Pharmacology lettersPlasma interleukin-6, tumour necrosis factor α and blood cytokine production in type 2 diabetes
Abstract
Type 2 diabetes is associated with increased circulating concentrations of markers of the acute-phase response and interleukin-6 (IL-6). An augmented acute-phase response may be a mechanism which explains many of the clinical and biochemical features of type 2 diabetes and its complications. We sought to confirm that circulating concentrations of the cytokine acute-phase mediators IL-6 and tumour necrosis factor α [TNFα] are elevated in type 2 diabetes, and investigated blood as a source of cytokines in type 2 diabetes. Blood samples from 20 type 2 diabetic and 17 age-matched healthy subjects were incubated in vitro for 24 hr with and without lipopolysaccharide (LPS) stimulation and secreted cytokines measured. Plasma IL-6 and TNFα were significantly increased in type 2 diabetes compared to normal subjects. However, basal production of IL-6 and TNFα in cultured diabetic blood was markedly depressed in comparison with non-diabetic samples. IL-6 and TNFα production was increased in blood in response to LPS, reaching similar levels in diabetic and non-diabetic subjects, though IL-6 was slightly but significantly higher in controls. We conclude that circulating levels of IL-6 and TNFα are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells in type 2 diabetes. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFα concentrations may be from non-circulating cells.
References (0)
Cited by (490)
Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats
2023, Life SciencesArbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.
How does neurovascular unit dysfunction contribute to multiple sclerosis?
2023, Neurobiology of DiseaseMultiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS) and the most common non-traumatic cause of neurological disability in young adults. Multiple sclerosis clinical care has improved considerably due to the development of disease-modifying therapies that effectively modulate the peripheral immune response and reduce relapse frequency. However, current treatments do not prevent neurodegeneration and disease progression, and efforts to prevent multiple sclerosis will be hampered so long as the cause of this disease remains unknown. Risk factors for multiple sclerosis development or severity include vitamin D deficiency, cigarette smoking and youth obesity, which also impact vascular health. People with multiple sclerosis frequently experience blood-brain barrier breakdown, microbleeds, reduced cerebral blood flow and diminished neurovascular reactivity, and it is possible that these vascular pathologies are tied to multiple sclerosis development. The neurovascular unit is a cellular network that controls neuroinflammation, maintains blood-brain barrier integrity, and tightly regulates cerebral blood flow, matching energy supply to neuronal demand. The neurovascular unit is composed of vessel-associated cells such as endothelial cells, pericytes and astrocytes, however neuronal and other glial cell types also comprise the neurovascular niche. Recent single-cell transcriptomics data, indicate that neurovascular cells, particular cells of the microvasculature, are compromised within multiple sclerosis lesions. Large-scale genetic and small-scale cell biology studies also suggest that neurovascular dysfunction could be a primary pathology contributing to multiple sclerosis development. Herein we revisit multiple sclerosis risk factors and multiple sclerosis pathophysiology and highlight the known and potential roles of neurovascular unit dysfunction in multiple sclerosis development and disease progression. We also evaluate the suitability of the neurovascular unit as a potential target for future disease modifying therapies for multiple sclerosis.
Effects of aging and type 2 diabetes on cardiac structure and function: Underlying mechanisms
2023, Experimental GerontologyWe characterized long-term changes in cardiac structure and function in a high-fat diet/streptozotocin mouse model of aging and type 2 diabetes mellitus (T2D) and examined how the intersection of both conditions alters plasma metabolomics. We also evaluated the possible roles played by oxidative stress, arginase activity and pro-inflammatory cytokines. C57BL/6 male mice (13-month-old) were used. Control animals (n = 13) were fed regular chow for 10 months (aged group). T2D animals (n = 25) were provided a single injection of streptozotocin and fed a high fat diet for 10 months. In select endpoints, young animals were used for comparison. To monitor changes in left ventricular (LV) structure and function, echocardiography was used. At the terminal study (23 months), blood was collected and hearts processed for biochemical or histological analysis. Echo yielded diminished diastolic function with aging and T2D. LV fractional shortening and ejection fraction decreased with T2D by 16 months peaking at 23 months. Western blots noted increases in fibronectin and type I collagen with aging/T2D and greater levels with T2D in α-smooth muscle actin. Increases in plasma and/or myocardial protein carbonyls, arginase activity and pro-inflammatory cytokines occurred with aging and T2D. Untargeted metabolomics and cheminformatics revealed differences in the plasma metabolome of T2D vs. aged mice while select classes of lipid metabolites linked to insulin resistance, were dysregulated. We thus, document changes in LV structure and function with aging that in select endpoints, are accentuated with T2D and link them to increases in OS, arginase activity and pro-inflammatory cytokines.
Role of theranostics in targeting inflammation in chronic diseases
2023, Recent Developments in Anti-Inflammatory TherapyInflammation is considered a part of a defensive mechanism to protect the body from the invasion of viruses/bacteria or any foreign body. Inflammation is classified mainly into two types based on the time of progression: acute and chronic. In acute inflammation, the reaction will vanish within hours whereas in chronic it will last for months or even for years. Chronic inflammation is associated with the diseases such as cancer, cardiovascular diseases, diabetes, asthma, COPD, glomerulonephritis, etc. “Theranostics” is a novel approach for the effective delivery of drugs to the targeted organs. It is a method of unification of therapy and diagnosis in a single window. Nanoparticles (NPs) are extensively used as theranostic agents, i.e., for both diagnostic and therapeutic purposes. Coupling drugs with theranostic agents can effectively deliver the drug to target tissues and can reduce side effects. Theranostics may be an effective tool to manage chronic inflammatory diseases.
The current study aimed to determine whether genetic differences in the tumor necrosis factor-α (TNF-α) and prostaglandin-endoperoxide synthase 2 (PTG2) genes are linked to type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN).
DN is a major cause of chronic kidney disease (CKD). Unfortunately, the precise pathogenic mechanisms of DN are not completely understood. Recent data suggest a link between inflammatory cytokines and the chronic complications of T2DM. TNF-α and PTG2 are key mediators of inflammation.
This is a case-control study that includes 100 patients (group 1: 50 diabetic patients with diabetic nephropathy and group 2: 50 patients without diabetic nephropathy) and 50 age- and sex-matched healthy controls (group 3). Genotyping of TNF-α (rs3651525) and PTGS2 (rs689466) by real-time PCR was applied.
TNF-α (rs3651525) and PTGS2 (rs689466) genotype frequency and allelic distribution are in Hardy-Weinberg equilibrium (HWE). When T2DM patients with nephropathy were compared to those without DN, regression analysis for the PTGS2 rs689466 and TNF-rs361525 single nucleotide polymorphisms (SNPs) demonstrated that none of the SNP genotypes showed a major risk factor for DN susceptibility. As regards TNF-α rs361525, GA and AA genotypes were significantly associated with a higher risk of T2DM when compared to GG, and A allele showed a 3.721-fold increased risk.
TNF-α rs361525 AA genotype (OR, 10.980; 95% CI 1.385–87.066) and TNF-rs361525 GA genotype (OR, 3.050; 95% CI 1.315–7.0758) are the most substantially linked parameters with the risk of diabetes mellitus in univariate analysis.
According to the multivariate analysis, the AA and GA genotypes of the SNP rs361525 significantly affect the development of diabetes mellitus. No remarkable association was found between the PTGS2 (rs689466) polymorphism and diabetes mellitus and diabetic nephropathy.
In contrast to the lack of a significant correlation between PTGS2 (rs689466) and DM or DN, TNF-α rs361525 was connected to the possibility of developing diabetes mellitus in our study.
Hypoglycemic effects of naturally processed Polygonum multiflorum extract in KK CgAy/J mice and its mechanism of action
2022, Food Science and Human WellnessIn 2021, there are approximately 537 million adults ageing 20
79 years affected by diabetes worldwide and the number is rising rapidly, hence it is important to manage and control diabetes mellitus and its associated complications. Food is one of the key factors in preventing and combating diseases such as diabetes. Both as a food and an herbal medicine, Polygonum multiflorum (PM) has been used as an anti-aging tonic, for hair darkening in traditional Chinese medicine for several centuries. The recent research effort of PM has been focused on antioxidant, anti-ageing and anti-tumor properties. In the present study, we utilized the traditional processing of harvested raw PM, and identified several stilbene components and then evaluated the potential anti-diabetic effects of the processed PM extract (PME). PME (0.075 %) was given to diabetic mice (KK CgAy/J) in drinking water and after 7 weeks, PME-treated mice had significantly lower glucose levels than mice in the diabetic control group (P < 0.01). The mechanism was explored with ELISA and Western blotting and results suggested that the effect was through maintaining β-cell function.