MCP-1and IL-1β expression in the myocardia of two young patients with Type 1 diabetes mellitus and fatal diabetic ketoacidosis

Convincing evidence exists for the early onset of diabetic cardiomyopathy and coronary artery disease (CAD) as distinct forms of cardiac disease in young patients with Type 1 diabetes mellitus (T1DM) and the pre-stages of T2DM, forms of dysregulated insulin signaling. Progression of both chronic cardiac conditions is mediated by oxidative stress and low grade inflammation. This study reports the expression of monocyte chemotactic protein-1 (MCP-1) chemokine and the interleukin (IL)-1β inflammatory cytokine in two young patients with suboptimal metabolic control and fatal diabetic ketoacidosis (DKA), two age-matched overweight/obesity cases and two age-matched controls. In addition, markers of oxidative stress, apoptosis, collagen deposition and cardiomyocyte hypertrophy were studied. Significant expression of MCP-1 and IL-1β was seen in the myocardia of the T1DM/DKA cases, with lesser amounts expressed in the overweight/obesity myocardia. All of the other markers except cardiomyocyte hypertrophy were expressed to a significantly greater extent in the T1DM/DKA and overweight/obesity cases in comparison to the age-matched controls. Cardiomyocyte hypertrophy was significantly greater in the overweight/obesity cases than in the T1DM/DKA or the control cases.     

B-cell lymphoma-2 family proteins-activated proteases as potential therapeutic targets for influenza A virus and severe acute respiratory syndrome coronavirus-2: Killing two birds with one stone?

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global health emergency. There are many similarities between SARS-CoV-2 and influenza A virus (IAV); both are single-stranded RNA viruses infecting airway epithelial cells and have similar modes of replication and transmission. Like IAVs, SARS-CoV-2 infections poses serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus, and development of drug resistance. New approaches to control these infectious agents may stem from cellular factors or pathways that directly or indirectly interact with viral proteins to enhance or inhibit virus replication. One of the emerging concepts is that host cellular factors and pathways are required for maintaining viral genome integrity, which is essential for viral replication. Although IAVs have been studied for several years and many cellular proteins involved in their replication and pathogenesis have been identified, very little is known about how SARS-CoV-2 hijacks host cellular proteins to promote their replication. IAV induces apoptotic cell death, mediated by the B-cell lymphoma-2 (Bcl-2) family proteins in infected epithelia, and the pro-apoptotic members of this family promotes viral replication by activating host cell proteases. This review compares the life cycle and mode of replication of IAV and SARS-CoV-2 and examines the potential roles of host cellular proteins, belonging to the Bcl-2 family, in SARS-CoV-2 replication to provide future research directions.     

Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes

Pancreatic islet beta-cell death occurs in type 1 and 2 diabetes mellitus, leading to absolute or relative insulin deficiency. beta-cell death in type 1 diabetes is due predominantly to autoimmunity. In type 2 diabetes beta-cell death occurs as the combined consequence of increased circulating glucose and saturated fatty acids together with adipocyte secreted factors and chronic activation of the innate immune system. In both diabetes types intra-islet inflammatory mediators seem to trigger a final common pathway leading to beta-cell apoptosis. Therefore anti-inflammatory therapeutic approaches designed to block beta-cell apoptosis could be a significant new development in type 1 and 2 diabetes.     

Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis

Accumulating research evidence suggests that individual dietary factors and dietary patterns might be implicated in the risk of development of rheumatoid arthritis (RA). This narrative review aims to present this evidence and provide nutritional recommendations for reducing RA risk in susceptible individuals. Overall, a ‘Western’ type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in refined carbohydrates and sugar and low in fiber and antioxidants might increase the risk of RA both directly through increasing inflammation and indirectly through increasing insulin resistance and obesity, with the latter being a known risk factor for RA. On the contrary, consumption of long-chain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of RA probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extra-virgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. Based on current research evidence, it is suggested that adherence to the MD enhanced with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Further research on RA susceptibility will allow for more specific dietary recommendations to be made.     

Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study.

BACKGROUND: Asthma is generally regarded as a disease with strong T(H)2-type cytokine expression, whereas in autoimmune disorders, such as coeliac disease (CD), insulin-dependent diabetes mellitus (IDDM), and rheumatoid arthritis (RA), T(H)1-type expression is seen. According to the cross-regulatory properties of T(H)1 and T(H)2 cells, one would assume that these diseases exist in different patient populations. OBJECTIVE: We sought to test the hypothesis that asthma could exist in children with T(H)1-type diseases, such as CD, IDDM, and RA. METHODS: Comparison was made of the cumulative incidence of asthma in children with CD, IDDM, or RA by linking Finnish Medical Birth Register data on the whole 1987 birth cohort (n = 60,254 births) with the data of several national health registers to obtain information on the incidences of these diseases during the first 7 years of life. RESULTS: The cumulative incidence of asthma in children with CD (24.6%) or RA (10.0%) was significantly higher than in children without CD (3.4%) or RA (3.4%; P < .001 and P = .016, respectively). Asthma tended to be more common in children with IDDM than in children without IDDM. CONCLUSION: These data indicate that the T(H)1 and T(H)2 diseases can coexist, indicating a common environmental denominator behind the disease processes.     

Relationship between serum levels of TGF-β1 and clinical parameters in patients with rheumatoid arthritis and Sjögren's syndrome secondary to rheumatoid arthritis

TGF-β1 is a pleiotropic cytokine, which prevents inappropriate autoimmune responses and balances the requirements of proper immune cell levels during pathologic states that trigger the immune response. We assessed the serum levels of TGF-β1 and determined the relationship between TGF-β1 and clinical parameters in patients with rheumatoid arthritis (RA) and Sjögren's syndrome (SS) secondary to RA (SS + RA). Comparison of the serum levels of TGF-β1 in patients with RA, SS + RA and NHD differed significantly (51.7 ± 12.4 ng/ml (RA); 33.0 ± 3.1 ng/ml (SS + RA) and versus 31.6 ± 2.0 ng/ml (NHD)). We further found correlations between TGF-β1 levels and radiologically defined joint damage determined by the Steinbrocker scoring system, symptoms and signs of SS. We conclude that serum levels of TGF-β1 may reflect ongoing autoimmune inflammation and correlate with joint damage in RA.     

Is BDNF biological link between depression and type 2 diabetes mellitus?

Epidemiological and clinical studies have demonstrated a strong association between depression and diabetes. Of note, depression is a risk factor for the development of type 2 diabetes mellitus (T2DM), while most patients with T2DM also have depression. Despite the abundance of evidence showing an epidemiological link between depression and T2DM, the cause of this association is still unknown. Brain-derived neurotrophic factor (BDNF) is widely expressed in the brain. Biological and clinical studies have repeatedly shown that BDNF is important in the pathogenesis of depression and T2DM. Therefore, we propose that BDNF may play an important role linking depression and T2DM. Studies examining the components of the BDNF system in patients with T2DM and depression may provide new understanding into the link between depression and T2DM. Such studies might also help us to identify potential treatment targets for these two common disorders.     

Psychological stress and type 1 diabetes mellitus: what is the link?

ABSTRACT

Introduction: Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by the destruction of insulin-producing β-cells of the pancreas. The current paradigm in this disease’s etiopathogenesis points toward the interplay of genetic and environmental factors. Among the environmental variables, dietary factors, intestinal microbiota, toxins, and psychological stress have been implicated in disease onset.

Areas covered: This review aims to investigate the relationship between psychological stress and T1DM by presenting evidence from epidemiological studies, animal models, and to provide the mechanism involved in this association. The literature search was conducted through PubMed to identify studies that investigate the connection between stress and T1DM. Experimental designs, such as case-control, and retrospective and prospective cohorts studies, were included.

Expert commentary: A wide array of evidence, ranging from epidemiological to animal models, points toward the role of psychological stressors in T1DM pathogenesis. Various mechanisms have been proposed, including the hypothalamic-pituitary-adrenal (HPA) axis, influence of the nervous system on immune cells, and insulin resistance. Further research could investigate the gene-stress interactions to evaluate the risk of T1DM development.     

Gallstones, the choledochoduodenal junction and initiation of acute pancreatitis: are two stones the culprits rather than one stone?

Reflux of biliary secretions into the pancreatic duct following gallstone obstruction of the common biliary pancreatic ampulla has been implicated as a cause of acute pancreatitis. However, the pancreatic duct pressure is higher than the biliary pressure and, therefore, the simple obstruction of the choledochoduodenal junction by one gallstone does not result in biliary pancreatic reflux. We propose a mechanism whereby simultaneous migration and sequential impaction above and below the common biliary pancreatic ampulla of two gallstones allows for the creation of a toxic bile-pancreatic juice mixture in the common bile duct, subsequent reversal of the pressure gradient and reflux of the toxic secretions into the pancreatic duct.     

IL-4 and IL-13 receptors: are they one and the same?

Interleukin 4 (IL-4) and IL-13 share several biological properties, suggesting that they also share a common receptor or receptor component. Indeed, as discussed here by Robin Callard and colleagues, the IL-13 receptor appears to be a functional receptor for IL-4.     

TNF inhibitors in rheumatoid arthritis and spondyloarthritis: Are they the same?

The advent of anti-tumour necrosis factor (TNF) drugs for rheumatoid arthritis (RA) or spondyloarthritis (SpA) has revolutionised the approach to patients with active disease who do not respond to conventional therapy. Although there are differences in their structure, morphology, pharmacokinetic properties and activity, all anti-TNF drugs ultimately neutralise the TNFα pathway of inflammation. However, despite their similar clinical efficacy, there are disagreements concerning drug survival and safety, with systematic reviews and meta-analyses confirming one result or the other. The fact that 20–30% of patients fail to respond to TNFα inhibitors indicates the possibility of primary resistance or the development of an immune response to the drugs themselves, which may act as antigens. The overall benefit of switching to another anti-TNF drug or a biological agent with a different mechanism of action, may be a valuable option in individual patients. There are few data concerning the use of anti-TNF drugs in patients with SpA but it seems that there are fewer adverse advents and higher drug survival in comparison with patients with RA.     

Is there a relationship between factor V Leiden and type 2 diabetes?

Background  

Diabetes is well known risk factor for thrombotic events. The association between diabetes and venous thromboembolism is still matter of debate. However, during diabetes an acquired thrombophilia is present and is due to the non-enzymatic glycosilation of clotting inhibitors as antithrombin thus leading to hypercoagulable state. A possibile relationship between the presence of FVL gene variant in type 1 or type 2 diabetes has been hypothysed by several reports in the Literature with non-univocal findings.     

Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls

Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1‐like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL‐18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL‐18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American‐European classification criteria. IL‐18 and TGF‐β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL‐18 were related (R = 0·52, P = 0·0005). No relation was found neither between IL‐18 versus IgG2, IgG3 or IgA, nor between serum TGF‐β1 versus any of the immunoglobulins. Since serum levels of IL‐18 are related to serum IgG1, IL‐18 may be of importance for IgG1 switch and/or release.     

Periodontal disease and type 2 diabetes mellitus: Is the HMGB1–RAGE axis the missing link?

Periodontitis is a major chronic inflammatory disease associated with increased production of numerous proinflammatory cytokines, which leads to the destruction of the periodontal tissue and ultimately loss of teeth. Periodontitis has powerful and multiple influences on the occurrence and severity of systemic conditions and diseases, such as diabetes mellitus, cardiovascular disease and respiratory disease. Meanwhile, diabetes is associated with increased prevalence, severity and progression of periodontal disease. There is also abundant evidence showing that diabetes plays important etiological roles in periodontitis. High mobility group box 1 (HMGB1) was recently identified as a lethal mediator of severe sepsis and comprises a group of intracellular proteins that function as inflammatory cytokines when released into the extracellular milieu. From a clinical perspective, extracellular HMGB1 can cause multiple organ failure and contribute to the pathogenesis of sepsis, rheumatoid arthritis, cardiovascular disease and diabetes. We recently reported that HMGB1 expression in periodontal tissues was elevated in patients with severe periodontitis. In addition, the receptor for advanced glycation end-products (RAGE), a receptor for HMGB1, was strongly expressed in gingival tissues obtained from patients with type 2 diabetes and periodontitis compared with systemically healthy patients with chronic periodontitis patients. From these data, we hypothesize that HMGB1 might play a role in the development of diabetes-associated periodontitis.     

β2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus

Background

Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects.

Methods

Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.

Results

Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed.

Conclusion

SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.     

Characterization of the autoimmune response against the nerve tissue S100β in patients with type 1 diabetes

Type 1 diabetes results from destruction of insulin-producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non-beta cell-specific antigens has also been reported, including targeting of the calcium-binding protein S100β. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100β, determined their affinity for the human leucocyte antigen (HLA)-DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100β reactivity, characterized by interferon (IFN)-γ secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100β as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non-beta cell-specific autoantigens may have a role in type 1 diabetes pathogenesis.     

β2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus

Background  

It is widely accepted that Type 2 Diabetes Mellitus (T2DM) and other complex diseases are the product of complex interplay between genetic susceptibility and environmental causes. To cope with such a complexity, all the statistical and conceptual strategies available should be used. The working hypothesis of this study was that two well-known T2DM risk factors could have diverse effect in individuals carrying different genotypes. In particular, our effort was to investigate if a well-defined group of genes, involved in peripheral energy expenditure, could modify the impact of two environmental factors like age and obesity on the risk to develop diabetes. To achieve this aim we exploited a multianalytical approach also using dimensionality reduction strategy and conservative significance correction strategies.