Autoimmune Type Research Articles

"Hair is your crown and glory" - Black women's experiences of living with alopecia and the role of social support.

Alopecia is an autoimmune condition that results in hair loss, mainly from the scalp. There are three specific types of autoimmune alopecia: alopecia areata (AA; small patches of hair loss), alopecia totalis (AT; total hair loss from the scalp) and alopecia universalis (AU; total hair loss from the scalp and body). Whilst research has explored the experiences of White women living with alopecia, there is a lack of research exploring the impact of alopecia on women in the Black community. The current study aimed to explore Black women's experience of living with autoimmune types of alopecia with a focus on the cultural importance of hair within the Black community and the impact of social support. Seven Black women (age range: 37-68 years; mean age: 51 years) were recruited purposively through alopecia support group organisations and social media to participate in a semi-structured interview; four participants were diagnosed with AA, two participants were diagnosed with AU, and one participant was diagnosed with AT. One-to-one interviews were conducted online, and interpretative phenomenological analysis was used to guide data collection and analysis. Participants discussed the significance of hair specifically within the Black community and the complex relationship between psychological wellbeing, coping and seeking support. This novel area, specific to Black women's psychological experience of alopecia, acknowledges the influence of cultural and ethnic differences. The findings suggest that proactive awareness from health professionals and social support groups are needed due to the nuances of Black women's alopecia experience to provide better support and to enhance the quality of life for Black women to manage their alopecia.

Multifaceted nature of young-onset diabetes - can genomic medicine improve the precision of diagnosis and management?

Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.

Challenges faced in establishing a pediatric liver transplant program in a lower-middle-income country with free healthcare service.

Liver transplant is the cure for children with liver failure. Sri Lanka is a lower-middle-income country with a predominant free, state health system. Pediatric liver transplant program in Sri Lanka is still in the budding state where the initial experience of the program is yet to be documented. A retrospective review was performed including the clinical characteristics of all pediatric liver transplant recipients of Colombo North Centre for Liver Diseases since the inception of the program from June 2020 to May 2023. There were 14 PLT performed in 3 years. The median recipient age and weight were 8 years (6 months-15 years) and 23.3 kg (6.4-49.2), respectively. The majority were boys (64%). All were from low-income backgrounds. Indications for LT were acute liver failure (5/14), decompensated chronic liver disease (5/14), and acute on chronic liver failure (4/14). Underlying liver diseases were Wilson disease (6/14), autoimmune liver disease (3/14), biliary atresia (2/14) and progressive familial intrahepatic cholestasis type 3 (1/14), and unknown etiology (2/14). The majority were living donor liver transplants (86%). Of the living donors, 42% (5/12) were Buddhist priests. There were three immediate deaths and two late deaths. The 3-month survival was 78%, and overall survival was 64%. Living donor transplants carried a higher success rate (92%) compared to diseased donor transplants (0%; 2/2). Initial experience of pediatric liver transplant program of Sri Lanka is promising despite being established in a free healthcare system amidst the crisis circumstances.

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Cutaneous Manifestations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED): A Comprehensive Review.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60-74.7%), North American (51-86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care.

Human autoantibodies neutralizing type I IFNs: From 1981 to 2023.

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID-19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto-Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto-Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto-Abs, focusing particularly on their known causes and consequences.

Effect of treatment with original or biosimilar adalimumab on SARS-CoV2 vaccination antibody titers

The technological process of production of biosimilars determines the degree of biosimilarity to the original biological drug. In particular, the focus is on the similarity of immunogenic responses. The primary endpoint of our retrospective study was to find the differences in SARS-CoV-2 antibody amount between patients treated with original adalimumab and biosimilar adalimumab MSB11022 (Idacio) and the differences in the SARS-CoV-2 antibody amount between patients treated with and without biological treatment. We collected the gender, autoimmune disease type, age, and treatment data of the patients in the outpatient clinic MEDICAL PLUS, s.r.o., Uherske Hradiste. These patients suffer from autoimmune rheumatic diseases. All patients received the mRNA vaccine (Pfizer/BioNTech – BNT162b2), with a 21-day (interquartile range, 21–24) gap between the two vaccinations. Patients receiving adalimumab were able to develop cellular immune responses after the second vaccination dose, as well as the individuals without adalimumab. In the period of 6–23 weeks after the second vaccination dose (D63 – D182), the SARS-CoV-2 antibody levels did not change significantly in the patients receiving the original adalimumab, while in the patients receiving biosimilar adalimumab a significant decrease was revealed. A statistically significant difference in the SARS-CoV-2 antibody amount between the patients without biological treatment (median: 504.3 U/mL) and with biological treatment (Original and Biosimilar – median: 47.2 and 28.2 U/mL, respectively) was confirmed on day 182. According to our observation, the effect of the treatment type on the increase/decrease of antibodies over time is dominant, while the impact of other variables (gender, methotrexate treatment, autoimmune disease type, and age) was confirmed as insignificant or minor.

Emergence of Autoimmune Type 1 Diabetes and Acute Adrenal Crisis Following Coronavirus Disease 2019

Emergence of Autoimmune Type 1 Diabetes and Acute Adrenal Crisis Following Coronavirus Disease 2019

Towards a new way to classify diabetes mellitus

Precision medicine makes it possible to classify patients into groups on the basis of molecular and genetic biomarkers, as well as clinical characteristics, in order to optimize therapeutic response. For example, several types of type 2 diabetes seem to coexist with classic insulin-dependent, autoimmune type 1 diabetes : diabetes with insulinopenia (generally severe), diabetes linked to aging or obesity (less severe), and diabetes with insulin resistance, whose patients will be those with the most numerous complications, notably macrovascular. In this article, we examine the possibilities offered by this new classification of diabetes with a view to personalized medicine.

Autoimmune polyglandular syndrome type 2 in the form of Carpenter syndrome in a 16.5-year-old girl

Autoimmune polyglandular syndrome type 2 in the form of Carpenter syndrome in a 16.5-year-old girl

Antigen-specific T cell responses in autoimmune diabetes.

Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting β-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.

Risk of New-Onset Inflammatory Central Nervous System Diseases After Tumor Necrosis Factor Inhibitors Treatment for Autoimmune Diseases: A Systematic Review and Meta-Analysis

Background: Tumor necrosis factor (TNF) inhibitors have been extensively utilized to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) diseases events following TNF inhibitors therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF blocking agents. We aimed to evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases, or TNF inhibitors. Method: Separate searches were conducted across PubMed, EMBASE, and the Cochrane Library from inception until March 1, 2024. Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group. Study eligibility assessment and data extraction were independently conducted by two investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis. The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors. Results: Eighteen studies involving 1,118,428 patients with autoimmune diseases contributing over 5,698,532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10,000 person-years. Overall, exposure to TNF inhibitors was associated with a 33% increased risk of any inflammatory CNS diseases compared to conventional therapies (RR = 1.36, 95%CI 1.01-1.84; I2 = 49%), mainly attributed to demyelinating diseases (RR = 1.38, 95% CI 1.04-1.81; I2 = 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR 1.36, 95%CI 0.84-2.21; inflammatory bowel disease 1.49, 95%CI 0.93-2.40; P for subgroup = 0.74) and TNF inhibitors (anti-TNF monoclonal antibodies versus etanercept: RR 1.04, 95%CI 0.93-1.15, I2 = 0%). Conclusions: Compared to conventional therapies, exposure to TNF inhibitors exposure was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune diseases or TNF inhibitor types.

Clinical safety and therapeutic efficacy of autologous bone-marrow derived stem cells in restoring glycemic control and treating complications in diabetic patients

Diabetes is one of the most common chronic diseases worldwide, with around 537 million adults aged 20-79 living with the disease. It is a global epidemic and has a rapidly rising incidence. Traditional treatments for diabetes have limited efficacy in achieving long-term disease control. In recent years, the autologous infusion of bone marrow-derived mononuclear cells (BMMNC) has become a novel and effective therapeutic approach in treating autoimmune type 1 diabetes (T1DM). BMMNC contains two important types of stem cells, bone marrow-derived hematopoietic stem cells (BMHSC) and bone marrow-derived mesenchymal stem cells (BMMSC), which are currently used independently or coordinately in the treatment of T1DM. In this review, we summarize the clinical data concerning BMMNC, BMHSC, and BMMSC infusion in patients with diabetes (including type 1, type 2, and secondary diabetes) and diabetes-related complications. Research suggests that the autologous infusion of bone marrow stem cells is safe and effective, offering the potential to be widely used in patients with diabetes.

Recurrent venous thrombosis - an unusual first presentation of autoimmune polyendocrinopathy syndrome type 3B.

A 45-year-old female presented with unprovoked recurrent venous thromboembolism (VTE), in unusual sites, and pancytopenia, posing a complex diagnostic challenge. Work-up for inherited thrombophilia, antiphospholipid syndrome (APLS) and paroxysmal nocturnal haemoglobinuria were unremarkable. Investigations revealed autoimmune thyroid disease, and a mixed iron/vitamin B12 deficiency due to pernicious anaemia and resultant atrophic gastritis. Hyperhomocysteinaemia due to vitamin B12 deficiency was identified as a potential contributor to her recurrent VTE. This case highlights the unusual initial presentation of autoimmune polyendocrinopathy syndrome type 3B (APS-3B) with recurrent thromboembolism, and emphasises the importance of considering hyperhomocysteinaemia in unprovoked and atypical VTE cases.

Late manifestation of autoimmune polyglandular syndrome type 1 with hypoparathyroidism and autoimmune thyroiditis

Autoimmune polyglandular syndrome type 1 (APS 1) is a rare genetic disorder caused by a mutation in the autoimmune regulator AIRE gene. The diagnosis is usually based on the combination of at least two components of the classic triad: mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Other autoimmune disorders, including thyroid diseases, also occur and may manifest before the primary components. The disease is more likely to manifest during infancy, but some components may develop in adult patients. As the components of the syndrome do not occur simultaneously, verification of the diagnosis is often delayed. A significant challenge in the management of patients with APS 1 is the selection of optimal drug doses due to polypragmasy and the frequent presence of autoimmune disorders and/or candidiasis of the gastrointestinal tract. We present a clinical case of a patient with an atypical course of APS 1, in whom the first endocrine components (hypoparathyroidism and hypothyroidism) were diagnosed in adulthood. This case highlights the phenotypic diversity of APS 1, and the difficulties in selecting therapy when several autoimmune endocrine diseases are combined.

The content of regulatory B-lymphocytes in autoimmune adrenal insufficiency

Introduction: Currently, the need to expand knowledge about the mechanisms of impaired immune tolerance in autoimmune adrenal insufficiency (AAI) remains relevant. It is not excluded that in AAI there are disturbances in the system of regulatory B-lymphocytes (Breg).Objective: To assess the state of the B-regulatory cells system of immunity in AAI.Material and methods: the content of Breg was evaluated in patients with AAI, including isolated AAI and AAI as part of autoimmune polyglandular syndrome type 2 (APS-2) and as part of APS-1, in patients with primary adrenal insufficiency (1-AI) of non-autoimmune genesis, conditionally healthy individuals without AI and autoimmune diseases.Results: A decrease in the content of Breg in vivo was revealed in patients with isolated AAI and AAI in the composition of APS-2 compared with conditionally healthy participants. The content of Breg in vivo in patients with 1-AI of non-autoimmune genesis did not statistically differ from the indicators of conditionally healthy participants.Conclusion: for the first time in the world, a tendency to a decrease in the content of Breg in AAI, caused by a disturbance of peripheral immune tolerance, was found. Thus, these cells can be considered as promising markers for the prognosis, early diagnosis, and differential diagnosis of AAI.

Bone Mineral Density and Vitamin D Status in Patients with Autoimmune Polyglandular Syndromes: A Single Tertiary Care Center Experience.

Immunological abnormalities, the resulting endocrinopathies, and their treatments may impact bone health and 25-hydroxyvitamin D (25-OHD) in patients with autoimmune polyglandular syndromes (APS). Several etiologies contribute to increased risk for low bone mineral density (BMD), including vitamin D deficiency. This study evaluated the vitamin D level and BMD of patients with APS. We performed a cross-sectional study on 44 patients with APS and 55 age and gender-matched control subjects. Among patients with APS, 14 were classified as APS-2 [Addison's disease (AD)+autoimmune thyroid disease (ATD) and/or type 1 diabetes(T1D)]. In contrast, the other 30 were APS-3 (ATD+T1D+other autoimmune diseases). Serum samples were analyzed for vitamin D levels. The lumbar spine and femoral neck BMD were measured by dual X-ray absorptiometry. Z-scores were obtained by comparison with age- and gender-matched average values (both patients and controls). The accepted normal levels were Z-score>-1 and 25-OHD>30 ng/ml. Patients with APS showed 25-OHD levels and BMD significantly lower than healthy controls (p<0.001 and p<0.05, respectively). The highest prevalence of abnormal BMD was observed in the APS-2 subgroup (13 out of 14 patients, 92.6%). Identifying and treating vitamin D deficiency and low BMD is critical in APS patients. The fact that the significant endocrine component of APS-2 is AD, and these patients receive chronic long-term glucocorticoid therapy can be shown as the reason for this result. However, more extensive prospective controlled studies are needed to confirm these findings.

Clinical Manifestations.

Perturbations in immune pathways are strongly associated with Alzheimer's disease. A positive association between autoimmune diseases and frontotemporal dementia has been reported. We explored whether early onset Alzheimer's disease (EOAD) would associate with autoimmune diseases. We compared 313 patients with EOAD from the Mayo Clinic Florida, Alzheimer's Disease Research Center (ADRC) Registry with matched cognitively normal controls (NC) based on age (+/- 2 years) and gender at 1:2 ratio. NC were derived from Mayo Clinic Biobank Project, Rochester (N = 313) and the Mayo Clinic Study of Aging (N = 313). Data abstraction was performed by trained statisticians using ICD 9&10 codes corresponding to 40 specified autoimmune diseases and/or documentation of specified immunomodulatory treatment. Data was also abstracted via retrospective record review. We further reviewed clinical records from EOAD patients with neuropathologically confirmed Alzheimer's disease patients enrolled in the ADRC (n = 10). Each autoimmune disease type was compared between cases and controls using Fisher's exact test. All tests were two-sided with alpha level set at 0.05 for statistical significance. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The prevalence of autoimmune disease in the general population was based off Hayter & Cook, 2012 and Roberts & Erdei, 2020. All data abstraction was done blinded to the clinical diagnosis and baseline demographics. Autoimmune disease history was abstracted from 949 patient records (313 EOAD, 10 pathologically-confirmed EOAD, 626 NCI). The median age was 57 years-old. (EOAD range 28,65 yrs.; NC 30,66 yrs.). Autoimmune thyroiditis (p = 0.0008), ulcerative colitis (p = 0.011, psoriasis (<0.0001), rheumatoid arthritis (p = 0.0005), and Raynaud's syndrome (p = 0.0021) were less prevalent in patients with EOAD compared to NC. Furthermore, patients with EOAD had a lower prevalence of immune mediated hematologic disorders. Patients with EOAD have a lower prevalence of autoimmune diseases than NC. Immune activation identified in early onset AD patients may be unrelated to autoimmunity. Findings should be explored in late onset AD patients.

A novel missense mutation in the AIRE gene underlying autoimmune polyglandular syndrome type 1.

The immune regulator gene AIRE plays an essential role in the establishment of immune tolerance and the prevention of autoimmunity. This transcription factor plays a critical role in promoting self-tolerance in the thymus by regulating the expression of a large number of self-antigens that share the common feature of being tissue-restricted in their expression pattern in the periphery. Dysfunction of AIRE in humans causes a rare disease, autoimmune polyglandular syndrome type 1 (APS1), characterized by an autoimmune response against peripheral tissues, particularly endocrine tissues. Although a few dominant mutations have been described, the inactivation of AIRE is usually caused by recessive mutations. Recent data suggests that alterations in AIRE function contribute not only to APS1 but also to more common forms of autoimmune disease. Here, we present a previously unreported missense mutation (NM_000383.2:c.260T > C) in exon 2 of the AIRE gene, predicted to cause the substitution (p.(Leu87Pro)) in the CARD domain of the AIRE protein. When inherited in conjunction with another dysfunctional AIRE allele, this mutation was associated with immune dysregulation in a pediatric patient. The presence of hypergammaglobulinemia, malabsorption syndrome, ectodermal dysplasia, mucocutaneous candidiasis, vitiligo, and hypothyroidism as well as the presence of multiple autoantibodies allowed us to confirm an APS1 diagnosis.

WPŁYW WIRUSA SARS-CoV-2 NA HOMEOSTAZĘ GLUKOZY I CUKRZYCĘ

Due to the prevalence, the diversity of disease course, and the range of systems attacked by viral particles, COVID-19 pandemic turned out to be a challenging experience for both medical staff and patients all over the world. It is essential to remember that the infection affects health state and wellbeing of patients including their comorbidities and chronic conditions. The example of such wide-spread coexisting conditions is diabetes mellitus. In this paper, we evaluate the influence of SARS-CoV-2 infection and diabetes mellitus, especially considering the autoimmune diabetes mellitus type 1. The review describes possible pathomechanisms of glucose homeostasis disturbances in relation to the destruction of pancreas and other organs by viral particles. Moreover, the aim of the paper is to show a complex connection between therapeutic management of both COVID-19 and diabetes. We describe suggested consequences of glucocortycoids treatment and modifications in insulin therapy applied in diabetes mellitus type 1.