Materiały źródłowe

• #1 Pathogenesis of type 1 diabetes mellitus – UpToDate

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

  Pathogenesis of type 1 diabetes mellitus […] Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans. This process occurs in genetically susceptible subjects, is probably triggered by one or more environmental agents, and usually progresses over many months or years during which the subject is asymptomatic and euglycemic. Thus, genetic markers for type 1A diabetes are present from birth, immune markers are detectable after the onset of the autoimmune process, and metabolic markers can be detected with sensitive tests once enough beta cell damage has occurred, but before the onset of symptomatic hyperglycemia. This long latent period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs.

• #2 Pediatric Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/919999-overview

  Type 1 diabetes mellitus is a chronic illness characterized by the bodys inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Most pediatric patients with diabetes have type 1 and a lifetime dependence on exogenous insulin. […] The most common cause of type 1 diabetes mellitus is the autoimmune destruction of insulin-producing cells. The development of autoimmune type 1 diabetes mellitus follows three stages: Stage I – Autoimmunity develops; lab analysis shows positive antibodies, but the patient has normoglycemia; this stage is asymptomatic/presymptomatic. Stage II – Dysglycemia/abnormal glucose tolerance develops, but the patient remains asymptomatic. Stage III – Overt hyperglycemia and symptoms of type 1 diabetes. […] Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. In addition, it stimulates fat storage. Insulin also inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in the liver and kidneys.

• #3 Type 1 Diabetes in Children – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441918/

  Type 1 diabetes is an autoimmune condition that leads to the destruction of pancreatic beta cells which in turn causes insufficient insulin production, resulting in hyperglycemia. […] Type 1 diabetes occurs when there is the autoimmune destruction of pancreatic beta cells leading to insufficient insulin production and resulting hyperglycemia. […] Both genetic and environmental contributions lead to immune-mediated loss of beta cell function resulting in hyperglycemia and life-long insulin dependence. […] A „triggering” insult (e.g., maternal and intrauterine environment, exposure to viruses, host microbiome, diet and many other factors are thought to contribute to disease susceptibility) is suspected to initiate a process that recruits antigen-presenting cells to transport beta cell self-antigens to autoreactive T cells. Through failures of self-tolerance, these T cells mediate beta-cell killing and inflammation leading to insulinopenia and symptomatic diabetes.

• #4 Type 1 Diabetes: Causes, Symptoms, Complications & Treatment

  https://my.clevelandclinic.org/health/diseases/21500-type-1-diabetes

  Type 1 diabetes develops when your immune system mistakenly attacks and destroys cells in your pancreas that make insulin. This destruction can happen over months or years, ultimately resulting in a total lack (deficiency) of insulin. […] Although scientists dont yet know the exact cause of Type 1 diabetes, they believe theres a strong genetic component. The risk of developing the disease with no family history is approximately 0.4%. If your biological mother has Type 1 diabetes, your risk is 1% to 4%, and your risk is 3% to 8% if your biological father has it. If both of your biological parents have Type 1 diabetes, your risk of developing the condition is as high as 30%. […] Scientists believe that certain factors, such as a virus or environmental toxins, can trigger your immune system to attack cells in your pancreas if you have a genetic predisposition for developing Type 1 diabetes.

• #5 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

  Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-producing pancreatic beta cells. Both genetic and environmental factors contribute to pathogenesis. In T1D, autoreactive T cells and autoantibodies destroy beta cells, causing insulin deficiency. The pathogenesis of type 1 diabetes (T1D) is mediated by an autoimmune attack targeted against the insulin-producing pancreatic beta cells. Both autoreactive T cells and autoantibodies contribute to selective destruction of beta cells, causing insulin deficiency and hyperglycemia. The process begins months to years before clinical diagnosis, as evidenced by detection of multiple autoantibodies during pre-symptomatic stages. Histological examination of pancreata from T1D patients reveals insulitis, characterized by infiltration of immune cells including T lymphocytes, B lymphocytes, macrophages, and dendritic cells into the islets. Cytokines secreted by these inflammatory cells induce beta cell apoptosis. 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. CD4+ and CD8+ T cells are major players in the autoimmune attack against beta cells. CD4+ T helper cells recognize beta cell peptides presented by HLA class II molecules. They differentiate into inflammatory Th1 and Th17 subsets in the islet infiltrate, secreting cytokines like IFN-, TNF-, and IL-17 that amplify local inflammation and recruit additional immune cells. The autoimmune destruction of beta cells leads to loss of insulin production and secretion, resulting in impaired glucose homeostasis. Pro-inflammatory cytokines like IL-1, TNF-, and IFN- secreted by infiltrating immune cells in insulitic islets are toxic to beta cells. They perturb cellular signaling pathways controlling glucose-stimulated insulin secretion. Ultimately, there is a prolonged subclinical period of insulitis where a majority of beta cell mass is destroyed before onset of symptomatic hyperglycemia.

• #6 Type 1 diabetes – Wikipedia

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

  Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body’s immune system destroys pancreatic cells (beta cells). […] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. […] People with type 1 diabetes tend to have more CD8+ T-cells and B-cells that specifically target islet antigens than those without type 1 diabetes, suggesting a role for the adaptive immune system in beta cell destruction. […] Destruction of beta cells results in inflammation of the islet of Langerhans, called insulitis. […] The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis, induced or exacerbated by CD8+ T-cells and macrophages. […] As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death.

• #7

  https://link.springer.com/article/10.1007/s00125-003-1089-5

  Type 1 diabetes mellitus results from a T-cell mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The contribution of T-cells in the pathogenesis is beyond doubt. Autoreactive T-cells have proven to be valuable tools to study pathogenic or diabetes-related processes. The challenge for the future is to determine which factors contribute to the loss of tolerance to beta-cell antigens, and to define what measures T-cells can provide to suppress autoreactivity, since it is becoming increasingly evident that T-cells provide a two-edged sword: some T-cells could be pathogenic, but others can regulate the disease process and thus form new targets for immunointervention. […] Type 1 diabetes mellitus is a T-cell dependent immune-mediated disease in which the insulin-producing pancreatic beta cells are destroyed. Evidence for this idea first came from histology of pancreata of newly-diagnosed Type 1 diabetic patients. T-cells are present in the inflammatory lesion (insulitis). Insulitis is only present in islets with beta cells, which implies that the islet infiltration is a beta-cell driven process.

• #8 Type 1 Diabetes in Children – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441918/

  Insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death. […] About one-third of patients with newly-diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5%, despite aggressive treatment. […] For the last several decades, therapies have focused on normalizing glucose while minimizing the risk of hypoglycemia while at the same time monitoring for chronic complications and acknowledging the important psychosocial factors that affect a growing and developing children with a chronic disease. […] A recent study revealed that probiotic supplementation before age 3 in infants with type 1 diabetes led to a reduction in the development of pancreatic islet cell autoimmunity.

• #9 Pediatric Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/919999-overview

  Hyperglycemia results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to DKA. […] Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

• #10 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. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. […] 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. […] 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.

• #11 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.

• #12 Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/117739-overview

  Approximately 85% of patients with type 1 DM have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme found within pancreatic beta cells. […] Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode the HLA-DR and -DQ forms are the major genetic determinants of type 1 DM. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. HLA-DQs are also considered specific markers of type 1 DM susceptibility. In contrast, some haplotypes (eg, HLA-DR2) confer strong protection against type 1 DM.

• #13 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.

• #14 Type 1 Diabetes: Causes, Symptoms, Complications & Treatment

  https://my.clevelandclinic.org/health/diseases/21500-type-1-diabetes

  Type 1 diabetes develops when your immune system mistakenly attacks and destroys cells in your pancreas that make insulin. This destruction can happen over months or years, ultimately resulting in a total lack (deficiency) of insulin. […] Although scientists dont yet know the exact cause of Type 1 diabetes, they believe theres a strong genetic component. The risk of developing the disease with no family history is approximately 0.4%. If your biological mother has Type 1 diabetes, your risk is 1% to 4%, and your risk is 3% to 8% if your biological father has it. If both of your biological parents have Type 1 diabetes, your risk of developing the condition is as high as 30%. […] Scientists believe that certain factors, such as a virus or environmental toxins, can trigger your immune system to attack cells in your pancreas if you have a genetic predisposition for developing Type 1 diabetes.

• #15 Diabetes Mellitus (DM) in Children and Adolescents – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hormonal-disorders-in-children/diabetes-mellitus-dm-in-children-and-adolescents

  Type 1 diabetes occurs when the pancreas produces little or no insulin. Type 1 diabetes is the most common type among children, causing about two thirds of all cases of diabetes. It is one of the most common chronic childhood diseases. By age 18, 1 in 300 children has developed type 1 diabetes. […] In type 1 diabetes, the pancreas does not produce enough insulin because the immune system attacks and destroys the cells in the pancreas that make insulin (islet cells). Such an attack may be triggered by environmental factors in people who have inherited certain genes that make them susceptible to developing diabetes. These genes are more common among certain ethnic groups (such as Scandinavians and Sardinians). […] Close relatives of a person with type 1 diabetes are at increased risk of developing diabetes. Siblings have about a 6% risk, and identical twins have a more than 50% risk. The risk of diabetes for a child who has a parent with type 1 diabetes is about 4 to 9% if the father is affected and is about 1 to 4% if the mother is affected. […] Children who have type 1 diabetes are at higher risk of some other disorders in which the body’s immune system attacks itself (autoimmune disorders), particularly certain types of thyroid disease, and celiac disease.

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

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

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] The genetic pathways involved in different stages of the disease are highly divergent, and genetics is currently the only tool capable of detecting those at risk before the development of islet autoimmunity. […] 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. […] The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins.

• #17 Type 1 diabetes: pathophysiology and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/type-1-diabetes-pathophysiology-and-diagnosis

  Type 1 diabetes is caused by the autoimmune destruction of the insulin-producing b-cells of the islets of Langerhans. Genetic and environmental factors are thought to play a part in the onset of the disease, which usually occurs in childhood and young adulthood. […] Current understanding of the pathogenesis of type 1 diabetes is based on a hypothesis first postulated by the American immunologist George Eisenbarth in the 1980s. It is thought that autoimmune b-cell destruction is triggered by an infective or environmental stimulus in genetically predisposed individuals. […] Type 1 diabetes is fundamentally caused by the autoimmune destruction of these insulin-producing cells. This results in an absolute deficiency of the hormone, with patients having a lifelong dependency on exogenous sources.

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

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

  The etiopathogenesis of type 1 diabetes mellitus (T1DM) is a complex multifactorial process that involves an intricate network of genetic, epigenetic, immunological, and environmental factors. […] Infections with certain viruses have been suggested as possible environmental triggers for the autoimmune process that leads to selective and progressive destruction of pancreatic cells and insufficiency of insulin production, which is its hallmark. […] It has been accepted that environmental factors, including viruses, can initiate and possibly sustain, accelerate, or slow down the autoimmune process and consequently damage insulin-producing pancreatic cells. […] Although the role of these agents, especially human enteroviruses, has been exhaustively studied as the most likely triggers of the activation of autoimmunity that destroys pancreatic islets and leads to T1DM, certain doubts remain.

• #19 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.

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

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

  The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins. […] Epigenetic regulation is a link between genetic information and environmental influences and results in cells observable phenotype. […] In T1D, it plays an important role as GWAS studies map many of the SNP variants to enhancer regions, which are important for transcription factor binding, thus regulating gene expression. […] Taken together, the methylation status of DNA, 3D chromatin landscape, and genetic variants in non-coding regions affect cells transcriptome and may consequently influence the intensity of the immune response and increase the risk for T1D, especially in the context of in utero development.

• #21 Covid-19 linked to elevated risk of type 1 diabetes in young children | New Scientist

  https://www.newscientist.com/article/2391359-covid-19-linked-to-elevated-risk-of-type-1-diabetes-in-young-children/

  Children between the ages of 4 months and 2 years seem more likely to have antibodies that attack insulin-producing cells, a feature of type 1 diabetes, if they have had covid-19, which may show how viral infections can lead to this type of diabetes. […] Insulin, an essential hormone that regulates the bodys blood sugar levels, is produced in the pancreas by islets of Langerhans, which are areas mainly made up cells called beta cells. In some cases, however, the body can develop an autoimmune response to these islets and produce autoantibodies against them. […] Too many of these autoantibodies being created over time will kill enough islets to trigger the onset of type 1 diabetes, where the body is unable to produce its own insulin. The presence of these autoantibodies more or less means that theres a 100 per cent path to type 1 diabetes, says Anette-Gabriele Ziegler at the Technical University of Munich in Germany.

• #22 Covid-19 linked to elevated risk of type 1 diabetes in young children | New Scientist

  https://www.newscientist.com/article/2391359-covid-19-linked-to-elevated-risk-of-type-1-diabetes-in-young-children/

  One of the risk factors for type 1 diabetes is thought to be some viral infections, including SARS-CoV-2, the virus that causes covid-19. A rise in diabetes cases linked to covid-19 has been reported, but the mechanism behind it isnt known, although some have been proposed. […] For example, some viruses may be able to infect the beta cells, changing them and triggering an autoimmune response. Alternatively, some parts of a virus may be so similar to the structure of beta cells that the immune system ends up fighting the virus and the insulin-secreting cell. […] The researchers found that the children who had SARS-CoV-2 antibodies were twice as likely to develop islet autoantibodies as those who hadnt been infected. Children who caught covid-19 before they were 18 months old had a 5 to 10 times higher risk of developing the autoantibodies making them the most at-risk group. […] We believe theres very strong possibility that preventing this early infection could very much alter whether children develop the disease.

• #23 More kids diagnosed with type 1 diabetes during COVID-19 | CIDRAP

  https://www.cidrap.umn.edu/covid-19/more-kids-diagnosed-type-1-diabetes-during-covid-19

  More kids were diagnosed as having type 1 diabetes after the COVID-19 pandemic began, and researchers have yet to determine the mechanism behind this increased incidence rate, the authors of a new meta-analysis said in JAMA Network Open today. […] The primary outcome was a change in the incidence rate of pediatric diabetes before and during the COVID-19 pandemic, and a second outcome was the incidence rate of DKA (diabetic ketoacidosis) among youths with new-onset diabetes during the pandemic. […] The authors found a higher incidence rate during the first year of the pandemic compared with the prepandemic period (incidence rate ratio [IRR], 1.14; 95% confidence interval [CI], 1.08 to 1.21). […] While other studies have showed increases in pediatric type 2 diabetes diagnoses during the pandemic were likely linked to more sedentary lifestyles, and school and activity closures, there is no clear mechanism by which to explain how SARS-CoV-2 infections contribute to type 1 diabetes.

• #24 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. […] 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.

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

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

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] The genetic pathways involved in different stages of the disease are highly divergent, and genetics is currently the only tool capable of detecting those at risk before the development of islet autoimmunity. […] 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. […] The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins.

• #26 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. […] 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.

• #27 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. […] 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.

• #28 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

  Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-producing pancreatic beta cells. Both genetic and environmental factors contribute to pathogenesis. In T1D, autoreactive T cells and autoantibodies destroy beta cells, causing insulin deficiency. The pathogenesis of type 1 diabetes (T1D) is mediated by an autoimmune attack targeted against the insulin-producing pancreatic beta cells. Both autoreactive T cells and autoantibodies contribute to selective destruction of beta cells, causing insulin deficiency and hyperglycemia. The process begins months to years before clinical diagnosis, as evidenced by detection of multiple autoantibodies during pre-symptomatic stages. Histological examination of pancreata from T1D patients reveals insulitis, characterized by infiltration of immune cells including T lymphocytes, B lymphocytes, macrophages, and dendritic cells into the islets. Cytokines secreted by these inflammatory cells induce beta cell apoptosis. 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. CD4+ and CD8+ T cells are major players in the autoimmune attack against beta cells. CD4+ T helper cells recognize beta cell peptides presented by HLA class II molecules. They differentiate into inflammatory Th1 and Th17 subsets in the islet infiltrate, secreting cytokines like IFN-, TNF-, and IL-17 that amplify local inflammation and recruit additional immune cells. The autoimmune destruction of beta cells leads to loss of insulin production and secretion, resulting in impaired glucose homeostasis. Pro-inflammatory cytokines like IL-1, TNF-, and IFN- secreted by infiltrating immune cells in insulitic islets are toxic to beta cells. They perturb cellular signaling pathways controlling glucose-stimulated insulin secretion. Ultimately, there is a prolonged subclinical period of insulitis where a majority of beta cell mass is destroyed before onset of symptomatic hyperglycemia.

• #29 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. […] 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.

• #30 Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy

  https://www.mdpi.com/1422-0067/24/15/11980

  More recently, a direct dysfunction of β-cells has been proposed for T1D development, with alterations of genes in these cells, including the INS gene itself. Among the causes of β-cell dysfunction is the endoplasmic reticulum (ER) stress that culminates in β-cell apoptosis. […] However, other mechanisms can concur in β-cell apoptosis, such as the perforin-granzyme pathway. Additionally, necrosis has been investigated as an additional mechanism of T1D pathogenesis with unclear results. […] Senescence recently attracted the attention of different researchers, although the triggers of this process remain unknown in T1D. Interestingly, it has been proposed that apoptosis and senescence are both involved in T1D pathogenesis. […] Other mechanisms of β-cell dysfunction include defective autophagy and mitochondrial function. However, due to the recent related discoveries, further studies are needed to realize clinical trials.

• #31 Newly discovered mechanism suggests novel approach to prevent type 1 diabetes

  https://medicalxpress.com/news/2013-11-newly-mechanism-approach-diabetes.html

  New research led by Harvard School of Public Health (HSPH) demonstrates a disease mechanism in type 1 diabetes (T1D) that can be targeted using simple, naturally occurring molecules to help prevent the disease. The work highlights a previously unrecognized molecular pathway that contributes to the malfunction of insulin-producing pancreatic beta cells in T1D in human patients and in mice, and shows that a chemical intervention can help beta cells function properly and survive. […] The researchers found that, in animal models and in humans with T1D, ER function is compromised by the immune attack. This reduced ER function results in ER stress and contributes to the death of beta cells and the insulin insufficiency that is characteristic of T1D. […] „The study is exciting because it suggests that improving ER function before the onset of disease could reduce T1D incidence,” said lead author Feyza Engin, research associate in the HSPH Department of Genetics and Complex Diseases.

• #32 Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy

  https://www.mdpi.com/1422-0067/24/15/11980

  More recently, a direct dysfunction of β-cells has been proposed for T1D development, with alterations of genes in these cells, including the INS gene itself. Among the causes of β-cell dysfunction is the endoplasmic reticulum (ER) stress that culminates in β-cell apoptosis. […] However, other mechanisms can concur in β-cell apoptosis, such as the perforin-granzyme pathway. Additionally, necrosis has been investigated as an additional mechanism of T1D pathogenesis with unclear results. […] Senescence recently attracted the attention of different researchers, although the triggers of this process remain unknown in T1D. Interestingly, it has been proposed that apoptosis and senescence are both involved in T1D pathogenesis. […] Other mechanisms of β-cell dysfunction include defective autophagy and mitochondrial function. However, due to the recent related discoveries, further studies are needed to realize clinical trials.

• #33 Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy

  https://www.mdpi.com/1422-0067/24/15/11980

  More recently, a direct dysfunction of β-cells has been proposed for T1D development, with alterations of genes in these cells, including the INS gene itself. Among the causes of β-cell dysfunction is the endoplasmic reticulum (ER) stress that culminates in β-cell apoptosis. […] However, other mechanisms can concur in β-cell apoptosis, such as the perforin-granzyme pathway. Additionally, necrosis has been investigated as an additional mechanism of T1D pathogenesis with unclear results. […] Senescence recently attracted the attention of different researchers, although the triggers of this process remain unknown in T1D. Interestingly, it has been proposed that apoptosis and senescence are both involved in T1D pathogenesis. […] Other mechanisms of β-cell dysfunction include defective autophagy and mitochondrial function. However, due to the recent related discoveries, further studies are needed to realize clinical trials.

• #34 Type 1 diabetes – Wikipedia

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

  Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body’s immune system destroys pancreatic cells (beta cells). […] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. […] People with type 1 diabetes tend to have more CD8+ T-cells and B-cells that specifically target islet antigens than those without type 1 diabetes, suggesting a role for the adaptive immune system in beta cell destruction. […] Destruction of beta cells results in inflammation of the islet of Langerhans, called insulitis. […] The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis, induced or exacerbated by CD8+ T-cells and macrophages. […] As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death.

• #35 Type 1 diabetes – Wikipedia

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

  Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body’s immune system destroys pancreatic cells (beta cells). […] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. […] People with type 1 diabetes tend to have more CD8+ T-cells and B-cells that specifically target islet antigens than those without type 1 diabetes, suggesting a role for the adaptive immune system in beta cell destruction. […] Destruction of beta cells results in inflammation of the islet of Langerhans, called insulitis. […] The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis, induced or exacerbated by CD8+ T-cells and macrophages. […] As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death.

• #36 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. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. […] 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. […] 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.

• #37 Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/117739-overview

  Approximately 85% of patients with type 1 DM have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme found within pancreatic beta cells. […] Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode the HLA-DR and -DQ forms are the major genetic determinants of type 1 DM. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. HLA-DQs are also considered specific markers of type 1 DM susceptibility. In contrast, some haplotypes (eg, HLA-DR2) confer strong protection against type 1 DM.

• #38 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.

• #39 Type 1 diabetes: MedlinePlus Medical EncyclopediaLock

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

  Type 1 diabetes is a lifelong disease and there is no cure. […] Tight control of blood glucose can prevent, delay, and minimize diabetes complications. But these problems can occur, even in people with good diabetes control. […] Type 1 diabetes cannot be prevented currently. This is a very active area of research. In 2019, a study using an injectable medicine was able to delay the onset of type 1 diabetes in high-risk children. There is no screening test for type 1 diabetes in people who have no symptoms. However, antibody testing can identify children at higher risk of developing type 1 diabetes if they have first-degree relatives (sibling, parent) with type 1 diabetes.

• #40 Type 1 Diabetes | Texas Children’s

  https://www.texaschildrens.org/content/conditions/type-1-diabetes

  Type 1 diabetes is a life-threatening, life-long disease that is characterized by the lack of insulin, causing excessively elevated glucose in a person’s blood (called hyperglycemia). […] Around 95% of cases of type 1 diabetes are caused by autoimmunity, that is, the body’s defense system (called immune system) attacking its own cells, in this case, the insulin-producing cells in the pancreas (beta-cells). The ultimate reason for this attack is unknown. However, we know that there are inherited (genetic) and environmental factors. […] We know that the environment also has a role in causing type 1 diabetes but the specific triggers have not been identified. […] Today, it is possible to accurately estimate the risk of type 1 diabetes based on the presence of certain markers in blood (named diabetes autoantibodies or islet autoantibodies) in addition to genes and family history. Research studies are ongoing with the ultimate goal of finding safe and effective treatments to prevent to type 1 diabetes in individuals at risk.

• #41 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. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. […] 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. […] 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.

• #42 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 generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. […] 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.

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

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

  The rapid growth in the incidence of T1DM suggests that environmental factors, including viruses, play a significant role in the pathogenesis of the disease. […] Certain viruses, particularly enteroviruses, are the primary suspects and candidates for risk factors of T1DM. […] Growing evidence continues to implicate enteroviruses as the most likely triggering agents of autoimmunity in T1DM patients, possibly through persistent infections, contributing to different stages of the disease. […] The long-term interaction between genetic, epigenetic, and environmental factors, including viral infection, can increase or decrease an individual’s likelihood of developing an autoimmune disease, depending on the imbalance between risk factors and protective effects; three main mechanisms have been proposed to explain the development of autoimmunity in T1DM: molecular mimicry, epitope spread, and bystander activation.

• #45 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. […] Certain viruses infect and damage pancreatic cells, whose innate antiviral immune response can be modulated by specific viral RNA receptors and sensors, including the melanoma differentiation-associated gene 5 (MDA5), encoded by the IFIH1 gene. […] MDA5 has been specifically linked to inflammation and cell death of pancreatic cells from rotavirus-infected mice models. […] MDA5 receptor activation is associated with inflammatory and immunoregulatory responses from pancreatic islets to viral infections and is expressed in pancreatic endocrine cells with preferential localization to -cells compared to -cells, suggesting that -cells are better equipped than -cells to respond to viral infections and initiate viral clearance mechanisms.

• #46 Pediatric Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/919999-overview

  Hyperglycemia results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to DKA. […] Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

• #47 Frontiers | Infectious diseases associated with pediatric type 1 diabetes mellitus: A narrative review

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.966344/full

  Type 1 diabetes mellitus (T1DM), arising from a complex interaction between immune, genetic and environmental factors, results from autoimmune-mediated destruction of insulin-producing pancreatic β-cells in genetically predisposed individuals. Even if the causative mechanisms are not yet completely defined, T1DM incidence is increasing worldwide. Several studies showed that genetic susceptibility alone does not explain the development of the disease and suggested that environmental factors play an important etiopathogenetic role. Among environmental factors, the most frequently studied include feeding, infections, gut microbiota, perinatal, and social factors. On the other hand, some evidence suggests that lack of exposure in early life to viruses or other infectious agents could increase the risk of T1DM, because of decreased immune stimulation, as supported by the ‘hygiene hypothesis’. It has been hypothesized that in genetically susceptible individuals environmental factors operate by triggering an autoimmune response or overloading the β-cells and promoting apoptosis. In T1DM, chronic hyperglycemia and, more recently defined, glycemic variability impairs endothelium function through different mechanisms: oxidative stress, polyol pathway activity, free-radical accumulation, non-enzymatic glycosylation of proteins, free-radical accumulation. All these factors are responsible for the development of various degrees of diabetic microangiopathy, like retinopathy, nephropathy, and peripheral neuropathy. Thanks to intensive insulin therapy protocols since diagnosis, reproducible long-lasting and rapid-acting human insulin preparations and advances in technological instruments for T1DM management, clinically evident microangiopathy in children and adolescents is almost rarely encountered. However, subclinical signs of vascular impairment can be detected also in adolescence, and are responsible for increased morbidity and mortality in young adulthood, and for impaired quality of life. The natural course of T1DM is sometimes complicated by other autoimmune diseases, in particular celiac disease and thyroid disease. Their prevalence and clinical severity are extremely variable, due to different retrospective studies and data collection. Customized insulin therapy, continuous self-monitoring of glucose levels, regular physical activity, adequate dietary habits, and screening for diabetes-related complications and co-morbid conditions are the cornerstone for correct management, long-life expectancy, and satisfactory quality of life. Vaccines against most recognized infectious diseases are strongly recommended, especially in pediatric patients.

• #48 Frontiers | Infectious diseases associated with pediatric type 1 diabetes mellitus: A narrative review

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.966344/full

  Type 1 diabetes mellitus (T1DM), arising from a complex interaction between immune, genetic and environmental factors, results from autoimmune-mediated destruction of insulin-producing pancreatic β-cells in genetically predisposed individuals. Even if the causative mechanisms are not yet completely defined, T1DM incidence is increasing worldwide. Several studies showed that genetic susceptibility alone does not explain the development of the disease and suggested that environmental factors play an important etiopathogenetic role. Among environmental factors, the most frequently studied include feeding, infections, gut microbiota, perinatal, and social factors. On the other hand, some evidence suggests that lack of exposure in early life to viruses or other infectious agents could increase the risk of T1DM, because of decreased immune stimulation, as supported by the ‘hygiene hypothesis’. It has been hypothesized that in genetically susceptible individuals environmental factors operate by triggering an autoimmune response or overloading the β-cells and promoting apoptosis. In T1DM, chronic hyperglycemia and, more recently defined, glycemic variability impairs endothelium function through different mechanisms: oxidative stress, polyol pathway activity, free-radical accumulation, non-enzymatic glycosylation of proteins, free-radical accumulation. All these factors are responsible for the development of various degrees of diabetic microangiopathy, like retinopathy, nephropathy, and peripheral neuropathy. Thanks to intensive insulin therapy protocols since diagnosis, reproducible long-lasting and rapid-acting human insulin preparations and advances in technological instruments for T1DM management, clinically evident microangiopathy in children and adolescents is almost rarely encountered. However, subclinical signs of vascular impairment can be detected also in adolescence, and are responsible for increased morbidity and mortality in young adulthood, and for impaired quality of life. The natural course of T1DM is sometimes complicated by other autoimmune diseases, in particular celiac disease and thyroid disease. Their prevalence and clinical severity are extremely variable, due to different retrospective studies and data collection. Customized insulin therapy, continuous self-monitoring of glucose levels, regular physical activity, adequate dietary habits, and screening for diabetes-related complications and co-morbid conditions are the cornerstone for correct management, long-life expectancy, and satisfactory quality of life. Vaccines against most recognized infectious diseases are strongly recommended, especially in pediatric patients.

• #49 Type 1 diabetes – Wikipedia

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

  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. […] Beta-cell destruction is not always complete, as 30-80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis. […] 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.

• #50 Type 1 diabetes – Wikipedia

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

  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. […] Beta-cell destruction is not always complete, as 30-80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis. […] 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.

• #51 The Role of Osteopontin in the Pathogenesis and Complications of Type 1 Diabetes Mellitus in Children – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/the-role-of-osteopontin-in-the-pathogenesis-and-complications-of-type-1-diabetes-mellitus-in-children/doi/jcrpe.3082

  Type 1 diabetes mellitus (T1DM) is the most common chronic metabolic disorder of childhood and adolescence. Osteopontin plays a significant role in the development and progression of several autoimmune diseases. Moreover, osteopontin promotes adipose tissue inflammation, dysfunction, and insulin resistance. To investigate the levels of serum osteopontin in pediatric patients with T1DM and to explore if these levels have a role in the prediction of diabetes complications. […] T1DM develops as a result of an autoimmune process, leading to beta-cell destruction. In the early stages of insulitis, activated natural killer cells, dendritic cells, macrophages, and T-cells are attracted to the islets. This early phase is followed by production of cytokines and free radicals, which contribute to beta-cell dysfunction and death.

• #52 The Role of Osteopontin in the Pathogenesis and Complications of Type 1 Diabetes Mellitus in Children – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/the-role-of-osteopontin-in-the-pathogenesis-and-complications-of-type-1-diabetes-mellitus-in-children/doi/jcrpe.3082

  OPN was demonstrated to induce adipose tissue inflammation and to increase pro-inflammatory cytokines release in the bloodstream. Consequently, OPN promotes the destruction of pancreatic beta-cell and development of T1DM. […] This study shows that increased osteopontin levels are independently associated with T1DM in pediatric patients and supports the hypothesis that osteopontin may have a role in the prediction of microvascular diabetes complications. […] Our study demonstrated that serum OPN levels are significantly higher in pediatric patients with T1DM compared to healthy participants. This finding is in agreement with the findings of Karamizadeh et al who found increased serum OPN levels in pediatric patients with T1DM compared with healthy children in an Iranian study. […] The current study revealed that serum OPN levels directly correlate with several cardio-metabolic risk factors, such as higher BMI, SBP, DBP, lower HDL, diagnosis of T1DM, but not with insulin dose, diabetes duration, and HbA1c.

• #53 The Role of Osteopontin in the Pathogenesis and Complications of Type 1 Diabetes Mellitus in Children – Journal of Clinical Research in Pediatric Endocrinology

  https://jcrpe.org/articles/the-role-of-osteopontin-in-the-pathogenesis-and-complications-of-type-1-diabetes-mellitus-in-children/doi/jcrpe.3082

  In conclusion, this study shows that increased OPN levels are independently associated with T1DM in pediatric patients and identify patients with an unfavorable metabolic profile. Therefore, our data provide a support to the hypothesis that OPN may have a role in the prediction of microvascular diabetes complications. Future studies are needed to demonstrate the clinical benefit of OPN as a possible novel marker of vascular dysfunction and a useful tool for risk stratification in pediatric patients with T1DM.

• #54 Brain function irregular in children with Type 1 diabetes, study says | News Center

  https://med.stanford.edu/news/all-news/2019/12/brain-function-abnormal-in-children-with-type-1-diabetes–study-.html

  Children with Type 1 diabetes show subtle but important differences in brain function compared with those who don’t have the disease, a study led by researchers at the Stanford University School of Medicine has shown. […] The study also reported that the abnormal brain-activity patterns were more pronounced in children who had had diabetes longer. […] „Our findings suggest that, in children with Type 1 diabetes, the brain isn’t being as efficient as it could,” said Lara Foland-Ross, PhD, senior research associate at the Center for Interdisciplinary Brain Sciences Research at Stanford. […] „Kids with diabetes have chronic swings in blood-glucose levels, and glucose is important for brain development,” Foland-Ross said. […] The study found that, although the children with diabetes performed the task as accurately as those in the control group, their brains were behaving differently.

• #55 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20191210/Study-finds-irregular-brain-function-in-children-with-Type-1-diabetes.aspx

  Children with Type 1 diabetes show subtle but important differences in brain function compared with those who don’t have the disease, a study led by researchers at the Stanford University School of Medicine has shown. […] The study also reported that the abnormal brain-activity patterns were more pronounced in children who had had diabetes longer. […] „Our findings suggest that, in children with Type 1 diabetes, the brain isn’t being as efficient as it could,” said Lara Foland-Ross, PhD, senior research associate at the Center for Interdisciplinary Brain Sciences Research at Stanford. […] „Kids with diabetes have chronic swings in blood-glucose levels, and glucose is important for brain development,” Foland-Ross said. […] The study found that, although the children with diabetes performed the task as accurately as those in the control group, their brains were behaving differently.

• #56 Brain function irregular in children with Type 1 diabetes, study says | News Center

  https://med.stanford.edu/news/all-news/2019/12/brain-function-abnormal-in-children-with-type-1-diabetes–study-.html

  In children with diabetes, the default-mode network, which is the brain’s „idle” system, was not shutting off during the task. […] These abnormalities were more pronounced in children who had been diagnosed with diabetes at younger ages, suggesting that the problem may worsen with time. […] „The longer the exposure you have to dynamic changes in blood-glucose levels, the greater the alterations in brain function with respect to the default-mode network,” Foland-Ross said. […] Studies in adults with diabetes suggest that in the later stages of the disease, the brain eventually loses its ability to compensate for this problem, she added.

• #57 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20191210/Study-finds-irregular-brain-function-in-children-with-Type-1-diabetes.aspx

  In children with diabetes, the default-mode network, which is the brain’s „idle” system, was not shutting off during the task. […] To compensate for the abnormal activation of the default-mode network, the brain’s executive control networks, responsible for aspects of self-regulation and concentration, were working harder than normal in the children with diabetes. […] These abnormalities were more pronounced in children who had been diagnosed with diabetes at younger ages, suggesting that the problem may worsen with time. […] „The longer the exposure you have to dynamic changes in blood-glucose levels, the greater the alterations in brain function with respect to the default-mode network,” Foland-Ross said. […] Studies in adults with diabetes suggest that in the later stages of the disease, the brain eventually loses its ability to compensate for this problem, she added.

• #58 Screening of key pathogenic genes of type 1 diabetes in children – Zhan – Translational Pediatrics

  https://tp.amegroups.org/article/view/113089/html

  The etiology of type 1 diabetes mellitus (T1DM) in pediatric populations remains poorly understood. The key to precise prevention and treatment of T1DM in identifying crucial pathogenic genes. These key pathogenic genes can serve as biological markers for early diagnosis and classification, as well as therapeutic targets. […] Accurate prevention and treatment of T1DM requires the identification of key pathogenic genes, which can serve as biological markers for early diagnosis and typing, as well as therapeutic targets. […] The specific pathological mechanism of T1DM in pediatric populations remains elusive. […] This study utilizes the sequencing data from peripheral blood mononuclear cell (PBMC) samples of children with T1DM from a public database and employs weighted gene correlation network analysis (WGCNA) to screen for key pathogenic genes. The diagnostic efficacy of these key pathogenic genes in children with T1DM is evaluated and the results of this study provide valuable insights into the pathogenesis of T1DM in children.

• #59 Screening of key pathogenic genes of type 1 diabetes in children – Zhan – Translational Pediatrics

  https://tp.amegroups.org/article/view/113089/html

  This study identified the key pathogenic genes of T1DM in children through WGCNA, including CCL25 and EGFR. We believe that CCL25 and EGFR are involved in the occurrence and progress of T1DM in children. […] CCL25 is a classic chemoattractant factor that can drive immune cell accumulation in specific regions. […] The immunopathogenesis of T1DM begins with the decline of self-tolerance, the presence of self-antibodies against cell antigens leading to cell destruction mediated by T cells. […] EGFR is involved in the regulation of mechanisms for various inflammatory reactions. […] CCL25 and EGFR are key factors in promoting inflammatory responses, and blocking the MFs of CCL25 and EGFR may help suppress inflammatory reactions, assisting in the treatment of childhood T1DM. CCL25 and EGFR are potential therapeutic targets. […] In conclusion, this study identified key pathogenic genes for pediatric T1DM using WGCNA, including CCL25 and EGFR. Both of them are upregulated in blood samples of childhood T1DM and have good diagnostic efficacy for childhood T1DM, serving as potential biological markers.

• #60 Screening of key pathogenic genes of type 1 diabetes in children – Zhan – Translational Pediatrics

  https://tp.amegroups.org/article/view/113089/html

  This study identified the key pathogenic genes of T1DM in children through WGCNA, including CCL25 and EGFR. We believe that CCL25 and EGFR are involved in the occurrence and progress of T1DM in children. […] CCL25 is a classic chemoattractant factor that can drive immune cell accumulation in specific regions. […] The immunopathogenesis of T1DM begins with the decline of self-tolerance, the presence of self-antibodies against cell antigens leading to cell destruction mediated by T cells. […] EGFR is involved in the regulation of mechanisms for various inflammatory reactions. […] CCL25 and EGFR are key factors in promoting inflammatory responses, and blocking the MFs of CCL25 and EGFR may help suppress inflammatory reactions, assisting in the treatment of childhood T1DM. CCL25 and EGFR are potential therapeutic targets. […] In conclusion, this study identified key pathogenic genes for pediatric T1DM using WGCNA, including CCL25 and EGFR. Both of them are upregulated in blood samples of childhood T1DM and have good diagnostic efficacy for childhood T1DM, serving as potential biological markers.

• #61 Reduced Humanin Levels in Children with Type 1 Diabetes Mellitus | ESPE2015 | 54th Annual ESPE (ESPE 2015) | ESPE Abstracts

  https://abstracts.eurospe.org/hrp/0084/hrp0084lbp-1269

  Reduced Humanin Levels in Children with Type 1 Diabetes Mellitus […] Recent studies in multiple models of type 1 diabetes mellitus (T1DM) have demonstrated the role of mitochondrial abnormalities in the pathogenesis of this disease and its complications. […] Humanin is a potent cyto-protective and metaboloprotective molecule in vitro and in vivo, including the protection of cells from apoptosis, improvements in insulin secretion and action, and both prevention and treatment of diabetes in the NOD mouse model, by ameliorating various aspects of the pathogenesis of the disease. […] T1DM patients exhibit lower humanin levels, an observation that is especially pronounced in females and early Tanner stages. […] Future studies will address the impact of humanin levels on pathophysiology and metabolic control of diabetes.

• #62 Reduced Humanin Levels in Children with Type 1 Diabetes Mellitus | ESPE2015 | 54th Annual ESPE (ESPE 2015) | ESPE Abstracts

  https://abstracts.eurospe.org/hrp/0084/hrp0084lbp-1269

  Reduced Humanin Levels in Children with Type 1 Diabetes Mellitus […] Recent studies in multiple models of type 1 diabetes mellitus (T1DM) have demonstrated the role of mitochondrial abnormalities in the pathogenesis of this disease and its complications. […] Humanin is a potent cyto-protective and metaboloprotective molecule in vitro and in vivo, including the protection of cells from apoptosis, improvements in insulin secretion and action, and both prevention and treatment of diabetes in the NOD mouse model, by ameliorating various aspects of the pathogenesis of the disease. […] T1DM patients exhibit lower humanin levels, an observation that is especially pronounced in females and early Tanner stages. […] Future studies will address the impact of humanin levels on pathophysiology and metabolic control of diabetes.

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

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

  The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins. […] Epigenetic regulation is a link between genetic information and environmental influences and results in cells observable phenotype. […] In T1D, it plays an important role as GWAS studies map many of the SNP variants to enhancer regions, which are important for transcription factor binding, thus regulating gene expression. […] Taken together, the methylation status of DNA, 3D chromatin landscape, and genetic variants in non-coding regions affect cells transcriptome and may consequently influence the intensity of the immune response and increase the risk for T1D, especially in the context of in utero development.

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

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

  The evidence points to two age-related disease endotypes, namely T1DE1 and T1DE2 (type 1 diabetes endotype 1 and 2, respectively). […] The genetic pathways involved in different stages of the disease are highly divergent, and genetics is currently the only tool capable of detecting those at risk before the development of islet autoimmunity. […] 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. […] The role of the microbiome in T1D is also the subject of much interest as the presence of the specific and varied intestinal microbiota is critical in the development of the innate immune system, most importantly Th17 and Treg lymphocytes, for maintaining the mucosal barrier and producing different metabolites and vitamins.

• #65 Type 1 Diabetes in Children – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441918/

  Insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death. […] About one-third of patients with newly-diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5%, despite aggressive treatment. […] For the last several decades, therapies have focused on normalizing glucose while minimizing the risk of hypoglycemia while at the same time monitoring for chronic complications and acknowledging the important psychosocial factors that affect a growing and developing children with a chronic disease. […] A recent study revealed that probiotic supplementation before age 3 in infants with type 1 diabetes led to a reduction in the development of pancreatic islet cell autoimmunity.

• #66 Double diabetes—when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02145-x

  Currently, the differentiation between type 1 diabetes (T1D) and type 2 diabetes (T2D) is not straightforward, and the features of both types of diabetes coexist in one subject. […] This state is known as double diabetes (DD), hybrid diabetes or type 1.5 diabetes and is generally described as the presence of the IR characteristic of metabolic syndrome in individuals diagnosed with type 1 diabetes. […] This phenomenon creates new diagnostic and therapeutic challenges. […] However, more precisely, insulin resistance underlies the pathogenesis of double diabetes, as explained further in the article. […] The pathophysiology of the coexistence of type 1 diabetes and insulin resistance is likely multifactorial and has not been fully established. […] It has been suggested that some type 1 diabetic individuals with a T2D family history develop T2D at some point in life if they have not developed T1D that is initially triggered by an independent pathological process.

• #67 Double diabetes—when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02145-x

  Currently, the differentiation between type 1 diabetes (T1D) and type 2 diabetes (T2D) is not straightforward, and the features of both types of diabetes coexist in one subject. […] This state is known as double diabetes (DD), hybrid diabetes or type 1.5 diabetes and is generally described as the presence of the IR characteristic of metabolic syndrome in individuals diagnosed with type 1 diabetes. […] This phenomenon creates new diagnostic and therapeutic challenges. […] However, more precisely, insulin resistance underlies the pathogenesis of double diabetes, as explained further in the article. […] The pathophysiology of the coexistence of type 1 diabetes and insulin resistance is likely multifactorial and has not been fully established. […] It has been suggested that some type 1 diabetic individuals with a T2D family history develop T2D at some point in life if they have not developed T1D that is initially triggered by an independent pathological process.

• #68 Double diabetes—when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02145-x

  This hypothesis points to an autoimmune process as a phenomenon that occurs accidentally and independently from insulin resistance and obesity in predisposed individuals. […] To a certain extent, the overload hypothesis is similar. […] Both of these hypotheses are supported by research, in which insulin resistance and excessive body mass were proven to have an impact on T1D development by accelerating its onset and increasing its risk. […] The identification of tools for assessing the exact degree of insulin sensitivity in patients with type 1 diabetes and distinguishing between individuals with a normal level of insulin resistance in type 1 diabetic patients and those with a pathologically high level of insulin resistance are highly important. […] The pathophysiology of double diabetes is presented in Fig. 1. […] The aforementioned issues indicate the need for more precise tools to diagnose double diabetes that focus on the presence of insulin resistance and not on the presence of metabolic syndrome itself, which may be unreliable and insufficient in double diabetes diagnosis.

• #69 Double diabetes—when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02145-x

  This hypothesis points to an autoimmune process as a phenomenon that occurs accidentally and independently from insulin resistance and obesity in predisposed individuals. […] To a certain extent, the overload hypothesis is similar. […] Both of these hypotheses are supported by research, in which insulin resistance and excessive body mass were proven to have an impact on T1D development by accelerating its onset and increasing its risk. […] The identification of tools for assessing the exact degree of insulin sensitivity in patients with type 1 diabetes and distinguishing between individuals with a normal level of insulin resistance in type 1 diabetic patients and those with a pathologically high level of insulin resistance are highly important. […] The pathophysiology of double diabetes is presented in Fig. 1. […] The aforementioned issues indicate the need for more precise tools to diagnose double diabetes that focus on the presence of insulin resistance and not on the presence of metabolic syndrome itself, which may be unreliable and insufficient in double diabetes diagnosis.

• #70 Type 1 Diabetes in Children – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441918/

  Insufficient endogenous insulin leads to hyperglycemia, hyperglucagonemia, glucosuria, and without treatment, eventually ketosis, acidosis, dehydration, and death. […] About one-third of patients with newly-diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA) which has a mortality rate of around 0.3-0.5%, despite aggressive treatment. […] For the last several decades, therapies have focused on normalizing glucose while minimizing the risk of hypoglycemia while at the same time monitoring for chronic complications and acknowledging the important psychosocial factors that affect a growing and developing children with a chronic disease. […] A recent study revealed that probiotic supplementation before age 3 in infants with type 1 diabetes led to a reduction in the development of pancreatic islet cell autoimmunity.

• #71 Diabetes: What It Is, Causes, Symptoms, Treatment & Types

  https://my.clevelandclinic.org/health/diseases/7104-diabetes

  Type 1 diabetes: This type is an autoimmune disease in which your immune system attacks and destroys insulin-producing cells in your pancreas for unknown reasons. Up to 10% of people who have diabetes have Type 1. Its usually diagnosed in children and young adults, but it can develop at any age. […] Type 1 diabetes and LADA happen when your immune system attacks the insulin-producing cells in your pancreas. […] Symptoms of T1D can develop quickly over a few weeks or months. You may develop additional symptoms that are signs of a severe complication called diabetes-related ketoacidosis (DKA). DKA is life-threatening and requires immediate medical treatment. […] Diabetes-related ketoacidosis (DKA): This complication mainly affects people with Type 1 diabetes or undiagnosed T1D. It happens when your body doesn’t have enough insulin. If your body doesn’t have insulin, it can’t use glucose for energy, so it breaks down fat instead. This process eventually releases substances called ketones, which turn your blood acidic. This causes labored breathing, vomiting and loss of consciousness. DKA requires immediate medical treatment.

• #72

  https://journals.lww.com/pccmjournal/fulltext/2025/01000/serum_phosphorus_and_hypophosphatemia_during.10.aspx

  To assess factors associated with serum phosphorus (P) and hypophosphatemia in children with type 1 diabetes mellitus (T1DM) treated for diabetic ketoacidosis (DKA). […] Hypophosphatemia developed during 656 of 852 (77%) episodes, including 49 of 852 (5.8%) episodes of severe hypophosphatemia with median (interquartile range) onset 8.0 hours (4.711.9hr) and 12.0 hours (8.117.6hr), respectively, following initiation of therapy. […] Higher glycohemoglobin was associated with greater odds of hypophosphatemia (odds ratio [OR], 1.22; p 0.001). […] Older age (3.0%/yr; p = 0.02), T1DM duration (4.1%/yr; p = 0.01), and initial serum P (23.4%/mg/dL; p 0.001) were associated with later hypophosphatemia. […] Higher glycohemoglobin was associated with greater odds of developing severe hypophosphatemia (OR, 1.17 [95% CI, 0.31.37]; p = 0.05).

• #73 A Rare Complication of Insulin Therapy in a Child with Newly Diagnosed Type 1 Diabetes: Insulin Edema – The Journal of Pediatric Research

  https://jpedres.org/articles/a-rare-complication-of-insulin-therapy-in-a-child-with-newly-diagnosed-type-1-diabetes-insulin-edema/doi/jpr.galenos.2021.65982

  Although insulin therapy has a critical role in the management of patients with type 1 diabetes, it may cause various side effects at varying rates. Insulin edema is a very rare complication that is mostly associated with the initiation of insulin therapy in patients with newly diagnosed diabetes or the intensification of insulin therapy in those with poor glycemic control. Its clinical spectrum ranges from mild peripheral edema to severe serosal effusions (peritoneal, pleural and pericardial) and heart failure. […] The clinical presentation of insulin edema can range from mild peripheral edema (mostly) to heart failure/serosal edema (very rarely). […] Although various mechanisms thought to cause edema have been proposed, the pathophysiological basis underlying insulin-associated edema has not yet been elucidated.

• #74 A Rare Complication of Insulin Therapy in a Child with Newly Diagnosed Type 1 Diabetes: Insulin Edema – The Journal of Pediatric Research

  https://jpedres.org/articles/a-rare-complication-of-insulin-therapy-in-a-child-with-newly-diagnosed-type-1-diabetes-insulin-edema/doi/jpr.galenos.2021.65982

  Although the pathophysiology of this disease has not yet been clarified, various mechanisms have been proposed. Leifer suggested that excessive fluid retention in tissues secondary to glycogen accumulation was responsible for the pathophysiology of insulin edema. […] Moreover, it was emphasized that insulin can enhance renal sodium absorption (anti-diuretic effect) by stimulating Na+/K+ -ATPase in the proximal tubule and also by increasing expression of Na+/H+ exchanger 3 and thus contributes to the development of this clinical condition. […] Apart from these suggested mechanisms, chronic hyperglycemia in these patients has been associated with increased capillary permeability, which leads to the passage of albumin, the major protein constituent of the intravascular space, to interstitial tissues (transcapillary escape of albumin) and an increase of oncotic pressure in the tissues and thus, results in edema. […] In conclusion, it should be kept in mind that there is a possibility of the development of insulin edema after the initiation or intensification of insulin therapy in patients with newly diagnosed or previously known diabetes.

• #75 A Rare Complication of Insulin Therapy in a Child with Newly Diagnosed Type 1 Diabetes: Insulin Edema – The Journal of Pediatric Research

  https://jpedres.org/articles/a-rare-complication-of-insulin-therapy-in-a-child-with-newly-diagnosed-type-1-diabetes-insulin-edema/doi/jpr.galenos.2021.65982

  Although the pathophysiology of this disease has not yet been clarified, various mechanisms have been proposed. Leifer suggested that excessive fluid retention in tissues secondary to glycogen accumulation was responsible for the pathophysiology of insulin edema. […] Moreover, it was emphasized that insulin can enhance renal sodium absorption (anti-diuretic effect) by stimulating Na+/K+ -ATPase in the proximal tubule and also by increasing expression of Na+/H+ exchanger 3 and thus contributes to the development of this clinical condition. […] Apart from these suggested mechanisms, chronic hyperglycemia in these patients has been associated with increased capillary permeability, which leads to the passage of albumin, the major protein constituent of the intravascular space, to interstitial tissues (transcapillary escape of albumin) and an increase of oncotic pressure in the tissues and thus, results in edema. […] In conclusion, it should be kept in mind that there is a possibility of the development of insulin edema after the initiation or intensification of insulin therapy in patients with newly diagnosed or previously known diabetes.

• #76 Diabetes Mellitus in Children and Adolescents – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/endocrine-disorders-in-children/diabetes-mellitus-in-children-and-adolescents

  Type 1 diabetes is the most common type in children, accounting for two thirds of new cases in children of all racial and ethnic groups. […] In type 1 diabetes, the pancreas produces little to no insulin because of autoimmune destruction of pancreatic beta-cells, possibly triggered by an environmental exposure in genetically susceptible people. […] Inherited susceptibility to type 1 diabetes is determined by multiple genes (60 risk loci have been identified). […] About 85% of people newly diagnosed with type 1 do not have a family history of type 1 diabetes. […] Children with type 1 diabetes are at higher risk of other autoimmune disorders, particularly thyroid disease and celiac disease. […] In type 1 diabetes, lack of insulin causes hyperglycemia and impaired glucose utilization in skeletal muscle.

• #77 Diabetes Mellitus (DM) in Children and Adolescents – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hormonal-disorders-in-children/diabetes-mellitus-dm-in-children-and-adolescents

  Type 1 diabetes occurs when the pancreas produces little or no insulin. Type 1 diabetes is the most common type among children, causing about two thirds of all cases of diabetes. It is one of the most common chronic childhood diseases. By age 18, 1 in 300 children has developed type 1 diabetes. […] In type 1 diabetes, the pancreas does not produce enough insulin because the immune system attacks and destroys the cells in the pancreas that make insulin (islet cells). Such an attack may be triggered by environmental factors in people who have inherited certain genes that make them susceptible to developing diabetes. These genes are more common among certain ethnic groups (such as Scandinavians and Sardinians). […] Close relatives of a person with type 1 diabetes are at increased risk of developing diabetes. Siblings have about a 6% risk, and identical twins have a more than 50% risk. The risk of diabetes for a child who has a parent with type 1 diabetes is about 4 to 9% if the father is affected and is about 1 to 4% if the mother is affected. […] Children who have type 1 diabetes are at higher risk of some other disorders in which the body’s immune system attacks itself (autoimmune disorders), particularly certain types of thyroid disease, and celiac disease.

• #78 Frontiers | Infectious diseases associated with pediatric type 1 diabetes mellitus: A narrative review

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.966344/full

  Type 1 diabetes mellitus (T1DM), arising from a complex interaction between immune, genetic and environmental factors, results from autoimmune-mediated destruction of insulin-producing pancreatic β-cells in genetically predisposed individuals. Even if the causative mechanisms are not yet completely defined, T1DM incidence is increasing worldwide. Several studies showed that genetic susceptibility alone does not explain the development of the disease and suggested that environmental factors play an important etiopathogenetic role. Among environmental factors, the most frequently studied include feeding, infections, gut microbiota, perinatal, and social factors. On the other hand, some evidence suggests that lack of exposure in early life to viruses or other infectious agents could increase the risk of T1DM, because of decreased immune stimulation, as supported by the ‘hygiene hypothesis’. It has been hypothesized that in genetically susceptible individuals environmental factors operate by triggering an autoimmune response or overloading the β-cells and promoting apoptosis. In T1DM, chronic hyperglycemia and, more recently defined, glycemic variability impairs endothelium function through different mechanisms: oxidative stress, polyol pathway activity, free-radical accumulation, non-enzymatic glycosylation of proteins, free-radical accumulation. All these factors are responsible for the development of various degrees of diabetic microangiopathy, like retinopathy, nephropathy, and peripheral neuropathy. Thanks to intensive insulin therapy protocols since diagnosis, reproducible long-lasting and rapid-acting human insulin preparations and advances in technological instruments for T1DM management, clinically evident microangiopathy in children and adolescents is almost rarely encountered. However, subclinical signs of vascular impairment can be detected also in adolescence, and are responsible for increased morbidity and mortality in young adulthood, and for impaired quality of life. The natural course of T1DM is sometimes complicated by other autoimmune diseases, in particular celiac disease and thyroid disease. Their prevalence and clinical severity are extremely variable, due to different retrospective studies and data collection. Customized insulin therapy, continuous self-monitoring of glucose levels, regular physical activity, adequate dietary habits, and screening for diabetes-related complications and co-morbid conditions are the cornerstone for correct management, long-life expectancy, and satisfactory quality of life. Vaccines against most recognized infectious diseases are strongly recommended, especially in pediatric patients.

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

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

  These patients are susceptible to other autoimmune diseases, such as Hashimotos thyroiditis, celiac disease, Addisons disease, and myasthenia gravis. […] Forty genetic loci have been associated with T1DM by a genome-wide association study and meta-analysis. […] A number of genetic loci in the major histocompatibility (HLA) region are associated with increased susceptibility to developing T1DM, including the alleles DR3/4, DQ 0201/0302, DR 4/4, and DQ 0300/0302. […] The risk of T1DM is approximately 5% if there is an affected first-degree relative and slightly higher if the affected parent is the father rather than the mother. […] To date, interventional trials have failed to delay the onset or prevent T1DM in those genetically at risk. […] Ongoing research by international networks is exploring ways to prevent, delay or reverse the progression of T1DM (e.g. TrialNet, TRIGR).

• #80 Frontiers | Infectious diseases associated with pediatric type 1 diabetes mellitus: A narrative review

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.966344/full

  Type 1 diabetes mellitus (T1DM), arising from a complex interaction between immune, genetic and environmental factors, results from autoimmune-mediated destruction of insulin-producing pancreatic β-cells in genetically predisposed individuals. Even if the causative mechanisms are not yet completely defined, T1DM incidence is increasing worldwide. Several studies showed that genetic susceptibility alone does not explain the development of the disease and suggested that environmental factors play an important etiopathogenetic role. Among environmental factors, the most frequently studied include feeding, infections, gut microbiota, perinatal, and social factors. On the other hand, some evidence suggests that lack of exposure in early life to viruses or other infectious agents could increase the risk of T1DM, because of decreased immune stimulation, as supported by the ‘hygiene hypothesis’. It has been hypothesized that in genetically susceptible individuals environmental factors operate by triggering an autoimmune response or overloading the β-cells and promoting apoptosis. In T1DM, chronic hyperglycemia and, more recently defined, glycemic variability impairs endothelium function through different mechanisms: oxidative stress, polyol pathway activity, free-radical accumulation, non-enzymatic glycosylation of proteins, free-radical accumulation. All these factors are responsible for the development of various degrees of diabetic microangiopathy, like retinopathy, nephropathy, and peripheral neuropathy. Thanks to intensive insulin therapy protocols since diagnosis, reproducible long-lasting and rapid-acting human insulin preparations and advances in technological instruments for T1DM management, clinically evident microangiopathy in children and adolescents is almost rarely encountered. However, subclinical signs of vascular impairment can be detected also in adolescence, and are responsible for increased morbidity and mortality in young adulthood, and for impaired quality of life. The natural course of T1DM is sometimes complicated by other autoimmune diseases, in particular celiac disease and thyroid disease. Their prevalence and clinical severity are extremely variable, due to different retrospective studies and data collection. Customized insulin therapy, continuous self-monitoring of glucose levels, regular physical activity, adequate dietary habits, and screening for diabetes-related complications and co-morbid conditions are the cornerstone for correct management, long-life expectancy, and satisfactory quality of life. Vaccines against most recognized infectious diseases are strongly recommended, especially in pediatric patients.

• #81 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

  Type 1 diabetes (T1D) is an autoimmune disease leading to destruction of insulin-producing pancreatic beta cells. Both genetic and environmental factors contribute to pathogenesis. In T1D, autoreactive T cells and autoantibodies destroy beta cells, causing insulin deficiency. The pathogenesis of type 1 diabetes (T1D) is mediated by an autoimmune attack targeted against the insulin-producing pancreatic beta cells. Both autoreactive T cells and autoantibodies contribute to selective destruction of beta cells, causing insulin deficiency and hyperglycemia. The process begins months to years before clinical diagnosis, as evidenced by detection of multiple autoantibodies during pre-symptomatic stages. Histological examination of pancreata from T1D patients reveals insulitis, characterized by infiltration of immune cells including T lymphocytes, B lymphocytes, macrophages, and dendritic cells into the islets. Cytokines secreted by these inflammatory cells induce beta cell apoptosis. 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. CD4+ and CD8+ T cells are major players in the autoimmune attack against beta cells. CD4+ T helper cells recognize beta cell peptides presented by HLA class II molecules. They differentiate into inflammatory Th1 and Th17 subsets in the islet infiltrate, secreting cytokines like IFN-, TNF-, and IL-17 that amplify local inflammation and recruit additional immune cells. The autoimmune destruction of beta cells leads to loss of insulin production and secretion, resulting in impaired glucose homeostasis. Pro-inflammatory cytokines like IL-1, TNF-, and IFN- secreted by infiltrating immune cells in insulitic islets are toxic to beta cells. They perturb cellular signaling pathways controlling glucose-stimulated insulin secretion. Ultimately, there is a prolonged subclinical period of insulitis where a majority of beta cell mass is destroyed before onset of symptomatic hyperglycemia.

• #82 Type 1 diabetes: pathophysiology and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/type-1-diabetes-pathophysiology-and-diagnosis

  Type 1 diabetes is caused by the autoimmune destruction of the insulin-producing b-cells of the islets of Langerhans. Genetic and environmental factors are thought to play a part in the onset of the disease, which usually occurs in childhood and young adulthood. […] Current understanding of the pathogenesis of type 1 diabetes is based on a hypothesis first postulated by the American immunologist George Eisenbarth in the 1980s. It is thought that autoimmune b-cell destruction is triggered by an infective or environmental stimulus in genetically predisposed individuals. […] Type 1 diabetes is fundamentally caused by the autoimmune destruction of these insulin-producing cells. This results in an absolute deficiency of the hormone, with patients having a lifelong dependency on exogenous sources.

• #83 Pathogenesis of type 1 diabetes mellitus – UpToDate

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

  Pathogenesis of type 1 diabetes mellitus […] Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans. This process occurs in genetically susceptible subjects, is probably triggered by one or more environmental agents, and usually progresses over many months or years during which the subject is asymptomatic and euglycemic. Thus, genetic markers for type 1A diabetes are present from birth, immune markers are detectable after the onset of the autoimmune process, and metabolic markers can be detected with sensitive tests once enough beta cell damage has occurred, but before the onset of symptomatic hyperglycemia. This long latent period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs.

• #84 Type 1 Diabetes Mellitus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/117739-overview

  Type 1 diabetes is a chronic illness characterized by the bodys inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. […] Type 1 DM is the culmination of lymphocytic infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas. As beta-cell mass declines, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. After 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism. […] Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules.

• #85 Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy

  https://www.mdpi.com/1422-0067/24/15/11980

  More recently, a direct dysfunction of β-cells has been proposed for T1D development, with alterations of genes in these cells, including the INS gene itself. Among the causes of β-cell dysfunction is the endoplasmic reticulum (ER) stress that culminates in β-cell apoptosis. […] However, other mechanisms can concur in β-cell apoptosis, such as the perforin-granzyme pathway. Additionally, necrosis has been investigated as an additional mechanism of T1D pathogenesis with unclear results. […] Senescence recently attracted the attention of different researchers, although the triggers of this process remain unknown in T1D. Interestingly, it has been proposed that apoptosis and senescence are both involved in T1D pathogenesis. […] Other mechanisms of β-cell dysfunction include defective autophagy and mitochondrial function. However, due to the recent related discoveries, further studies are needed to realize clinical trials.

• #86 Newly discovered mechanism suggests novel approach to prevent type 1 diabetes

  https://medicalxpress.com/news/2013-11-newly-mechanism-approach-diabetes.html

  New research led by Harvard School of Public Health (HSPH) demonstrates a disease mechanism in type 1 diabetes (T1D) that can be targeted using simple, naturally occurring molecules to help prevent the disease. The work highlights a previously unrecognized molecular pathway that contributes to the malfunction of insulin-producing pancreatic beta cells in T1D in human patients and in mice, and shows that a chemical intervention can help beta cells function properly and survive. […] The researchers found that, in animal models and in humans with T1D, ER function is compromised by the immune attack. This reduced ER function results in ER stress and contributes to the death of beta cells and the insulin insufficiency that is characteristic of T1D. […] „The study is exciting because it suggests that improving ER function before the onset of disease could reduce T1D incidence,” said lead author Feyza Engin, research associate in the HSPH Department of Genetics and Complex Diseases.

• #87 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

  Type 1 Diabetes (T1D) is a potentially life-threatening multifactorial autoimmune disorder characterized by T-cell-mediated destruction of pancreatic cells, resulting in a deficiency of insulin synthesis and secretion. […] The bulk of risk is explained by difference at a several but strongly associated loci involving the HLA region HLA class II, DQ and DR loci and HLA class I region on chromosome 6p21 that account for~50% of familial T1D. […] Candidate triggers such as infections, early life diet, vitamin D levels, gut microbiota composition, vaccinations, pollutants and toxins, and geographic variation when combine with genetic susceptibility and specific epigenetic modifications, the perfect storm occurs and autoimmune destruction of pancreatic cells is initiated. […] The gene polymorphisms and environmental triggers combinations that impact the risk of T1D and lead to the disease development are tremendously high.

• #88 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

  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. […] The aim of increasing correct diagnosis of classical versus monogenic T1D has been assisted by the introduction of the genomic risk score (GRS), which assesses an individuals risk of T1D based on their possession of a collection of multiple (1040) T1D risk variants. […] Given the strong genetic component of T1D development, 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.

Zobacz więcej