Materiały źródłowe

• #1 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident.

• #2 On type 1 diabetes mellitus pathogenesis in: Endocrine Connections Volume 7 Issue 1 (2018)

  https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0347.xml

  Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident.

• #3 Type 1 diabetes: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000305.htm

  Type 1 diabetes is a lifelong (chronic) disease in which there is a high level of sugar (glucose) in the blood. […] Insulin is a hormone produced in the pancreas by special cells, called beta cells. The pancreas is below and behind the stomach. Insulin is needed to move glucose into cells. Inside the cells, glucose is stored and later used for energy. With type 1 diabetes, beta cells produce little or no insulin. […] The exact cause of type 1 diabetes is unknown. It is an autoimmune disorder. This is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. In people with type 1 diabetes, an infection or another trigger causes the body to mistakenly attack the beta cells in the pancreas that make insulin. The tendency to develop autoimmune diseases, including type 1 diabetes, can be inherited from your parents.

• #4 The heterogeneous pathogenesis of type 1 diabetes mellitus | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-019-0254-y

  Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic -cells that is mediated by the immune system. […] Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. […] Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. […] Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of -cells to inflammatory mediators. […] Environmental factors that modify the immune system, such as microbiota composition, microbial infections and nutrition, affect the development and course of the autoimmune response.

• #5 Etiopathogenesis of Type 1 Diabetes – T1D

  https://detect-t1d.com/clinician-portal/etiopathogenesis-of-t1d/

  Genetic susceptibility is mediated by polygenic features in HLA class II genes, which account for 40% to 50% of familial risk. […] Individuals with T1D are also more likely to have other autoimmune disorders as well as monogenic polyglandular autoimmune syndromes. […] However, 90% of people diagnosed with T1D have no family history of the disease.

• #6 Pathogenesis of type 1 diabetes mellitus – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-type-1-diabetes-mellitus/print

  The pathogenesis of type 1A diabetes is quite different from that of type 2 diabetes mellitus, in which both decreased insulin release (not on an autoimmune basis) and insulin resistance play an important role. Genome-wide association studies indicate that type 1 and type 2 diabetes’ genetic loci do not overlap, although inflammation (eg, interleukin-1 mediated) may play a role in islet beta cell loss in both types. […] GENETIC SUSCEPTIBILITY […] Polymorphisms of multiple genes are reported to influence the risk of type 1A diabetes (including HLA-DQalpha, HLA-DQbeta, HLA-DR, preproinsulin, the PTPN22 gene, CTLA-4, interferon-induced helicase, IL2 receptor (CD25), a lectin-like gene (KIAA0035), ERBB3e, and undefined gene at 12q). A meta-analysis of data from genome-wide association studies confirmed the above associations and identified four additional risk loci (BACH2, PRKCQ, CTSH, C1QTNF6) associated with an increased risk of type 1 diabetes.

• #7 Etiopathogenesis of Type 1 Diabetes – T1D

  https://detect-t1d.com/clinician-portal/etiopathogenesis-of-t1d/

  Genetic susceptibility is mediated by polygenic features in HLA class II genes, which account for 40% to 50% of familial risk. […] Individuals with T1D are also more likely to have other autoimmune disorders as well as monogenic polyglandular autoimmune syndromes. […] However, 90% of people diagnosed with T1D have no family history of the disease.

• #8 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://www.mdpi.com/2073-4425/13/4/706

  Collectively, the poor response of susceptible β-cells to enteroviral exposure could lead to their persistent infection, which, combined with an aberrant INF-mediated response, could result in significant changes in β-cell functions, such as ER stress, unfolded protein response, synthesis of novel autoantigens, dedifferentiation, and apoptosis. […] The theory of environmental factors, including diet, microbiome, toxins, and, above all, infections, being responsible for the initiation of islet autoimmunity is gaining ground in recent years. […] Enteroviral infections seem to have an important role in T1D pathology as β-cells are supposed to be susceptible to enteroviruses.

• #9 Diabetes: Mechanism, Pathophysiology and Management-A Review

  https://www.itmedicalteam.pl/articles/diabetes-mechanism-pathophysiology-and-managementa-review-101424.html

  Type 1 diabetes is an autoimmune disease in which the -cells of the pancreas do not produce sufficient insulin, a hormone which helps use blood sugar (glucose) for energy. […] T1DM is the result of a combination of genetic and environmental influences. It most commonly results from autoimmune destruction of insulin-producing -cells in the pancreas. […] Eisenbarth proposed that one or more environmental factors, such as enteroviruses, dietary factors or toxins, might trigger the development of T-cell dependent autoimmunity in genetically susceptible individuals. […] Autoimmunity is manifested by detectable antibodies to ICA512/IA-2, insulin autoantibody (IAA) and glutamic acid decarboxylase (GAD). […] Insulitis with gradual -cell destruction leads to pre-diabetes and finally to overt DM.

• #10 Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

  https://www.spandidos-publications.com/10.3892/br.2024.1770

  Evidence suggests that genetic characteristics, notably the genetics of HLA, specifically of the molecules DQ2 and DQ8, are a necessary but insufficient condition for the development of T1DM. […] This suggests that the origin of the disease depends on the interaction between multiple factors, involving predisposing genes and exposure to environmental factors that act as triggers. […] The potential of viral infections to trigger pancreatic islet autoimmunity in patients with T1DM has been a longstanding hypothesis. […] There is an increasing body of evidence that implicates persistent infections by certain viruses, particularly human enteroviruses, as more likely environmental triggers that may contribute to different stages of disease development. […] Studies show that infections with certain viruses play a crucial role in the pathogenesis of T1DM and can determine whether a genetically susceptible individual will develop this metabolic disease.

• #11 Diabetes: Mechanism, Pathophysiology and Management-A Review

  https://www.itmedicalteam.pl/articles/diabetes-mechanism-pathophysiology-and-managementa-review-101424.html

  Type 1 diabetes is an autoimmune disease in which the -cells of the pancreas do not produce sufficient insulin, a hormone which helps use blood sugar (glucose) for energy. […] T1DM is the result of a combination of genetic and environmental influences. It most commonly results from autoimmune destruction of insulin-producing -cells in the pancreas. […] Eisenbarth proposed that one or more environmental factors, such as enteroviruses, dietary factors or toxins, might trigger the development of T-cell dependent autoimmunity in genetically susceptible individuals. […] Autoimmunity is manifested by detectable antibodies to ICA512/IA-2, insulin autoantibody (IAA) and glutamic acid decarboxylase (GAD). […] Insulitis with gradual -cell destruction leads to pre-diabetes and finally to overt DM.

• #12 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://www.mdpi.com/2073-4425/13/4/706

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. […] It is becoming apparent that T1D is a highly heterogeneous disease influenced by a complex network of different factors, such as age, genetic predisposition, and environmental interactions, and that pancreatic β-cells play a significant role in initiating pathogenic processes through the crosstalk with immune cells. […] The early immune responses triggering insulitis are innate and include the activation of pattern recognition receptors by endogenous “danger signals” or exogenous ligands produced during viral infections on β-cells, which is a possible link between environmental risk factors and the development of T1D. […] Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic β-cells and immune cells and that the crosstalk between them is of utmost importance in T1D development.

• #13 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://www.mdpi.com/2073-4425/13/4/706

  Collectively, the poor response of susceptible β-cells to enteroviral exposure could lead to their persistent infection, which, combined with an aberrant INF-mediated response, could result in significant changes in β-cell functions, such as ER stress, unfolded protein response, synthesis of novel autoantigens, dedifferentiation, and apoptosis. […] The theory of environmental factors, including diet, microbiome, toxins, and, above all, infections, being responsible for the initiation of islet autoimmunity is gaining ground in recent years. […] Enteroviral infections seem to have an important role in T1D pathology as β-cells are supposed to be susceptible to enteroviruses.

• #14 Etiology and pathogenesis of type 1 diabetes – Malin Flodström-Tullberg group | Karolinska Institutet

  https://ki.se/en/research/research-areas-centres-and-networks/research-groups/etiology-and-pathogenesis-of-type-1-diabetes-malin-flodstrom-tullberg-group

  Type 1 diabetes is a common, chronic and life-threatening disease. […] Malin Flodstrm-Tullberg’s research group focuses on understanding the etiology and pathogenesis of the disease. […] The group studies genetic, environmental and pancreatic beta cell intrinsic factors and how these affect the immune system and contribute to disease development. […] Of particular interest is the role of the environment including microbial diversity and infections with common viruses, so-called enteroviruses, in the disease process. […] The role of interferons in the pathogenesis of type 1 diabetes. […] Defining the mechanism behind Coxsackievirus induced pancreatic beta cell damage and discovering new biomarkers for type 1 diabetes. […] Type III interferons are expressed in human pancreas at type 1 diabetes onset and induce immunostimulatory and antiviral activities in human beta cells.

• #15 What causes type 1 diabetes?

  https://www.bc.edu/bc-web/bcnews/science-tech-and-health/biology-and-genetics/new-insights-into-type-1-diabetes.html

  In autoimmune diseases, autoantibodies and immune cells target human proteins and insulin is the main target of the immune system in type 1 diabetes. […] Altindis and his colleagues have focused on molecular mimicry, a mechanism of autoimmune disease in which a foreign antigen that shares a structural similarity with a host protein can modify disease pathogenesis. […] Based on the central role of insulin in type 1 diabetes autoimmunity, we hypothesized that type 1 diabetes is caused by a molecular mimicry mechanism in which exposure to a microbial insulin stimulates the immune system against human insulin, Altindis said. […] Using cellular and animal models of type 1 diabetes, Altindis and his colleagues showed that molecular mimicry might be triggering type 1 diabetes. […] Colonization of the gut microbiome with Parabacteriodes distasonis increased type 1 diabetes rates by increasing the inflammation in different tissues, specifically in the pancreas, in mice used in type 1 diabetes T1D research, the team reported in the article „A Gut Microbial Peptide and Molecular Mimicry in the Pathogenesis of Type 1 Diabetes.”

• #16 Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

  https://www.spandidos-publications.com/10.3892/br.2024.1770

  Studies report the association between viral infections and the development of T1DM, but the immunological mechanisms involved and the link between viral infections and disease onset or progression are still unclear. […] One of the most commonly discussed possibilities is molecular mimicry which involves cross-reactive immunity against epitopes shared between viruses and human pancreatic -cells. […] This triggers a cross-reactive autoimmune response that eliminates the viral infection and the -cells of the pancreatic islets. […] This mechanism may explain how certain viruses may play a role in triggering T1DM. […] Enteroviruses have been widely associated with the pathogenesis of T1DM due to enterovirus-induced thymic dysfunction in natal or perinatal life. […] Infection of the thymus by enteroviruses can interfere with T cell maturation or lead to the production of autoreactive T cells, both being potentially involved in the development of T1DM. […] It has been shown that CV-B4 infection can have multiple effects on the thymus resulting in the dysregulation of tolerance involved in the pathogenesis of T1DM, but the specifics require further study.

• #17 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  The destruction of the cells of the endocrine pancreas in T1DM occurs most probably via apoptosis, a mechanism also known as programmed cell death, which includes a cascade of cysteine-asparaginase activations, known as caspases. Indeed, animal studies and in vitro experiments do support apoptosis as a major cell death type for cells; however, necrosis and necroptosis may be also important in humans. According to one hypothesis, inflammatory reaction with high levels of the proinflammatory cytokines IL-1, TNF- (tumor necrosis factor-) and INF- (interferon-) is induced by the autoreactive T lymphocytes within the islet microenvironment. These cytokines activate the caspase cascade. Other theories suggest that apoptosis is induced directly by contact of autoreactive T lymphocytes with cells via the perforating system or Fas/Fas ligand interaction. Even in this case, cytokines secretion disorder is required. The subpopulation of Tregs is of great interest and their quantitative and qualitative deficits in patients with the disease are very important. Prior to the onset of T1DM, a chronic atrophic inflammation within the islets of Langerhans is observed histologically, with the participation of T lymphocytes, macrophages, B lymphocytes and dendritic cells. This condition usually evolves over many months or years, when patients are asymptomatic and euglycemic. Symptomatic hyperglycemia occurs after a long latency period, which reflects the large number of functioning cells that need to be destroyed before the clinical manifestation of the disease.

• #18 On type 1 diabetes mellitus pathogenesis in: Endocrine Connections Volume 7 Issue 1 (2018)

  https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0347.xml

  Type 1 diabetes mellitus (T1DM) represents only around 10% of the diabetes cases worldwide, but occurs with increasing incidence much earlier in life. T1DM results from the autoimmune destruction of cells of the endocrine pancreas. […] The aim of this comprehensive review is to present updated information on the pathogenesis of T1DM. We will present genetic, environmental and immunologic factors that eventually destroy cells of the endocrine pancreas and lead to insulin deficiency. […] The destruction of the cells of the endocrine pancreas in T1DM occurs most probably via apoptosis, a mechanism also known as programmed cell death, which includes a cascade of cysteine-asparaginase activations, known as caspases. Indeed, animal studies and in vitro experiments do support apoptosis as a major cell death type for cells; however, necrosis and necroptosis may be also important in humans.

• #19 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  The destruction of the cells of the endocrine pancreas in T1DM occurs most probably via apoptosis, a mechanism also known as programmed cell death, which includes a cascade of cysteine-asparaginase activations, known as caspases. Indeed, animal studies and in vitro experiments do support apoptosis as a major cell death type for cells; however, necrosis and necroptosis may be also important in humans. According to one hypothesis, inflammatory reaction with high levels of the proinflammatory cytokines IL-1, TNF- (tumor necrosis factor-) and INF- (interferon-) is induced by the autoreactive T lymphocytes within the islet microenvironment. These cytokines activate the caspase cascade. Other theories suggest that apoptosis is induced directly by contact of autoreactive T lymphocytes with cells via the perforating system or Fas/Fas ligand interaction. Even in this case, cytokines secretion disorder is required. The subpopulation of Tregs is of great interest and their quantitative and qualitative deficits in patients with the disease are very important. Prior to the onset of T1DM, a chronic atrophic inflammation within the islets of Langerhans is observed histologically, with the participation of T lymphocytes, macrophages, B lymphocytes and dendritic cells. This condition usually evolves over many months or years, when patients are asymptomatic and euglycemic. Symptomatic hyperglycemia occurs after a long latency period, which reflects the large number of functioning cells that need to be destroyed before the clinical manifestation of the disease.

• #20 Type 1 Diabetes: Pathophysiology, Molecular Mechanisms, Genetic Insights – Clinical Tree

  https://clinicalpub.com/type-diabetes-pathophysiology-molecular-mechanisms-genetic-insights/

  Selective destruction of pancreatic beta cells results in insulinopenia. The impairment in insulin secretion is also partially functional and caused by the inhibition of insulin secretion by cytokines interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-), TNF-, and interferon gamma (IFN-). Insulin resistance may also play a role in T1DM pathogenesis and cannot be explained simply by obesity or puberty. […] After diagnosis, T1DM patients are more insulin resistant than nondiabetic controls despite similar adiposity, body fat composition, and high-density lipoprotein (HDL) cholesterol. […] Significant insulin resistance has been documented in T1DM patients at or near hemoglobin A1c (HbA1c) targets, suggesting that resistance to insulin action on glucose and nonesterified fatty acid suppression are not mediated by prevailing glycemia.

• #21 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  The destruction of the cells of the endocrine pancreas in T1DM occurs most probably via apoptosis, a mechanism also known as programmed cell death, which includes a cascade of cysteine-asparaginase activations, known as caspases. Indeed, animal studies and in vitro experiments do support apoptosis as a major cell death type for cells; however, necrosis and necroptosis may be also important in humans. According to one hypothesis, inflammatory reaction with high levels of the proinflammatory cytokines IL-1, TNF- (tumor necrosis factor-) and INF- (interferon-) is induced by the autoreactive T lymphocytes within the islet microenvironment. These cytokines activate the caspase cascade. Other theories suggest that apoptosis is induced directly by contact of autoreactive T lymphocytes with cells via the perforating system or Fas/Fas ligand interaction. Even in this case, cytokines secretion disorder is required. The subpopulation of Tregs is of great interest and their quantitative and qualitative deficits in patients with the disease are very important. Prior to the onset of T1DM, a chronic atrophic inflammation within the islets of Langerhans is observed histologically, with the participation of T lymphocytes, macrophages, B lymphocytes and dendritic cells. This condition usually evolves over many months or years, when patients are asymptomatic and euglycemic. Symptomatic hyperglycemia occurs after a long latency period, which reflects the large number of functioning cells that need to be destroyed before the clinical manifestation of the disease.

• #22 Type 1 diabetes – Wikipedia

  https://en.wikipedia.org/wiki/Type_1_diabetes

  The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis, induced or exacerbated by CD8+ T-cells and macrophages. Necroptosis can be triggered by activated T cells which secrete toxic granzymes and perforin or indirectly as a result of reduced blood flow or the generation of reactive oxygen species. As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death. Pancreases from people with type 1 diabetes also have signs of beta cell apoptosis, linked to activation of the janus kinase and TYK2 pathways. […] Partial ablation of beta-cell function is enough to cause diabetes; at diagnosis, people with type 1 diabetes often still have detectable beta-cell function. Once insulin therapy is started, many people experience a resurgence in beta-cell function, and can go some time with little-to-no insulin treatment called the „honeymoon phase”. This eventually fades as beta-cells continue to be destroyed, and insulin treatment is required again. Beta-cell destruction is not always complete, as 30-80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis.

• #23 Type 1 diabetes mellitus: retrospect and prospect | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-024-01197-z

  The pathogenesis of T1D involves both cellular and humoral-mediated autoimmune destruction of pancreatic beta cells. Autoreactive CD4+ and CD8+ T cells infiltrate the islets, releasing inflammatory cytokines and directly attacking beta cells. B cells produce autoantibodies that form immune complexes activating complement. […] The autoimmune destruction of beta cells leads to loss of insulin production and secretion, resulting in impaired glucose homeostasis. Normal beta cells have a remarkable capacity to upregulate or downregulate insulin secretion in response to blood glucose levels. In T1D, this ability to tightly regulate insulin release is damaged early in pathogenesis due to beta cell stresses that disrupt secretory function. […] CD4+ and CD8+ T cells are major players in the autoimmune attack against beta cells.

• #24 Type 1 diabetes mellitus: retrospect and prospect | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-024-01197-z

  The pathogenesis of T1D involves both cellular and humoral-mediated autoimmune destruction of pancreatic beta cells. Autoreactive CD4+ and CD8+ T cells infiltrate the islets, releasing inflammatory cytokines and directly attacking beta cells. B cells produce autoantibodies that form immune complexes activating complement. […] The autoimmune destruction of beta cells leads to loss of insulin production and secretion, resulting in impaired glucose homeostasis. Normal beta cells have a remarkable capacity to upregulate or downregulate insulin secretion in response to blood glucose levels. In T1D, this ability to tightly regulate insulin release is damaged early in pathogenesis due to beta cell stresses that disrupt secretory function. […] CD4+ and CD8+ T cells are major players in the autoimmune attack against beta cells.

• #25 On type 1 diabetes mellitus pathogenesis in: Endocrine Connections Volume 7 Issue 1 (2018)

  https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0347.xml

  The disturbed immune response includes the humoral immunity arm too, producing autoantibodies that may precede the onset of clinical manifestation of T1DM for years. The main autoantibodies detected in patients with T1DM are those against GAD65, tyrosyl phosphatase (IA-2), insulin (IAA) and zinc transporter (ZnT8). […] T1DM is the result of the autoimmune destruction of cells of the endocrine pancreas, leading to insulin deficiency. The process of this autoimmune destruction occurs in genetically susceptible individuals following the contribution of one or more environmental factors and usually develops over several months or years, when patients are asymptomatic and euglycemic but present positive relevant autoantibodies. Symptomatic hyperglycemia and diabetes supervene after a long latency period, which reflects the large percentage of cells that need to be destroyed or dysfunctioned first before overt diabetes become evident.

• #26 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9032728/

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing -cells in pancreatic islets. […] T-lymphocyte-mediated insulitis, followed by the presence of one or more type of autoantibody (AAb) against insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 or IA-2, and zinc transporter 8 (ZnT8), is indicative of the immunological onset of T1D. […] It is becoming apparent that T1D is a highly heterogeneous disease influenced by a complex network of different factors, such as age, genetic predisposition, and environmental interactions, and that pancreatic -cells play a significant role in initiating pathogenic processes through the crosstalk with immune cells. […] The early immune responses triggering insulitis are innate and include the activation of pattern recognition receptors by endogenous danger signals or exogenous ligands produced during viral infections on -cells, which is a possible link between environmental risk factors and the development of T1D.

• #27 Type 1 diabetes mellitus: retrospect and prospect | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-024-01197-z

  Autoantibodies directed against islet autoantigens are a hallmark of T1D. Their presence indicates ongoing autoimmunity years before clinical diagnosis. Common islet autoantibody specificities include insulin, GAD65, IA-2, and ZnT8. These autoantibodies are produced by B cells that receive T cell help in the islet infiltrate and pancreatic lymph nodes. […] The clinical presentation of type 1 diabetes (T1D) reflects the metabolic consequences of insulin deficiency caused by autoimmune beta cell destruction. […] Preventing and ultimately curing type 1 diabetes (T1D) remains an elusive goal despite extensive research. Prevention encompasses primary strategies to intercept disease before onset, secondary efforts to preserve residual beta cell mass at diagnosis, and tertiary approaches to halt progression of complications. A cure likely requires regenerating functional beta cells or restoring endogenous insulin production. […] A complete cure likely requires reconstituting a fully functional beta cell mass capable of glucose-responsive insulin secretion after autoimmunity has developed. This remains an aspirational goal.

• #28 On type 1 diabetes mellitus pathogenesis in: Endocrine Connections Volume 7 Issue 1 (2018)

  https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0347.xml

  The disturbed immune response includes the humoral immunity arm too, producing autoantibodies that may precede the onset of clinical manifestation of T1DM for years. The main autoantibodies detected in patients with T1DM are those against GAD65, tyrosyl phosphatase (IA-2), insulin (IAA) and zinc transporter (ZnT8). […] T1DM is the result of the autoimmune destruction of cells of the endocrine pancreas, leading to insulin deficiency. The process of this autoimmune destruction occurs in genetically susceptible individuals following the contribution of one or more environmental factors and usually develops over several months or years, when patients are asymptomatic and euglycemic but present positive relevant autoantibodies. Symptomatic hyperglycemia and diabetes supervene after a long latency period, which reflects the large percentage of cells that need to be destroyed or dysfunctioned first before overt diabetes become evident.

• #29 Predictors and Pathogenesis of Type 1 Diabetes | Oncohema Key

  https://oncohemakey.com/predictors-and-pathogenesis-of-type-1-diabetes/

  Fig. 3.1 Model showing the progress of disease and potential stages of predictability and prevention of T1D relating it to the loss of -cell mass and time. […] As described above, in addition to genetic susceptibility, various other trigger agents are involved in the initiation and progression of autoimmune T1D. […] More than two dozen autoantigen-related autoantibodies have been implicated although four major islet autoantibodies have drawn significant attention: insulin (or proinsulin or IAA), GAD isoforms (65 and 67), tyrosine phosphatase-related islet antigens (IA-2 or ICA512), and the most recently identified zinc transporter (ZnT8). […] However, the positive detection of any one of the autoantibodies mentioned only imparts a marginal increase in the risk of developing T1D and to date it has not been possible to reliably predict progression to clinical disease although incremental increases in disease risk were found in individuals who were positive for two, three, or more autoantibodies.

• #30 Predictors and Pathogenesis of Type 1 Diabetes | Oncohema Key

  https://oncohemakey.com/predictors-and-pathogenesis-of-type-1-diabetes/

  Relative risk was also found to vary dependant on autoantibody type with some reports emerging that the most influencing antibody is insulin, as identified in NOD mice and as the only -cell-specific autoantibody identified in T1D. […] Cumulative evidence indicates the multifactorial nature of T1D due to associated complex immunology, and this necessitates the use of a combinatorial screening method to identify the individuals at risk of developing T1D. […] Cytokines have been proposed as one of the major inducers of -cell damage especially the type 1 cytokines (Th1) such as interferon gamma (IFN-), tumor necrosis factor- (TNF-), and IL-2 and they are considered high risk with approximately 40 % of patients going on to develop T1D within 5 years. […] Given that T1D is primarily an autoimmune disease, the mechanisms of which are poorly understood, the actions of a handful of antigens such as insulin, GAD isoforms (GAD65 67), IA-2, and ZnT8 are known to transform into autoantigens.

• #31 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9032728/

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic -cells and immune cells and that the crosstalk between them is of utmost importance in T1D development. […] -cells are not just passive targets but actively participate and possibly amplify pathogenic processes. […] Recent findings also reveal the possible involvement of hybrid and chimeric neoepitopes, formed in the transpeptidation reaction in stressed -cells, in diabetogenic CD4+ T-cell activation. […] The exposure of human -cells to pro-inflammatory cytokines IFN, IL1-, and IFN results in chromatin remodelling, alternative splicing, and first exon usage, leading to the differential expression of genes, most notably increased expression of HLA-I, which, together with ER stress and -cell apoptosis, may lead to an increased presentation of neoantigens, thus contributing to the recruitment of auto-reactive CD8+ T cells that selectively attack -cells.

• #32 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9032728/

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic -cells and immune cells and that the crosstalk between them is of utmost importance in T1D development. […] -cells are not just passive targets but actively participate and possibly amplify pathogenic processes. […] Recent findings also reveal the possible involvement of hybrid and chimeric neoepitopes, formed in the transpeptidation reaction in stressed -cells, in diabetogenic CD4+ T-cell activation. […] The exposure of human -cells to pro-inflammatory cytokines IFN, IL1-, and IFN results in chromatin remodelling, alternative splicing, and first exon usage, leading to the differential expression of genes, most notably increased expression of HLA-I, which, together with ER stress and -cell apoptosis, may lead to an increased presentation of neoantigens, thus contributing to the recruitment of auto-reactive CD8+ T cells that selectively attack -cells.

• #33 PATHOGENESIS OF TYPE 1 DIABETES – UCDR

  https://www.ucdr.be/index.php/pathogenesis-of-type-1-diabetes/

  Two other research lines from the Eizirik group focus on the role of endoplasmic reticulum (ER) stress and alternative splicing in -cell dysfunction and death. […] They were the first to show that cytokines induce ER stress in -cells and that ER stress markers are present in islets from type 1 diabetes individuals. […] Recent findings from his group identified the key role for IFNa in the induction of three hallmarks of early human b-cell dysfunction in type 1 diabetes, namely HLA class I overexpression, ER stress and apoptosis. […] The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. […] Interferon-alpha mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes.

• #34 PATHOGENESIS OF TYPE 1 DIABETES – UCDR

  https://www.ucdr.be/index.php/pathogenesis-of-type-1-diabetes/

  Two other research lines from the Eizirik group focus on the role of endoplasmic reticulum (ER) stress and alternative splicing in -cell dysfunction and death. […] They were the first to show that cytokines induce ER stress in -cells and that ER stress markers are present in islets from type 1 diabetes individuals. […] Recent findings from his group identified the key role for IFNa in the induction of three hallmarks of early human b-cell dysfunction in type 1 diabetes, namely HLA class I overexpression, ER stress and apoptosis. […] The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. […] Interferon-alpha mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes.

• #35 Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

  https://www.mdpi.com/1422-0067/24/4/3300

  Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. […] Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. […] The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. […] The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. […] The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications.

• #36 Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes | IntechOpen

  https://www.intechopen.com/chapters/43297

  Unlike type 2 diabetes, which is caused by the loss of insulin sensitivity, type 1 diabetes is caused by insulin deficiency following destruction of insulin-producing pancreatic cells. […] Accumulating evidence suggests an involvement of endoplasmic reticulum (ER) stress in multiple biological processes during the development of type 1 diabetes. […] Furthermore, cell loss caused by autoimmune attack results in an increased ER burden on the rest pancreatic cells and induces unfolded protein response (UPR) and ER stress, which further exacerbates cell death. […] In type 1 diabetes, autoimmune-mediated destruction of cell leads to insufficient insulin production and inability of cells to take up glucose. […] To fulfill the requirement for secreting large amount of insulin, the pancreatic cells are equipped with highly developed ER, leading to the vulnerability of cell to ER stress.

• #37 Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes | IntechOpen

  https://www.intechopen.com/chapters/43297

  In type 1 diabetes, the loss of cell increases the burden of insulin secretion on the residual cells. […] On the other hand, it also increases the ER burden of residual cells, which further exacerbates cell death. […] The accumulation of unfolded or mis-folded proteins in the ER leads a protective pathway to restore ER function, termed as unfolded protein response (UPR). […] Exhaustion of the protein folding machineries or insufficient energy supply increases the accumulation of unfolded or mis-folded proteins in ER, which is responsible for the activation of UPR. […] However, once the stress is beyond the compensatory capacity of UPR, the cells would undergo apoptosis. […] The mechanisms underlying ER stress induced cell death are not fully elucidated, due to the fact that multiple potential participants involved but little clarity on the dominant death effectors in a particular cellular context.

• #38 Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes | IntechOpen

  https://www.intechopen.com/chapters/43297

  In type 1 diabetes, the loss of cell increases the burden of insulin secretion on the residual cells. […] On the other hand, it also increases the ER burden of residual cells, which further exacerbates cell death. […] The accumulation of unfolded or mis-folded proteins in the ER leads a protective pathway to restore ER function, termed as unfolded protein response (UPR). […] Exhaustion of the protein folding machineries or insufficient energy supply increases the accumulation of unfolded or mis-folded proteins in ER, which is responsible for the activation of UPR. […] However, once the stress is beyond the compensatory capacity of UPR, the cells would undergo apoptosis. […] The mechanisms underlying ER stress induced cell death are not fully elucidated, due to the fact that multiple potential participants involved but little clarity on the dominant death effectors in a particular cellular context.

• #39 Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes | IntechOpen

  https://www.intechopen.com/chapters/43297

  The primary purpose of ER stress response is to compensate the damage caused by the disturbances of normal ER function. However, persistence of ER dysfunction would eventually render cells undergoing apoptosis. […] Collectively, there is convincing evidence that ER stress plays an essential role in cell destruction during the course of type 1 diabetes.

• #40 Examining the Role of Innate Immunity in Type 1 Diabetes Pathogenesis – Helmsley Charitable Trust

  https://helmsleytrust.org/news-and-insights/examining-the-role-of-innate-immunity-in-type-1-diabetes-pathogenesis/

  Type 1 Diabetes Program Officer […] To make novel interventions that change the course of the disease a reality, more research is necessary into the mechanisms that cause it in the first place. […] In T1D, the target is pancreatic beta cells, which produce insulin. This leads to subsequent inability to regulate blood sugar levels and long-term health consequences. […] The vast majority of research to date on immunology in T1D has focused on the adaptive immune response. […] there is a growing body of evidence that the innate immune system also plays a role in the development of T1D. Innate immune cells, like macrophages, infiltrate the pancreas during the onset of T1D, producing inflammatory substances that may influence the activation of T cells and the continued attack on beta cells in early stage T1D.

• #41 Examining the Role of Innate Immunity in Type 1 Diabetes Pathogenesis – Helmsley Charitable Trust

  https://helmsleytrust.org/news-and-insights/examining-the-role-of-innate-immunity-in-type-1-diabetes-pathogenesis/

  Type 1 Diabetes Program Officer […] To make novel interventions that change the course of the disease a reality, more research is necessary into the mechanisms that cause it in the first place. […] In T1D, the target is pancreatic beta cells, which produce insulin. This leads to subsequent inability to regulate blood sugar levels and long-term health consequences. […] The vast majority of research to date on immunology in T1D has focused on the adaptive immune response. […] there is a growing body of evidence that the innate immune system also plays a role in the development of T1D. Innate immune cells, like macrophages, infiltrate the pancreas during the onset of T1D, producing inflammatory substances that may influence the activation of T cells and the continued attack on beta cells in early stage T1D.

• #42 Understanding and Targeting Innate Immunity in Type 1 Diabetes Pathogenesis – Helmsley Charitable Trust

  https://helmsleytrust.org/request_for_proposal/innate-immunity-t1d-rfp/

  T1D is a complex autoimmune disease where insulin-producing beta cells in the pancreas are targeted by immune cells. […] Understanding these drivers of disease could lead to discoveries of new drug targets, guide intervention strategies to halt the disease, or improve prediction of disease development. […] However, innate immune cells are the first and most abundant type of immune cells in the pancreas, especially in individuals with T1D. […] Moreover, data, mostly generated from animal experiments, suggests that these cells might play different roles in T1D: from activating T cells and/or recruiting them to the pancreatic islets, to promoting inflammation or inducing immune tolerance. […] However, what leads to an increase in innate immune cells in the pancreas during T1D, its significance, and what role these cells play in disease in humans is not yet fully understood.

• #43 Understanding and Targeting Innate Immunity in Type 1 Diabetes Pathogenesis – Helmsley Charitable Trust

  https://helmsleytrust.org/request_for_proposal/innate-immunity-t1d-rfp/

  T1D is a complex autoimmune disease where insulin-producing beta cells in the pancreas are targeted by immune cells. […] Understanding these drivers of disease could lead to discoveries of new drug targets, guide intervention strategies to halt the disease, or improve prediction of disease development. […] However, innate immune cells are the first and most abundant type of immune cells in the pancreas, especially in individuals with T1D. […] Moreover, data, mostly generated from animal experiments, suggests that these cells might play different roles in T1D: from activating T cells and/or recruiting them to the pancreatic islets, to promoting inflammation or inducing immune tolerance. […] However, what leads to an increase in innate immune cells in the pancreas during T1D, its significance, and what role these cells play in disease in humans is not yet fully understood.

• #44 Type 1 diabetes: B cell-derived natural antibodies suppress autoimmune pathogenesis – UAB News

  https://www.uab.edu/news/research/item/13888-type-1-diabetes-b-cell-derived-natural-antibodies-suppress-autoimmune-pathogenesis

  The UAB researchers created group A carbohydrate-reactive monoclonal antibodies to probe possible targets of the IgM antibodies, and they found that the monoclonal antibodies recognized insulin secretory granule-associated GlcNAc antigen portions, known as epitopes, on pancreatic beta cells. […] These epitopes appeared to be generated during autophagosomal degradation of mature carbohydrates, one of the steps of apoptosis, or the programmed cell death, of beta cells. […] Experiments showed that the GlcNAc-reactive B cell response to group A streptococci appeared to delay Type 1 diabetes, potentially by facilitating efficient clearance of apoptotic beta cells, thereby limiting activation of killer and helper T cells that ultimately would destroy healthy beta cells. […] Collectively, our observations indicate a significant involvement of cryptic glycan epitopes in immunological recognition of senescent beta cells, and that clonal composition of the GlcNAc-specific B cell repertoire during early life can significantly influence immune responsiveness to Type 1 diabetes autoantigens.

• #45 Type 1 diabetes: B cell-derived natural antibodies suppress autoimmune pathogenesis – UAB News

  https://www.uab.edu/news/research/item/13888-type-1-diabetes-b-cell-derived-natural-antibodies-suppress-autoimmune-pathogenesis

  The UAB researchers created group A carbohydrate-reactive monoclonal antibodies to probe possible targets of the IgM antibodies, and they found that the monoclonal antibodies recognized insulin secretory granule-associated GlcNAc antigen portions, known as epitopes, on pancreatic beta cells. […] These epitopes appeared to be generated during autophagosomal degradation of mature carbohydrates, one of the steps of apoptosis, or the programmed cell death, of beta cells. […] Experiments showed that the GlcNAc-reactive B cell response to group A streptococci appeared to delay Type 1 diabetes, potentially by facilitating efficient clearance of apoptotic beta cells, thereby limiting activation of killer and helper T cells that ultimately would destroy healthy beta cells. […] Collectively, our observations indicate a significant involvement of cryptic glycan epitopes in immunological recognition of senescent beta cells, and that clonal composition of the GlcNAc-specific B cell repertoire during early life can significantly influence immune responsiveness to Type 1 diabetes autoantigens.

• #46 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9032728/

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing -cells in pancreatic islets. […] T-lymphocyte-mediated insulitis, followed by the presence of one or more type of autoantibody (AAb) against insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 or IA-2, and zinc transporter 8 (ZnT8), is indicative of the immunological onset of T1D. […] It is becoming apparent that T1D is a highly heterogeneous disease influenced by a complex network of different factors, such as age, genetic predisposition, and environmental interactions, and that pancreatic -cells play a significant role in initiating pathogenic processes through the crosstalk with immune cells. […] The early immune responses triggering insulitis are innate and include the activation of pattern recognition receptors by endogenous danger signals or exogenous ligands produced during viral infections on -cells, which is a possible link between environmental risk factors and the development of T1D.

• #47 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://www.mdpi.com/2073-4425/13/4/706

  Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. […] It is becoming apparent that T1D is a highly heterogeneous disease influenced by a complex network of different factors, such as age, genetic predisposition, and environmental interactions, and that pancreatic β-cells play a significant role in initiating pathogenic processes through the crosstalk with immune cells. […] The early immune responses triggering insulitis are innate and include the activation of pattern recognition receptors by endogenous “danger signals” or exogenous ligands produced during viral infections on β-cells, which is a possible link between environmental risk factors and the development of T1D. […] Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic β-cells and immune cells and that the crosstalk between them is of utmost importance in T1D development.

• #48 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident.

• #49 On type 1 diabetes mellitus pathogenesis in: Endocrine Connections Volume 7 Issue 1 (2018)

  https://ec.bioscientifica.com/view/journals/ec/7/1/EC-17-0347.xml

  Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident.

• #50 On type 1 diabetes mellitus pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5776665/

  Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident.

• #51 Pathogenesis of Type 1 Diabetes Mellitus and Rodent Experimental Models – Gvazava – Acta Naturae

  https://actanaturae.ru/2075-8251/article/view/10352/en_US

  T1DM symptoms are believed to manifest themselves usually when 90-95% of -cells die. […] According to modern concepts of T1DM pathogenesis, -cells can die as a result of various pathological processes. One of these is the destruction or necrosis of -cells, and another is apoptosis or genetically programmed cell death. […] Cytokines play an important role in the cell death process. Cytokines, such as IFN and IL-2, are considered triggers of insulitis, which are capable of activating a mechanism of signaling leading to the death of pancreatic -cells. […] The main feature of type 1 diabetes mellitus is the autoimmune destruction of pancreatic -cells, which leads to insufficient insulin production. […] Insufficient insulin production in animal models is caused by the action of many different mechanisms, ranging from chemical ablation of -cells to the spontaneous development of autoimmune diabetes.

• #52 Type 1 diabetes – Wikipedia

  https://en.wikipedia.org/wiki/Type_1_diabetes

  The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis, induced or exacerbated by CD8+ T-cells and macrophages. Necroptosis can be triggered by activated T cells which secrete toxic granzymes and perforin or indirectly as a result of reduced blood flow or the generation of reactive oxygen species. As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death. Pancreases from people with type 1 diabetes also have signs of beta cell apoptosis, linked to activation of the janus kinase and TYK2 pathways. […] Partial ablation of beta-cell function is enough to cause diabetes; at diagnosis, people with type 1 diabetes often still have detectable beta-cell function. Once insulin therapy is started, many people experience a resurgence in beta-cell function, and can go some time with little-to-no insulin treatment called the „honeymoon phase”. This eventually fades as beta-cells continue to be destroyed, and insulin treatment is required again. Beta-cell destruction is not always complete, as 30-80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis.

• #53 Type 1 diabetes – Wikipedia

  https://en.wikipedia.org/wiki/Type_1_diabetes

  Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon, which acts in antagonism with insulin to regulate blood sugar and metabolism. Progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon hypoglycemia prevents a glucagon-mediated rescue of glucose levels. […] Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while C-peptide levels (indicative of islet-derived insulin), decline by up to 45%. Insulin production will continue to fall as the immune system destroys beta cells, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia. Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia. Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.

• #54 Type 1 diabetes – Wikipedia

  https://en.wikipedia.org/wiki/Type_1_diabetes

  Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon, which acts in antagonism with insulin to regulate blood sugar and metabolism. Progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon hypoglycemia prevents a glucagon-mediated rescue of glucose levels. […] Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while C-peptide levels (indicative of islet-derived insulin), decline by up to 45%. Insulin production will continue to fall as the immune system destroys beta cells, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia. Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia. Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.

• #55 Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9032728/

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] Indeed, it is becoming obvious that the pathogenesis of T1D involves both pancreatic -cells and immune cells and that the crosstalk between them is of utmost importance in T1D development. […] -cells are not just passive targets but actively participate and possibly amplify pathogenic processes. […] Recent findings also reveal the possible involvement of hybrid and chimeric neoepitopes, formed in the transpeptidation reaction in stressed -cells, in diabetogenic CD4+ T-cell activation. […] The exposure of human -cells to pro-inflammatory cytokines IFN, IL1-, and IFN results in chromatin remodelling, alternative splicing, and first exon usage, leading to the differential expression of genes, most notably increased expression of HLA-I, which, together with ER stress and -cell apoptosis, may lead to an increased presentation of neoantigens, thus contributing to the recruitment of auto-reactive CD8+ T cells that selectively attack -cells.

• #56 The heterogeneous pathogenesis of type 1 diabetes mellitus | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-019-0254-y

  Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process. […] The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.

• #57 The heterogeneous pathogenesis of type 1 diabetes mellitus | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-019-0254-y

  Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process. […] The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.

• #58 ADA journals convene special symposium to examine topics in heterogeneity of type 1 diabetes – ADA Meeting News

  https://www.adameetingnews.org/ada-journals-convene-special-symposium-to-examine-topics-in-heterogeneity-of-type-1-diabetes/

  A special joint symposium presented Monday, June 24, by the ADA’s journals—Diabetes®, Diabetes Care®, and Diabetologia®—highlighted various aspects of type 1 diabetes heterogeneity and how increasing knowledge may lead to personalized or pathogenic-derived treatment. […] Carmella Evans-Molina, MD, PhD, Indiana University School of Medicine, discussed the therapeutic challenges associated with heterogeneity in type 1 diabetes and how improving our understanding of various aspects of that heterogeneity might accelerate the development of new therapies. […] “Heterogeneity has a really important role in helping us understand type 1 diabetes progression and in helping us inform clinical trial interventions,” Dr. Evans-Molina said. “The impacts of metabolic heterogeneity during disease progression, for example, have really important implications in our trial design, and there are likely baseline immune signatures that can help us identify people who are potentially prime to respond to disease-modifying therapy.”

• #59 Genetics, pathogenesis and clinical interventions in type 1 diabetes | Nature

  https://www.nature.com/articles/nature08933

  Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. […] The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. […] Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. […] Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies. […] Recent progress towards understanding the pathogenetics and genetics of diabetes has been rapid, thanks to extensive research in rodent models and in diabetes patients.

• #60 Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus | Cardiovascular Diabetology – Endocrinology Reports | Full Text

  https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-024-00181-w

  This review explores the immunomodulatory potential of Teplizumab and its impact on pancreatic -cell function in T1D. Characterized by the autoimmune destruction of insulin-producing beta cells, T1Ds management involves maintaining glycemic control through exogenous insulin. Teplizumab, a humanized monoclonal antibody targeting the CD3 antigen, has shown promise in delaying T1D onset and preserving residual -cell function. […] The synthesis of findings from various trials demonstrates Teplizumabs efficacy in preserving C-peptide levels and reducing exogenous insulin requirements, particularly in recent-onset T1D. […] T1D stems from the autoimmune destruction of insulin-producing pancreatic beta cells. This process involves beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes.

• #61 Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus | Cardiovascular Diabetology – Endocrinology Reports | Full Text

  https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-024-00181-w

  The concerted action of activated TH1 CD4+T cells, CD8+cytotoxic T cells, and macrophages contributes to beta cell destruction through granzymes, perforin, cytokines, and reactive oxygen molecules. […] Teplizumab exhibits promise in preserving -cell function in recent-onset T1D by altering autoreactive CD8+T cell phenotypes and depleting effector T cells while preserving regulatory T cells. This modulation is crucial for -cell function, evidenced by improved and stabilized function post-treatment. […] Teplizumab is linked to preserving residual -cell function and reducing exogenous insulin use. […] Teplizumab, a subject of interest for over two decades, is believed to influence the progression of Type 1 Diabetes from stage 2 to stage 3 by preserving -cell function. […] The retention of insulin production facilitated by Teplizumab, even beyond the new-onset period, has been associated with a more favourable prognosis. […] Teplizumab is more effective in preventing beta-cell function loss as evaluated by C-peptide and providing glycemic control at lower insulin doses if administered to patients before or after the diagnosis of T1D.

• #62 Teplizumab’s immunomodulatory effects on pancreatic β-cell function in type 1 diabetes mellitus | Cardiovascular Diabetology – Endocrinology Reports | Full Text

  https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-024-00181-w

  The concerted action of activated TH1 CD4+T cells, CD8+cytotoxic T cells, and macrophages contributes to beta cell destruction through granzymes, perforin, cytokines, and reactive oxygen molecules. […] Teplizumab exhibits promise in preserving -cell function in recent-onset T1D by altering autoreactive CD8+T cell phenotypes and depleting effector T cells while preserving regulatory T cells. This modulation is crucial for -cell function, evidenced by improved and stabilized function post-treatment. […] Teplizumab is linked to preserving residual -cell function and reducing exogenous insulin use. […] Teplizumab, a subject of interest for over two decades, is believed to influence the progression of Type 1 Diabetes from stage 2 to stage 3 by preserving -cell function. […] The retention of insulin production facilitated by Teplizumab, even beyond the new-onset period, has been associated with a more favourable prognosis. […] Teplizumab is more effective in preventing beta-cell function loss as evaluated by C-peptide and providing glycemic control at lower insulin doses if administered to patients before or after the diagnosis of T1D.

• #63 Autoimmunity: Treating type-1 diabetes with an epigenetic drug | eLife

  https://elifesciences.org/articles/05720

  Fu et al. reveal that I-BET151 works to resolve inflammation of the islet cells (insulitis) mainly by two mechanisms. Firstly, it encourages macrophages in the pancreas to convert from being pro-inflammatory to being anti-inflammatory type. This inhibits the further recruitment of T cells and dampens inflammation. Secondly, I-BET151 enhances the proliferation of islet cells and enhances insulin production. […] Another critical aspect of the development of type-1 diabetes, along with the inflammation caused by immune cells, is the response of the cells. Attack by the immune system suppresses the function of the cells and can cause them to undergo a form of programmed cell death called apoptosis. This, in turn, can further stimulate an immune response. […] Fu et al. show that I-BET151 enhances the proliferation of cells in addition to preventing further immunological attacks. This implies that as long as there are functional cells left, this drug can reverse the disease progression. […] With the ability to simultaneously target macrophages and cells in a cell type-specific manner, I-BET151 appears to be a promising therapeutic drug for the treatment of type-1 diabetes.

• #64 Modifying the body’s immune system to help treat Type 1 diabetes // Show Me Mizzou // University of Missouri

  https://showme.missouri.edu/2022/modifying-the-bodys-immune-system-to-help-treat-type-1-diabetes/

  Scientists at University of Missouri collaborate with Harvard, Georgia Tech to develop a novel diabetes treatment involving transplanting pancreas cells that produce insulin. […] In a new study, a team of researchers from the University of Missouri, Georgia Tech and Harvard University has demonstrated the successful use of a novel Type 1 diabetes treatment in a large animal model. Their approach involves transplanting insulin-producing pancreas cells called pancreatic islets from a donor to a recipient, without the need of long-term immunosuppressive drugs. […] In people living with Type 1 diabetes, their immune system can malfunction, causing it to attack itself, said Haval Shirwan, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, and one of the studys lead authors.

• #65 Modifying the body’s immune system to help treat Type 1 diabetes // Show Me Mizzou // University of Missouri

  https://showme.missouri.edu/2022/modifying-the-bodys-immune-system-to-help-treat-type-1-diabetes/

  Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. […] Over the last two decades, Shirwan and Esma Yolcu, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys rogue immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the surface of the islets. […] Therefore, our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells. […] Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.

• #66 Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02778-6

  In this review, we bring together the latest knowledge of the factors underpinning T1D heterogeneity in distinct patient groups and how these differences are being used to design personalized medicine approaches to diagnose, prevent, and hopefully treat the disease. […] The predictable progression of T1D from early stages of autoimmunity to dysglycemia ahead of the symptomatic clinical disease could ease the design of reliable clinical trials using intermediate endpoint that require~50% smaller sample size that those using T1D as the endpoint. […] Gene therapy offers a promising alternative to insulin injection for T1D treatment. Gene therapy is the procedure of transporting or manipulating genetic substances inside the cell as a therapeutic technique to cure disease; it aims to modify faulty genes that are accountable for disease progression and thereby prevent disease onset or reverse its development.

• #67 Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02778-6

  Given the strong genetic component of T1D development, gene therapy offers a promising alternative to insulin injection for T1D treatment. […] The paradoxical assumption is that preventing T1D in NOD mice does not certainly convey what triggered the disease nor how to converse it. […] The NOD mouse model could be suitable to understand the genetic and immunologic features and causes of T1D including reversing the hyperglycemia when occurs. […] Gene therapy can also be used to induce insulin production in non–cells. […] The discovery of -cell mitogenic effects of ANGPTL8 (Angiopoietin Like 8), which was renamed Betatrophin to underline its effect on cell replication, initially, created large interest but consequently, have been subjected to substantial debate regarding its anticipated mitogenic effects.

• #68 Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02778-6

  Given the strong genetic component of T1D development, gene therapy offers a promising alternative to insulin injection for T1D treatment. […] The paradoxical assumption is that preventing T1D in NOD mice does not certainly convey what triggered the disease nor how to converse it. […] The NOD mouse model could be suitable to understand the genetic and immunologic features and causes of T1D including reversing the hyperglycemia when occurs. […] Gene therapy can also be used to induce insulin production in non–cells. […] The discovery of -cell mitogenic effects of ANGPTL8 (Angiopoietin Like 8), which was renamed Betatrophin to underline its effect on cell replication, initially, created large interest but consequently, have been subjected to substantial debate regarding its anticipated mitogenic effects.

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