Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human embryonic stem cells (hESCs) are potential renewable sources of cells in replacement therapies for many diseases including type 1 diabetes. We have established a three dimensional (3D) model to culture and differentiate hESCs that are encapsulated in calcium alginate microcapsules. This system promotes cellular interactions that are essential for both maintaining pluripotency and differentiation. This 3D model also provides opportunity to separate out hESCs from fibroblasts used as feeder layer during culture. In this study, we compared the viability and proliferation of the encapsulated hESCs cultured in serum replacement (SR) medium, human fetal fibroblast-conditioned medium (hFF-CM), in the presence and absence of Y-27632, a ROCK inhibitor. Treatment of hESCs with Y-27632 promoted cell survival, cell cluster formation and proliferation rate in both SR medium and hFF-CM. These encapsulated hESC clusters were then directly differentiated to definitive endoderm cells that expressed mesendoderm (Brachyury 70-fold), definitive endoderm (SOX17>300-fold, FOXA2>800-fold, and CXCR4>100-fold) and primitive gut tube (HNF1beta>120-fold) as compared to the undifferentiated hESCs. These data show that microcapsules can be used for differentiation of hESCs into definitive endoderm in 3D and could have potential application for immune-isolation and prevention of teratomas formation of hESCs during transplantation.
 ...
PMID:Alginate microcapsule for propagation and directed differentiation of hESCs to definitive endoderm. 1983 85

The term autoimmune enteropathy (AIE) was applied to a form of "intractable diarrhoea" with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness.
 ...
PMID:From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome. 1991 78

Considerable progress has been made in understanding the Fas pathway at the molecular and cellular levels, but fundamental questions about the overall biological role of the Fas pathway remain unresolved. A major question is why lymphoproliferation caused by the lpr mutation of Fas and gld mutation of FasL ligand (FasL) is dominated by CD4(-) and CD8(-) double-negative alphabeta T cells (DN T cells) that are otherwise rare components of the peripheral T cell repertoire. A second unresolved question is why inactivation of the Fas pathway prevents organ-specific autoimmunity (including as type 1 diabetes and multiple sclerosis) while causing systemic lymphoproliferation? Understanding the mechanisms of these processes could uncover important aspects of the biological role of the Fas pathway and could have significant therapeutic implications. For example, revealing the basis of how inactivation of the Fas pathway prevents organ-specific autoimmunity could lead to new immunotherapeutic strategies to promote self tolerance without causing immunosuppression, as the Fas pathway is not essential for T cell activation. Here we discuss recent and new findings from my laboratory that address these questions. On the basis of these findings, we propose a new role for the Fas pathway in sequestration of DN T cells within the gut epithelium.
 ...
PMID:Analysis of gene profile, steady state proliferation and apoptosis of double-negative T cells in the periphery and gut epithelium provides new insights into the biological functions of the Fas pathway. 2006 10

Hyperglucagonemia following oral glucose ingestion in patients with type 1 diabetes (and type 2 diabetes) has been claimed to result from impaired intraislet insulin inhibition of glucagon. We looked at plasma glucagon responses to the oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) in patients with type 1 diabetes. Nine patients without residual beta-cell function [age: 25 +/- 9 yr; body mass index (BMI): 24 +/- 2 kg/m(2); fasting plasma glucose (FPG): 9.5 +/- 2.1 mM; Hb A(1c): 8.4 +/- 1.2% (mean +/- SD)] and eight healthy subjects (age: 28 +/- 5 yr; BMI: 24 +/- 3 kg/m(2); FPG: 5.3 +/- 0.2 mM; Hb A(1c): 5.0 +/- 0.1%) were examined on two separate occasions: 4-h 50-g OGTT and IIGI. Isoglycemia during IIGIs was obtained using 53 +/- 5 g of glucose in patients with type 1 diabetes and 30 +/- 3 g in control subjects (P < 0.001), resulting in gastrointestinal-mediated glucose disposal [100% x (glucose(OGTT) - glucose(IIGI)/glucose(OGTT))] of -6 +/- 9 and 40 +/- 6% (P < 0.01), respectively. Equal glucagon suppression during the two glucose stimuli was observed in healthy subjects, whereas patients with type 1 diabetes exhibited less inhibition in response to OGTT compared with IIGI (AUC: 1,519 +/- 129 vs. 1,240 +/- 86 pM.4 h; P = 0.03). This difference was even more pronounced during the initial 40 min with paradoxical hypersecretion of glucagon during OGTT and suppression during IIGI (AUC: 37 +/- 13 vs. -33 +/- 16 pM.40 min; P = 0.02). These results suggest that the inappropriate glucagon response to glucose in patients with type 1 diabetes occurs as a consequence of the oral administration way, suggesting a role of the gastrointestinal tract, possibly via glucagonotropic signaling from gut hormones (e.g., glucose-dependent insulinotropic polypeptide), in type 1 diabetic hyperglucagonemia.
 ...
PMID:Inappropriate glucagon response after oral compared with isoglycemic intravenous glucose administration in patients with type 1 diabetes. 2010 44

Selected bacteria, viruses, parasites and nonliving, immunologically active microbial substances prevent autoimmune diabetes in animal models. Such agents might also have a protective effect in humans by providing immune stimuli critical during childhood development. The 'hygiene hypothesis' proposes that reduced exposure to environmental stimuli, including microbes, underlies the rising incidence of childhood autoimmune diseases, including type 1 diabetes mellitus (T1DM). This hypothesis is supported by data that highlight the importance of infant exposure to environmental microbes for appropriate development of the immune system, which might explain the observation that administration of microbes or their components inhibits autoimmune disease in animals. This finding raises the possibility of using live, nonpathogenic microbes (for example, probiotics) or microbial components to modulate or 're-educate' the immune system and thereby vaccinate against T1DM. Progress has been assisted by the identification of receptors and pathways through which gut microbes influence development of the immune system. Such mechanistic data have moved a field that was once regarded as being on the scientific fringe to the mainstream, and support increased funding to advance this promising area of research in the hope that it might deliver the long awaited answer of how to safely prevent T1DM.
 ...
PMID:Immunomodulation with microbial vaccines to prevent type 1 diabetes mellitus. 2017 74

The question if enteroviruses could cause beta-cell damage and type 1 diabetes has become more and more relevant when recent studies have provided new evidence supporting this scenario. One important observation is the recent discovery of IFIH1 as a risk gene for type 1 diabetes. This gene is an innate immune system receptor for enteroviruses offering one possible mechanism for the diabetogenic effect of enteroviruses. This is further emphasized by the observations suggesting that the innate immune system is activated in the pancreatic islets of type 1 diabetic patients and that the innate immune system is important for the defense against the virus and for the regulation of adaptive immune system. Important progress has also been gained in studies analyzing pancreas tissue for possible presence of enteroviruses. Several studies have found enteroviruses in the pancreatic islets of type 1 diabetic patients using various methods. The virus seems to be located in the islets while exocrine pancreas is mostly uninfected. One recent study found the virus in the intestinal mucosa in the majority of diabetic patients. Enteroviruses can also infect cultured human pancreatic islets causing either rapid cell destruction or a persistent-like noncytolytic infection. Combined with all previous, epidemiological findings indicating the risk effect of enteroviruses in cross-sectional and prospective studies, these observations fit to a scenario where certain diabetogenic enterovirus variants establish persistent infection in gut mucosa and in the pancreatic islets. This in turn could lead to a local inflammation and the breakdown of tolerance in genetically susceptible individuals. This is also supported by mouse experiments showing that enteroviruses can establish prolonged infection in the pancreas and intestine, and some virus strains cause beta-cell damage and diabetes. In conclusion, recent studies have strengthened the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes. These findings open also new opportunities to explore the underlying mechanism and get closer to causal relationship.
 ...
PMID:Enteroviruses in the pathogenesis of type 1 diabetes. 2042 41

Celiac disease (CD) is more common in individuals with insulin dependent diabetes mellitus (T1D) than in the general population. HLA class II molecules DQ8 (DQB1*0302-DQA1*0301) and DQ2 (DQB1*0201-DQA1*0501) have been identified as key genetic risk factors in both diseases. While DQ8 conveys a higher risk for T1D, DQ2 is more frequent in CD. Less is known about the contribution of HLA class I. The gut immune system has been implicated in the pathogenesis of both diseases. The MICA, which is mainly expressed in the gastrointestinal epithelium and recognized by gammadeltaT lymphocytes and natural killer (NK) cells via the NKG2D, might play a role. The aim of our study was to identify possible HLA class I and MICA alleles and conserved extended haplotypes as risk factors for the development of CD in T1D. Three groups consisting of 37 individuals with T1D and CD, 67 individuals with only T1D and 70 controls were analyzed. HLA class I and MICA alleles were determined using Luminex technology. An occurrence of CD in individuals with T1D was most significantly associated with B*08 (P = 7.3 x 10(-13)), contributing more than any of the HLA class II alleles (DRB1*0301, P = 5.00 x 10(-10); DQB1*0201, P = 7.65 x 10(-8)). Moreover, the association with CD became stronger when B*08(B*08-DQA*0501-DQB1*0201-DRB1*0301, P = 5.07 x 10(-12)) was present in the DRB1*0301-DQB1*0201-DQA1*0501 (P = 5.00 x 10(-10)) extended haplotype. We suggest a combined influence of alleles present in the MICA*008-B*08-A1-DR3-DQ2 extended haplotype on the development of CD in Slovenian individuals with T1D, where B*08 or/and a gene located close to it may play an important role, independently of HLA class II.
 ...
PMID:An influence of HLA-A, B, DR, DQ, and MICA on the occurrence of Celiac disease in patients with type 1 diabetes. 2049 97

Several studies have shown that gut bacteria have a role in diabetes in murine models. Specific bacteria have been correlated with the onset of diabetes in a rat model. However, it is unknown whether human intestinal microbes have a role in the development of autoimmunity that often leads to type 1 diabetes (T1D), an autoimmune disorder in which insulin-secreting pancreatic islet cells are destroyed. High-throughput, culture-independent approaches identified bacteria that correlate with the development of T1D-associated autoimmunity in young children who are at high genetic risk for this disorder. The level of bacterial diversity diminishes overtime in these autoimmune subjects relative to that of age-matched, genotype-matched, nonautoimmune individuals. A single species, Bacteroides ovatus, comprised nearly 24% of the total increase in the phylum Bacteroidetes in cases compared with controls. Conversely, another species in controls, represented by the human firmicute strain CO19, represented nearly 20% of the increase in Firmicutes compared with cases overtime. Three lines of evidence are presented that support the notion that, as healthy infants approach the toddler stage, their microbiomes become healthier and more stable, whereas, children who are destined for autoimmunity develop a microbiome that is less diverse and stable. Hence, the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children.
 ...
PMID:Toward defining the autoimmune microbiome for type 1 diabetes. 2061 93

The rat treated with streptozotocin has been proposed as the most appropriate model of systemic oxidative stress for studying antioxidant therapies. In that sense, rosemary extracts have long been recognized as having antioxidant properties, and folic acid may be able to improve endothelial progenitor cell function. A mixture containing both has been tested as a possible nutraceutical to improve health complications in diabetes. We have developed the methodology to evaluate metabolic changes in the urine of streptozotocin-induced diabetic rats after supplementing their diet with rosemary extract obtained with supercritical fluids (SFE) containing 10% folic acid in an acute but short-term study. It has been done with a metabolomics approach using LC-QTOF as an analytical tool. About 20 endogenous metabolites have been identified by databases and MS/MS showing statistically significant changes. Among them, several amino acids and their metabolites point to changes due to the effect of the gut microbiota. In addition, the comparison between control and streptozotocin-diabetic rats has permitted the showing of some metabolic coincidences between type 1 diabetes and other (possible) autoimmune diseases such as autism and/or Crohn's disease, and the nutraceutical intervention has succeeded in inducing changes in such biomarkers.
 ...
PMID:Metabolomic approach with LC-QTOF to study the effect of a nutraceutical treatment on urine of diabetic rats. 2108 57

The incidence of type 1 diabetes is increasing and this may double the burden of disease in our youngest by 2020. The recent increase in incidence is mostly happening in the very young and those with moderate genetic susceptibility. Many environmental factors have been implicated, but no major determinants have been clearly identified, and the mechanisms of involvement remain elusive. This review summarizes current research efforts directed at understanding the possible reasons for this increase, including the role of viruses, gut microbiota, early life feeding patterns, perinatal factors and childhood growth patterns. It also provides a road map for future research directions.
 ...
PMID:The changing epidemiology of type 1 diabetes: why is it going through the roof? 2121 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>