Crosstalk between ferroptosis and miRNA in type 2 diabetes mellitus and possible therapeutic targeting

After completing this article, readers should be able to: 1. Outline the current concepts of the pathogenesis of type 1 diabetes (T1D) with regard to dietary triggers and genetic susceptibility. 2. Discuss the evidence, both epidemiologic and that derived from studies of animal models, that supports the association between infant feeding practices and T1D. 3. Describe the roles for intestinal immunity and permeability in supporting the hypothetical model of cow milk protein mediation of T1D autoimmunity. 4. Delineate the goals and rationale for prospective clinical trials evaluating neonatal nutrition and the development of T1D. 5. List the putative dietary modulators of T1D. Type 1 diabetes (T1D), a disease that has unacceptably high morbidity and mortality, is increasing in incidence, prompting the redoubling of efforts toward its prevention. Progress toward prevention and cure relies on elucidation of the disease’s pathogenesis, which, to date, has remained poorly defined. The defining features of T1D, insulin deficiency and hyperglycemia, result from an immune-mediated destruction of insulin-secreting beta cells in the pancreatic islets. The loss of beta cell mass is believed to be gradual for most individuals, accounting for the sometimes prolonged asymptomatic periods of autoimmunity preceding overt diabetes (Fig. 1). Indeed, the chronic autoimmune nature of the disease is well established, as is the genetic predisposition. Specific associations with molecules of the human lymphocyte antigen (HLA) define both susceptibility to and protection from T1D. However, T1D is a polygenic disorder with more than 20 loci associated with susceptibility or resistance to the disease, of which the HLA may account for less than 50% of the genetic predisposition. Genetics clearly comprises a major component of the development of T1D, but the interaction between the environment and the immune system abnormalities is believed to weigh heavily in disease development. Indeed, trends in T1D incidence, both geographic and temporal, suggest a strong …

It has been proposed that mitochondrial dysfunction is involved in the pathogenesis of type 2 diabetes (T2D). To dissect the underlying mechanisms, we performed a multiplexed proteomics study on liver mitochondria isolated from a spontaneous diabetic rat model before/after they were rendered diabetic. Altogether, we identified 1091 mitochondrial proteins, 228 phosphoproteins, and 355 hydroxyproteins. Mitochondrial proteins were found to undergo expression changes in a highly correlated fashion during T2D development. For example, proteins involved in beta-oxidation, the tricarboxylic acid cycle, oxidative phosphorylation, and other bioenergetic processes were coordinately up-regulated, indicating that liver cells confronted T2D by increasing energy expenditure and activating pathways that rid themselves of the constitutively increased flux of glucose and lipid. Notably, activation of oxidative phosphorylation was immediately related to the overproduction of reactive oxygen species, which caused oxidative stress within the cells. Increased oxidative stress was also evidenced by our post-translational modification profiles such that mitochondrial proteins were more heavily hydroxylated during T2D development. Moreover, we observed a distinct depression of antiapoptosis and antioxidative stress proteins that might reflect a higher apoptotic index under the diabetic stage. We suggest that such changes in systematic metabolism were causally linked to the development of T2D. Comparing proteomics data against microarray data, we demonstrated that many T2D-related alterations were unidentifiable by either proteomics or genomics approaches alone, underscoring the importance of integrating different approaches. Our compendium could help to unveil pathogenic events in mitochondria leading to T2D and be useful for the discovery of diagnosis biomarker and therapeutic targets of T2D.

Diabetes prevalence and incidence among youth have been increasing globally. Type 1 Diabetes (T1D) in children or adolescents accounts for 5–10% of all diagnosed cases of diabetes. Emerging evidence indicates that genetic factors, especially genes in the human leukocyte antigen region, are not the only factors involved in the predisposition of an individual to T1D. The pathogenesis and development of T1D is driven by both genetic predisposition and environmental factors. Studies indicate that gut microbiota is one of the potential environmental influencers involved in the pathophysiology of TID. Gut microbiota mediates the development of diabetes by altering intestinal permeability, modifying intestinal immunity, and molecular mimicry. The gut microbial diversity, taxonomic profile, and functional potential of gut microbes are significantly altered in individuals with T1D as compared to healthy individuals. However, studies are still needed to identify the specific microbes and microbial metabolites that are involved in the development and pathogenesis of T1D. This will help the development of microbiome-based therapeutic strategies for the prevention and treatment of T1D. The present review article highlights the following: (i) the current knowledge and knowledge gaps in understanding the association between T1D and gut microbiome specifically focusing on the composition and functional potential of gut microbiome in children and adolescents, (ii) the possible mechanisms involved in gut microbiome-mediated T1D pathogenesis, and (iii) challenges and future direction in this field. Abbreviations: B/F ratio: Bacteroidetes to Firmicutes ratio; F/B ratio: Firmicutes to Bacteroidetes ratio; FDR: First-degree relatives; GPR: G protein-coupled receptors; HLA: human leucocyte antigen; IL: interleukin; IFN- γ: interferon-γ; KEGG: Kyoto Encyclopedia of Genes and Genomes; LPS: lipopolysaccharide; mTOR: mammalian target of rapamycin; PICRUSt: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; SCFA: short chain fatty acids; T1D: Type 1 diabetes; T2D: Type 2 diabetes; TJ: tight junction; Tregs: regulatory T cells.

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. β-cell failure and insulin resistance in peripheral tissues that are induced by lipid overload are main hallmarks of T2D. The mechanisms that link obesity-driven alterations of lipid metabolism and T2D are still elusive, thereby impeding the development of effective prevention and treatment strategies. Although genetic variants that have been identified in high-throughput studies comprise an appreciable proportion of the genetic component of T2D, they explain < 20% of the estimated heritability of T2D. A growing body of evidence suggests an intrinsic role for epigenetic modifications in the pathogenesis of T2D. The epigenetic regulation of gene expression in tissues that play a key role in the obesity-related development of T2D has been demonstrated, including PDX1 in pancreatic islets, PPARGC1A in skeletal muscles, ADIPOQ in adipose tissue, and TXNIP in the liver. The present review summarizes our current knowledge of crosstalk between the epigenetic control of gene expression, particularly via DNA methylation, toxic lipid mediators, and the pathogenesis of obesity-related T2D.

Type 1 diabetes (T1D) is the result of selective destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. T1D is due to a complex interplay between the beta-cell, the immune system, and the environment in genetically susceptible individuals. The initiating mechanism(s) behind the development of T1D are largely unknown, and no genes or proteins are specific for most T1D cases. Different pro-apoptotic cytokines, IL-1 beta in particular, are present in the islets during beta-cell destruction and are able to modulate beta-cell function and induce beta-cell death. In beta-cells exposed to IL-1 beta, a race between destructive and protective events are initiated and in susceptible individuals the deleterious events prevail. Proteins are involved in most cellular processes, and it is thus expected that their cumulative expression profile reflects the specific activity of cells. Proteomics may be useful in describing the protein expression profile and thus the diabetic phenotype. Relatively few studies using proteomics technologies to investigate the T1D pathogenesis have been published to date despite the defined target organ, the beta-cell. Proteomics has been applied in studies of differentiating beta-cells, cytokine exposed islets, dietary manipulated islets, and in transplanted islets. Although that the studies have revealed a complex and detailed picture of the protein expression profiles many functional implications remain to be answered. In conclusion, a rather detailed picture of protein expression in beta-cell lines, islets, and transplanted islets both in vitro and in vivo have been described. The data indicate that the beta-cell is an active participant in its own destruction during diabetes development. No single protein alone seems to be responsible for the development of diabetes. Rather the cumulative pattern of changes seems to be what favors a transition from dynamic stability in the unperturbed beta-cell to dynamic instability and eventually to beta-cell destruction.

Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility

Inflammation triggers pulmonary vascular remodelling. Ferroptosis, a nonapoptotic form of cell death that is triggered by iron-dependent lipid peroxidation and contributes to the pathogenesis of several inflammation-related diseases, but its role in pulmonary hypertension (PH) has not been studied. We examined endothelial cell ferroptosis in PH and the potential mechanisms. Pulmonary artery endothelial cells (PAECs) and lung tissues from monocrotaline (MCT)-induced PH rats were analysed for ferroptosis markers, including lipid peroxidation, the labile iron pool (LIP) and the protein expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) and NADPH oxidase-4 (NOX4). The effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on endothelial cell ferroptosis and pulmonary vascular remodelling in MCT-induced rats were studied in vitro and in vivo. Ferroptosis was observed in PAECs from MCT-induced PH rats in vitro and in vivo and was characterized by a decline in cell viability accompanied by increases in the LIP and lipid peroxidation, the downregulation of GPX4 and FTH1 expression and the upregulation of NOX4 expression. High-mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signalling was measured by western blotting. These changes were significantly blocked by Fer-1 administration in vitro and in vivo. These results suggest that Fer-1 plays a role in inhibiting ferroptosis-mediated PAEC loss during the progression of PH. The ferroptosis-induced inflammatory response depended on the activation of HMGB1/TLR4 signalling, which activated the NLRP3 inflammasome in vivo. We are the first to suggest that pulmonary artery endothelial ferroptosis triggers inflammatory responses via the HMGB1/TLR4/NLRP3 inflammasome signalling pathway in MCT-induced rats. Treating PH with a ferroptosis inhibitor and exploring new treatments based on ferroptosis regulation might be promising therapeutic strategies for PH.

Type 1 diabetes (T1D) is an autoimmune disease characterized by a selective destruction of insulin-secreting β-cells. Both T cells and B cells serve a crucial role in pathogenesis and development of T1D. CD20 is a specific membrane antigen of B lymphocytes, while interleukin (IL)-10 is an important cytokine secreted by T helper 2 cells and has a short half-life in vivo. The combined effect of anti-CD20 and IL-10 on immune function of mice with T1D remains unknown. In the present study, 30 non-obese diabetic (NOD) mice were treated with anti-CD20 and adenoviral vector-mediated interleukin-10 (Ad-mIL-10) therapy. Alterations in CD4+, CD8+, CD4+CD25+Foxp3+ T cells, T-box expressed in T-cells (T-bet), GATA-binding protein-3 (GATA-3) interferon-γ (IFN-γ) and IL-4 were detected by flow cytometry, reverse transcription-quantitative polymerase chain reaction in NOD mice spleen tissue. The present results suggested that anti-CD20 and IL-10 treatment in NOD mice can modulate the immune functions by upregulating GATA-3 and IL-4 expression as well as downregulating T-bet and IFN-γ expression, which are involved in the pathogenesis of T1D. The current findings may provide a potential method for T1D treatment and a novel preventive therapy for T1D. Combination of anti-CD20 and Ad-mIL-10 treatment had not only immune regulatory effects but also protective effects on islet β-cells in NOD mice with T1DM at the early stages, by regulating T-bet/GATA-3 expression and Th1/Th2 cell differentiation, which has the potential for diabetes prevention and therapy.

Type 1 diabetes (T1D) is an autoimmune disease characterized by T-cell mediated destruction of pancreatic B cells, absolute deficiency in insulin, and hyperglycemia. The incidence of T1D is increased sharply after the middle of the 20th century, suggesting that the environmental factors affect the occurrence and development of T1D. The diversity of human intestinal flora forms early in life and tends to stabilize around age 3. Early intestinal flora is in a dynamic process of change and is closely related to the maturation of the immune system, suggesting that early environmental exposure may be involved in the development of T1D. A variety of factors such as antibiotics and cesarean section can affect the colonization of early intestinal flora. To clarify the influence of these factors on early intestinal flora and its association with T1D, it is necessary to understand the pathogenesis of T1D and to provide an effective means for the primary prevention of T1D.

The gut microbiota has been presumed to have a role in the pathogenesis of type 1 diabetes (T1D). Significant changes in the microbial composition of T1D patients have been reported in several case-control studies. This study is aimed at systematically reviewing the existing literature, which has investigated the alterations of the intestinal microbiome in T1D patients compared with healthy controls (HCs) using 16S ribosomal RNA-targeted sequencing. The databases of MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched until April 2019 for case-control studies comparing the composition of the intestinal microbiome in T1D patients and HCs based on 16S rRNA gene sequencing techniques. The Newcastle-Ottawa Scale was used to assess the methodological quality. Ten articles involving 260 patients with T1D and 276 HCs were included in this systematic review. The quality scores of all included studies were 6–8 points. In summary, a decreased microbiota diversity and a significantly distinct pattern of clustering with regard to β-diversity were observed in T1D patients when compared with HCs. At the phylum level, T1D was characterised by a reduced ratio of Firmicutes/Bacteroidetes in the structure of the gut community, although no consistent conclusion was reached. At the genus or species level, T1D patients had a reduced abundance of Clostridium and Prevotella compared with HCs, whereas Bacteroides and Ruminococcus were found to be more enriched in T1D patients. This systematic review identified that there is a close association between the gut microbiota and development of T1D. Moreover, gut dysbiosis might be involved in the pathogenesis of T1D, although the causative role of gut microbiota remains to be established. Further well-controlled prospective studies are needed to better understand the role of the intestinal microbiome in the pathogenesis of T1D, which may help explore novel microbiota-based strategies to prevent and treat T1D.

Background: The relatively common co-occurrence of type 1 diabetes (T1D) and celiac disease (CD) suggests these disorders share common pathogenic etiologies. Summary: T1D and CD are strongly linked to closely related high-risk human lymphocyte antigens (HLA-DR-DQ). High-risk HLA molecules bind specific fragments of gluten or the islet self-antigen(s) and present these antigens to antigen-responsive T cells. In an appropriate proinflammatory environment, the autoimmune response results in destruction of the intestinal enterocyte and/or the pancreatic beta cell. Environmental factors have been implicated in the etiology of T1D and CD because (1) identical twins are only partially concordant for these disorders and (2) incidence rates of T1D and CD have been steadily rising for decades. Prospective studies in infants genetically predisposed to T1D and CD showed that antibody positivity to both disorders begins in the first 1–3 years of life. Viral infections and early exposure to gluten or cow’s milk in the infant diet have been implicated in disease pathogenesis. However, delaying introduction of gluten in the infant diet until 12 months of age had no impact on the development of islet or celiac autoimmunity. Weaning nursing infants to hydrolyzed infant formula had no impact on the development of T1D. Viral infections have been suspected of playing a role in T1D pathogenesis for decades. A large international prospective study (TEDDY) has shown increased risk of T1D autoimmunity particularly when >5 respiratory infections or febrile infections have occurred in the 9 months preceding the appearance of islet antibodies. Provocative data in animal models of T1D suggest the microbiome may play an important role in the pathogenesis of T1D. Breastfeeding, diet, infections, antibiotics, and method of birth alter the composition of the microbiome. Human data indicate subtle differences in the microbiome of children with T1D autoimmunity, while intestinal dysbiosis has been clearly demonstrated in CD. Alterations of the integrity of the intestinal mucosa plays an important role in the pathogenesis of CD, and the NOD mouse model suggests an important role of a leaky intestinal epithelium in T1D as well. Key Message: Immunogenetics and the environment are closely interrelated in the pathogenesis of T1D and CD. Large well-designed prospective studies in at-risk populations informed by scientifically rigorous studies in animal models are likely to have the greatest impact on our understanding of the complex pathogenesis of these detrimental autoimmune disorders.

Introduction and purpose Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of pancreatic β cells, which leads to insulin deficiency and hyperglycemia. One significant factor that may influence the development of type 1 diabetes is a change in the intestinal microbiota. This study aim is to present the significance and role of intestinal microbiota in the pathogenesis of T1D. This subject is important, as it offers prospects for new therapeutic solutions, especially given the significant social impact of T1D. Description Type 1 diabetes (T1D) causes a number of symptoms and complications, including an increased risk of developing cardiovascular diseases. Diagnosis includes measurements of glucose concentration, glycated hemoglobin, and specific antibodies in the blood. The basic therapy for T1D is insulin replacement therapy. Numerous studies have shown that both the composition and function of the intestinal microbiota are impaired in patients with T1D. It has been observed that an increase in the number of Bacterioides and a decrease in the number of Firmicutes, which are the main microorganisms of the intestinal microbiome, are correlated with a high risk of developing T1D. Summary Type 1 Diabetes (T1D) is a serious health problem that affects many people worldwide and the incidence of the disease is constantly increasing. There is a growing number of studies that emphasize the influence of the intestinal microbiota on the development of T1D. It is important to enlarge our knowledge about this disease. Further studies are needed to determine the importance and the role of the intestinal microbiota in the pathogenesis of T1D.

Type 2 diabetes (T2D) is a complex metabolic disorder with an increasing incidence worldwide. The disease is characterized by a combination of impairment in insulin secretion from pancreatic beta cells and insulin resistance of peripheral tissues, especially muscle and liver, resulting from interaction between multiple environmental and genetic factors. Life-style changes and obesity are the major causes for the current epidemic of T2D. The rapidly increasing prevalence of Type 2 diabetes makes it a major healthcare problem worldwide. In the developing nations this poses a serious health care burden. In recent years there has been a swing in the onset to younger age group. To date, Genome-Wide Association Scan (GWAS) studies have identified more than 65 common genetic variants associated with T2D or glucose/insulin levels. The recently discovered genes by GWAS suggest a shift from genes involved in insulin action to those involved in insulin secretion, indicating pivotal role of beta- cell dysfunction in the pathogenesis of T2D. However, in most cases the causal variants are not known. Also, the molecular mechanism of the patho-physiology of the disease is still obscure. Functional studies will be required to identify the mechanisms by which the associated signals impair islet function and increase risk of T2D. Understanding the pathophysiology of T2D will provide new and useful information(s) for prevention of the disease and development of new drugs for the treatment of T2D. Pharmacogenetics is another promising clinical application of the genetic findings for T2D. Also, efforts are being made to understand the genetic basis of differences in disease susceptibility by studying the genetic variations among different populations, an area that is important for the future of medicine.

Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.

Type 1 diabetes (T1D) stems from pancreatic β cell destruction by islet reactive immune cells. Similar as other autoimmune disorders, there is no curative remedy for T1D thus far. Chronic insulitis is the hallmark of T1D, which creates a local inflammatory microenvironment that impairs β cell function and ultimately leads to β cell death. Immune regulation shows promise in T1D treatment by providing a time window for β cell recovery. However, due to the complex nature of T1D pathogenesis, the therapeutic effect of immune regulation is often short-lasting and unsatisfying in monotherapies. Lymphotoxins (LTs) were first identified in 1960s as the lymphocyte-producing cytokine that can kill other cell types. As a biological cousin of tumor necrosis factor alpha (TNFα), LTs play unique roles in T1D development. Herein in this review, we summarized the advancements of LTs in T1D pathogenesis. We particularly highlighted their effect on the formation of peri-islet tertiary lymphoid organs (TLOs), and discussed their synergistic effect with other cytokines on β cell toxicity and autoimmune progression. Given the complex and dynamic crosstalk between immune cells and β cells in T1D setting, blockade of lymphotoxin signaling applied to the existing therapies could be an efficient approach to delay or even reverse the established T1D.