of the literature to clarify the above content. Furthermore, this paper also delves into the correlation between novel risk factors, such as long noncoding RNAs, gut microbiota, and nonalcoholic fatty liver disease, with diabetic vascular complications.
Topics: Humans; Diabetes Mellitus; Diabetic Angiopathies; Risk Factors; Hyperglycemia; Cardiovascular Diseases
PubMed: 37800828
DOI: 10.1097/MD.0000000000035285 -
Frontiers in Endocrinology 2023As a metabolic disease, diabetes often leads to health complications such as heart failure, nephropathy, neurological disorders, and vision loss. Diabetic retinopathy...
INTRODUCTION
As a metabolic disease, diabetes often leads to health complications such as heart failure, nephropathy, neurological disorders, and vision loss. Diabetic retinopathy (DR) affects as many as 100 million people worldwide. The mechanism of DR is complex and known to impact both neural and vascular components in the retina. While recent advances in the field have identified major cellular signaling contributing to DR pathogenesis, little has been reported on the protein post-translational modifications (PTM) - known to define protein localization, function, and activity - in the diabetic retina overall. Protein glycosylation is the enzymatic addition of carbohydrates to proteins, which can influence many protein attributes including folding, stability, function, and subcellular localization. -linked glycosylation is the addition of sugars to an oxygen atom in amino acids with a free oxygen atom in their side chain (i.e., threonine, serine). To date, more than 100 congenital disorders of glycosylation have been described. However, no studies have identified the retinal -linked glycoproteome in health or disease. With a critical need to expedite the discovery of PTMomics in diabetic retinas, we identified both global changes in protein levels and the retinal -glycoproteome of control and diabetic mice.
METHODS
We used liquid chromatography/mass spectrometry-based proteomics and high throughput screening to identify proteins differentially expressed and proteins differentially -glycosylated in the retinas of wildtype and diabetic mice.
RESULTS
Changes in both global expression levels of proteins and proteins differentially glycosylated in the retinas of wild-type and diabetic mice have been identified. We provide evidence that diabetes shifts both global expression levels and -glycosylation of metabolic and synaptic proteins in the retina.
DISCUSSION
Here we report changes in the retinal proteome of diabetic mice. We highlight alterations in global proteins involved in metabolic processes, maintaining cellular structure, trafficking, and neuronal processes. We then showed changes in -linked glycosylation of individual proteins in the diabetic retina.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Proteomics; Diabetic Retinopathy; Retina; Glycosylation; Proteome
PubMed: 37693346
DOI: 10.3389/fendo.2023.1229089 -
Diabetologia Jul 2024An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes.... (Review)
Review
An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes. The COVID-19 pandemic has re-kindled an interest in the complex relationship between diabetes and infection. Some infections occur almost exclusively in people with diabetes, often with high mortality rates without early diagnosis and treatment. However, more commonly, diabetes is a complicating factor in many infections. A reciprocal relationship occurs whereby certain infections and their treatments may also increase the risk of diabetes. People with diabetes have a 1.5- to 4-fold increased risk of infection. The risks are the most pronounced for kidney infection, osteomyelitis and foot infection, but are also increased for pneumonia, influenza, tuberculosis, skin infection and general sepsis. Outcomes from infection are worse in people with diabetes, with the most notable example being a twofold higher rate of death from COVID-19. Hyperglycaemia has deleterious effects on the immune response. Vascular insufficiency and neuropathy, together with altered skin, mucosal and gut microbial colonisation, contribute to the increased risk of infection. Vaccination is important in people with diabetes although the efficacy of certain immunisations may be compromised, particularly in the presence of hyperglycaemia. The principles of treatment largely follow those of the general population with certain notable exceptions.
Topics: Humans; COVID-19; Diabetes Mellitus; SARS-CoV-2; Diabetes Complications; Infections
PubMed: 38374451
DOI: 10.1007/s00125-024-06102-x -
Ugeskrift For Laeger Sep 2023Diabetic ketoacidosis (DKA) in children with severe hypertriglyceridaemia (S-HTG) is infrequent. This case report presents a seven-year-old girl without a family history...
Diabetic ketoacidosis (DKA) in children with severe hypertriglyceridaemia (S-HTG) is infrequent. This case report presents a seven-year-old girl without a family history of dyslipidaemia with moderate DKA, lipaemic plasma, retinal lipaemia, and P-triglyceride 185 mmol/l. The course was uneventful on standard treatment and lipids normalized. She had abdominal pain but no biochemical or ultrasound evidence of pancreatitis. S-HTG affected laboratory analysis; CO2 could not be analyzed, and there was haemolysis and uncertain electrolyte results with P-Na+ 125 mmol/l, i.e. pseudo hyponatraemia, despite ultracentrifugation.
Topics: Female; Humans; Child; Diabetic Ketoacidosis; Hyperlipidemias; Hypertriglyceridemia; Pancreatitis; Triglycerides; Diabetes Mellitus
PubMed: 37873990
DOI: No ID Found -
Frontiers in Immunology 2023Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces... (Review)
Review
Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.
Topics: Humans; Inflammation; Diabetes Complications; Receptor-Interacting Protein Serine-Threonine Kinases; Diabetic Nephropathies; Threonine; Serine; Diabetes Mellitus
PubMed: 37954576
DOI: 10.3389/fimmu.2023.1274654 -
Graefe's Archive For Clinical and... Dec 2023Pars plana vitrectomy (PPV) is the main treatment modality for patients with severe diabetic retinopathy. With the development of systems for microincision, wide-angle... (Review)
Review
Pars plana vitrectomy (PPV) is the main treatment modality for patients with severe diabetic retinopathy. With the development of systems for microincision, wide-angle viewing, digitally assisted visualization, and intraoperative optical coherence tomography, contemporary PPV for diabetic retinopathy has been performed on a wider range of indications than previously considered. In this article, we reviewed, in conjunction with our collective experiences with Asian patients, the applications of new technologies for PPV in eyes with diabetic retinopathy and highlighted several important procedures and entities not generally reiterated in the literature, in order for vitreoretinal surgeons to optimize their approaches when facing the challenges imposed by the complications in diabetic eyes.
Topics: Humans; Vitrectomy; Diabetic Retinopathy; Visual Acuity; Eye; Tomography, Optical Coherence; Retinal Detachment; Diabetes Mellitus
PubMed: 37314522
DOI: 10.1007/s00417-023-06134-w