RARE DISEASE
Rare diabetes mellitus type 1
Rare diabetes mellitus type 1
Rare diabetes mellitus type 1
Synonyms: Rare insulin-dependent diabetes mellitus
Synonyms: Rare insulin-dependent diabetes mellitus
Synonyms: Rare insulin-dependent diabetes mellitus
Drug discovery
22
drugs
With orphan designations
Overview
Rare diabetes mellitus type 1 encompasses atypical autoimmune or idiopathic forms, including fulminant type 1 diabetes (FT1D), characterized by abrupt β-cell destruction and rapid-onset diabetic ketoacidosis (DKA). FT1D often lacks classic autoimmune markers and requires immediate intensive care [6][13]. Diagnosis hinges on hyperglycemia (>288 mg/dL), low HbA1c (<8.5%), and undetectable C-peptide levels [6][16].
Therapies
Emergency: IV insulin, fluid resuscitation, and electrolyte correction for DKA [6][18]
Maintenance: Continuous subcutaneous insulin infusion (CSII) with hybrid closed-loop systems [3][18]
Experimental: Investigational immunotheracies (anti-PD-1 agents) and pancreatic islet transplantation trials [8][13]
Categories: rare endocrine diseases
Research Papers
331 drug discovery papers about Rare diabetes mellitus type 1, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
331 drug discovery papers about Rare diabetes mellitus type 1, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-22 | β-Hydroxybutyrate Improves Glucose Metabolism in Streptozotocin-Induced Type 1 Diabetes by Inhibiting Gut and Liver Glucose Transporters via GPR109A.
Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.
2026-06-19 | Phenylketonuria and type 1 diabetes: a clinical and nutritional challenge in a young adult-a case report.
Phenylketonuria and type 1 diabetes are lifelong metabolic disorders requiring complex and potentially conflicting nutritional strategies. Their coexistence is rare, yet management may become particularly challenging during transition from pediatric to adult care. We describe the case of a young adult with phenylketonuria who developed type 1 diabetes. A 27-year-old man with longstanding phenylketonuria was referred to an adult metabolic-diabetes center after the diagnosis of type 1 diabetes. Clinical, biochemical, nutritional, and continuous glucose monitoring data were reviewed. The intervention included structured therapeutic education, transition from fixed insulin doses to a dynamic regimen based on carbohydrate counting, and revision of medical nutrition therapy using phenylketonuria-adapted low-protein foods and sugar-free phenylalanine-free amino acid supplements. At diagnosis, HbA1c was 11.5%, with markedly reduced C-peptide levels and high titer anti-GAD antibodies. Initial diabetes management was associated with poor adherence to the phenylketonuria diet, increased intake of conventional protein sources, and elevated phenylalanine levels. After individualized insulin titration and nutritional intervention, HbA1c improved from 11.5% to 7.8%, phenylalanine levels decreased from 842 to 705 μmol/L, insulin requirement declined from 0.55 to 0.3 IU/kg/day, and continuous glucose monitoring showed improved glycemic control without increased hypoglycemia. The Glycemia Risk Index improved from high-risk Zone E to low-intermediate-risk Zone B. This case highlights the need for personalized multidisciplinary care integrating continuous glucose monitoring, carbohydrate counting, and phenylketonuria specific nutrition to optimize both metabolic conditions.
2026-06-01 | Insulin Resistance Unveiled: Cushing's Disease in a Patient With Type 1 Diabetes Mellitus and Worsening Glycemic Control.
Type 1 diabetes mellitus is an autoimmune disease often characterized by endogenous insulin deficiency and often sensitivity to exogenous insulin administration. Cushing's disease, though rare, should be considered as a cause of insulin resistance and increased insulin requirements in individuals with type 1 diabetes mellitus. A 21-year-old female with type 1 diabetes mellitus presented with steadily increasing insulin requirements via her hybrid closed-loop insulin pump. She subsequently developed hypertension, weight gain, violaceous striae, and cystic acne. Laboratory evaluation revealed unsuppressed cortisol of 16.6 μg/dL after a 1-mg dexamethasone suppression test, with a simultaneous adrenocorticotropin hormone level of 73.3 pg/mL. Pituitary MRI showed a 1.9 cm sellar mass with local invasion. She underwent transsphenoidal hypophysectomy. Postoperative cortisol was 8.9 μg/dL after intraoperative dexamethasone exposure. Residual hypercortisolism was confirmed, necessitating gamma knife radiation and pharmacologic treatment with a steroidogenesis inhibitor. We present a case of Cushing's disease due to a corticotropin-secreting pituitary macroadenoma in a young woman with type 1 diabetes. Her initial presentation included rising insulin requirements, followed by overt hypercortisolism. Despite surgery, persistent hypercortisolism required further intervention with gamma knife radiation and osilodrostat. She experienced reductions in both weight and insulin needs, with normalization of cortisol levels on maintenance osilodrostat. Cushing's syndrome should be considered in the differential diagnosis of patients with type 1 diabetes and increasing insulin requirements. This case underscores the importance of regular review of automated insulin delivery data and consideration of endocrine causes of insulin resistance and increased insulin requirements in those with type 1 diabetes.
2026-02-06 | Pelvic Gastrointestinal Stromal Tumor (GIST) Mimicking Ovarian Cancer in a Kidney-Liver Transplant Recipient Under Chronic Immunosuppression.
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that predominantly originate in the gastrointestinal tract. Extra-gastrointestinal GISTs can occur in atypical locations such as the pelvis, which may mimic gynecologic malignancies, creating diagnostic challenges. This case report presents a 39-year-old female with a history of Type 1 diabetes mellitus and prior kidney and liver transplantation who presented with progressive abdominal bloating and discomfort. Initial pelvic ultrasound revealed a large right adnexal mass (18.8 × 12.8 × 9.8 cm), suggestive of an ovarian mass. CT imaging confirmed a complex pelvic tumor exerting mass effect on surrounding organs, initially concerning for gynecologic malignancy. Following an unrevealing endoscopic evaluation, the patient underwent exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking. Intraoperative findings included a large right pelvic mass with extensive adhesions, friable tumor implants, and mesenteric lymphadenopathy. Postoperative pathology confirmed a high-grade GIST with epithelioid features, positive for DOG1 and CD117, with a Ki-67 index exceeding 30%. Molecular testing identified a KIT Exon 9 mutation, leading to initiation of imatinib therapy. Overall, this case represents an extra-GI/pelvic GIST that mimicked a primary ovarian neoplasm. We achieved a complete macroscopic cytoreduction (no gross residual disease) but explicitly note pT4 (due to intraoperative rupture), informing adjuvant KIT inhibition. This case emphasizes the diagnostic challenge of extra-GI/pelvic GISTs mimicking ovarian tumors. Studies show that GISTs mimicking primary ovarian tumors (GIST-OTs) typically occur in younger women, have lower recurrence rates (6.8% vs. 54.5% in metastatic ovarian GISTs), and achieve complete resection more frequently (> 90% vs. 57% in metastatic cases). Immunohistochemical profiling (DOG1 and CD117) and molecular testing are crucial for accurate diagnosis and treatment planning. Although imatinib remains the cornerstone of GIST management, dose adjustments based on specific mutations may be necessary, as patients with KIT Exon 9 mutations might benefit from higher dosing. Multidisciplinary approaches combining imaging, histology, and molecular profiling are essential for optimizing outcomes in these complex cases. This extra-GI/pelvic GIST occurred under chronic posttransplant immunosuppression after renal and liver transplantation; as such, we highlight the transplant-oncology interface, notably, an elevated posttransplant cancer risk, rare but documented GIST after kidney transplant, and TKI-calcineurin-inhibitor interactions that require coordinated management.
2026-02-02 | Successful rapid desensitization to multiple insulin preparations in an adult with type 1 diabetes: a case report and literature review.
Insulin allergy, although rare in type 1 diabetes (T1DM), poses a significant clinical challenge due to the indispensable role of insulin therapy. Rapid induction of insulin tolerance is critical for affected individuals, especially in acute complications such as diabetic ketoacidosis (DKA). We report a case of a 50-year-old male with newly diagnosed T1DM who developed type I hypersensitivity reactions to multiple insulin analogs, manifesting as localized erythema, pruritus, and induration. After conventional management, including switching insulin preparations, proved ineffective, a rapid desensitization protocol was initiated using continuous subcutaneous insulin infusion (CSII). Preceding the pump initiation, half of the estimated basal dose of insulin glargine was administered subcutaneously. CSII with insulin aspart was then started at an extremely low initial rate, with increments every 30 minutes. The target basal infusion rate was successfully achieved within 5 hours without the use of antihistamines or corticosteroids. The procedure was well-tolerated, with no systemic or local allergic reactions. Following desensitization, the patient successfully transitioned to daily injections of glargine and pre-meal aspart insulin, with no recurrence of allergic reactions during long-term follow-up. A CSII-based rapid desensitization protocol is a safe, effective, and efficient strategy for managing insulin allergy in T1DM, including cases with sensitivities to multiple insulin preparations. This approach is particularly suitable for patients requiring urgent insulin therapy.
gene therapies
2024-12-19 | Monogenic Type 1 Diabetes: A High Yield Pool in Which to Discover New Mechanisms and Candidate Therapeutics for Type 1 Diabetes.
Rare monogenic forms of disease provide a unique opportunity to understand novel pathways in human biology. With the rapid advances in genomics and next-generation sequencing, we now have the tools to interrogate the genomes of patients on a large scale to identify candidate genes in patients with rare monogenic forms of type 1 diabetes (T1D). These cases are more likely to represent genetic defects in critical pathways of immune tolerance, and the study of these patients provides a high-yield pool in which to discover new mechanisms of disease in T1D. These studies are also expected to have high translational impact for the T1D community by helping to identify at-risk individuals and provide compelling candidate targets for prevention and treatment.
2024-11-13 | A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.
Wolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene's mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype-phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7. Bioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays. We showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316-460del), and two open reading frame-conserving mRNAs (c.271-513del and c.316-456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316-460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells. This study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype-phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease. The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).
2024-10-04 | Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.
Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.
2024-06-14 | CRISPR: An Elixir for Autoimmune Diseases? A Systematic Review
Genetic studies have linked the gene polymorphisms and autoimmune disorders. In response, the Clustered Regularly Interspaced Short Palindromic Repeats and its associated protein 9 (CRISPR-Cas9) has become a promising tool for treating these diseases. The broad acceptance of CRISPR, due to its simplicity, precision, and adaptability, has significantly rushed scientificresearch, and fostered radical discoveries in both model species and human cells. CRISPR-Cas9 offers versatile applications for rare diseases like urea cycle disorders or hepatorenal tyrosinemia and in reducing cholesterol by targeting Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). It can also immunomodulate the autoimmune diseases by specifically targeting genes associated with these conditions. This targeted approach holds the potential to modify the immune response, leading to the potential alleviation of disease progression. Our review underscores the ongoing exploration of CRISPR-Cas9 therapy for autoimmune disorders, emphasizing its transformative possibilities in this field. We specifically highlight the potential target genes for CRISPR-Cas9 immunomodulation in prevalent autoimmune disorders such as systemic lupus erythematosus, multiple sclerosis, insulin-dependent diabetes mellitus, psoriasis, type 1 coeliac disease, and rheumatoid arthritis. The future holds immense promise as the remarkable advances in CRISPR-Cas9 therapies pave the way for a revolutionary transformation in the treatment of various autoimmune disorders
2022-08-26 | Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines.
Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1aC825X and wfs1bW493X. We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS.
proteins
2026-08-14 | Evaluating the use of GLP-1 receptor agonists in Wolfram syndrome patients.
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study, with additional longitudinal data for participants co-enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study. We characterized the prevalence of GLP-1 RA use and the documented rationale for initiation, and evaluated within-participant pre-post changes in glycemic (HbA1c, body mass index) and visual (LogMAR best-corrected visual acuity, retinal nerve fiber layer thickness) parameters, along with adverse effects and reasons for discontinuation. Thirty of the 84 participants (35.7%) had received a GLP-1 RA in addition to insulin. No statistically significant changes in HbA1c or body mass index were observed at one or two years. Best-corrected visual acuity (LogMAR) declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common (56.7% of users) and were the leading cause of discontinuation. In this largest reported evaluation of GLP-1 RA use in Wolfram syndrome, these agents were already integrated into clinical care and were generally tolerated, but showed no glycemic or visual benefit over one to two years. Given the retrospective, uncontrolled design, the small number of participants with paired pre-post measurements, and the absence of a longitudinally followed comparator group, these findings are preliminary and hypothesis-generating rather than definitive, and provide a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.
2026-06-08 | DIABETES MELLITUS IN WOLFRAM SYNDROME 1: CHARACTERISTICS AND PERSPECTIVES IN TREATMENT
Wolfram syndrome 1 is a rare autosomal recessive disorder caused by mutations in the WFS1 gene related to endoplasmic reticulum (ER) function. The course of the disease most often begins with diagnosis of insulin-dependent non-autoimmune diabetes mellitus with an early onset. Its clinical character is presented with an acronym DIDMOAD: diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D). This article focuses on the clinical features of diabetes mellitus in Wolfram syndrome. We also describe current approach to its therapy and discuss possible treatment options placing the main emphasis on the GLP1 receptor agonists and cell regenerative therapy. Methods and materials: A qualitative synthesis of the data focusing on GLP-1 agonists, cell regenerative therapy and diabetes mellitus in Wolfram syndrome was performed. This literature review of GLP-1 receptor agonists and cell regenerative therapy effect on metabolic control, and current perspectives of treatment in patients with Wolfram syndrome, a monogenic type of diabetes, included recent publications, primarily from the past 10 years, and was conducted from November 2025 to April 2026 using the PubMed database. A systematic search was performed using specific keywords and medical subject headings (MeSH terms) related to GLP-1 agonists and Wolfram syndrome. The primary search terms included: “diabetes mellitus”, “GLP-1 agonists”, “Wolfram syndrome”, “WFS1”, “monogenic diabetes”, “islet transplantation”, and “cell regenerative therapy”. The criteria for inclusion of articles were as follows: published before April 2026, written in English, peer-reviewed original research articles. Exclusion criteria included publications not available in full text, articles in languages other than English. Editorials, commentaries, and conference abstracts without full data were also excluded. Titles and abstracts of the retrieved articles were screened to determine eligibility based on the inclusion and exclusion criteria.
2026-06-08 | Delayed Hypersensitivity Reaction to Insulin: A Case Report.
Advances in the purification of animal insulin preparations and the introduction of recombinant human insulin have markedly reduced the frequency of insulin hypersensitivity reactions. However, preservatives such as metacresol and other excipients contained in insulin formulations may still induce hypersensitivity reactions, which may be immediate, corresponding to type I hypersensitivity, or delayed, suggesting type III or, more commonly, type IV hypersensitivity according to the Gell and Coombs classification. We report the case of a 25-year-old woman with a 2-year history of type 1 diabetes mellitus who was initially treated with insulin detemir and insulin glulisine. Fifteen months after the initiation of insulin therapy, she developed delayed erythematous skin lesions associated with mild headaches and abdominal pain. Several alternative insulin preparations were subsequently tried, but all reproduced the same symptoms despite antihistamine therapy. Dose splitting and rotation of injection sites failed to improve the reaction. Specific IgE antibodies to human insulin, porcine insulin, protamine, and latex were negative. Skin prick tests performed with different insulin preparations were negative on immediate reading; however, 12 hours later, the patient developed a diffuse and extensive cutaneous reaction, including facial involvement. Because all tested insulin preparations triggered a reaction, their excipient profiles were reviewed, and metacresol was identified as the only common excipient among them. As no metacresol-free insulin preparation was available in Morocco, tolerance induction with insulin was undertaken in an attempt to induce tolerance despite probable hypersensitivity to metacresol. The procedure was successful and resulted in sustained tolerance to all insulin preparations. Insulin allergy remains a rare yet challenging condition that requires careful diagnostic evaluation. Identification of the causative mechanism, including possible hypersensitivity to excipients such as metacresol, is crucial to guide appropriate management.
2026-05-19 | Simultaneous Pancreas and Kidney Transplantation in a Patient With Congenital Hemophilia A: A rare Case Report and Management Insights.
Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for end-stage kidney disease (ESKD) and type 1 diabetes mellitus. However, even with careful perioperative control of hemostasis, SPK carries a high risk of postoperative bleeding, which is exacerbated in patients with hemophilia A. Here, we report the first known successful SPK in a patient with congenital hemophilia A. A 52-year-old man was diagnosed with hemophilia A at 2 years of age. He developed type 1 diabetes mellitus at 25 years of age, which progressed to ESKD at 43 years of age. A comprehensive preoperative FVIII replacement protocol was applied during the perioperative period, using continuous infusion with bolus supplementation to maintain target VIII activity levels (100% intraoperatively, 80% during the first postoperative week, and ≥30% thereafter). This case demonstrates that SPK transplantation can be safely performed in patients with congenital hemophilia A, by implementing appropriate FVIII replacement strategies and close multidisciplinary collaboration.
2025-10-08 | Continuous Subcutaneous Insulin Infusion (CSII)-Associated Granulomatous Suppurative Reaction in Four Children With Type 1 Diabetes.
With the increasing use of continuous glucose monitors and continuous subcutaneous insulin infusion (CSII) devices in pediatric patients with type 1 diabetes (T1DM), dermatologic complications are being reported more frequently. We describe four children with T1DM who developed persistent erythematous nodules with suppurative granulomatous inflammation at prior CSII injection sites. Treatment responses varied: one child improved after transitioning to subcutaneous insulin injections, another with oral dapsone, a third after switching CSII devices and limiting placement to the abdomen, and a fourth with topical corticosteroids and antibiotic ointment. This rare complication appears unrelated to specific device models or insulin types, highlighting the need for further studies to identify risk factors and guide optimal management.
antibodies
2026-08-12 | Anti-GAD65 antibody-associated cerebellar ataxia in a young adult with type 1 diabetes: a case report and literature review.
Anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia (anti-GAD-CA) is a rare autoimmune neurological disorder. Although frequently associated with latent autoimmune diabetes in adults (LADA), it can occasionally coexist with type 1 diabetes mellitus (T1DM). We report a 27-year-old woman with a 14-year history of T1DM who presented with subacute onset of balance impairment, vertigo, and hypophonic speech. Neurological examination and laboratory investigations were consistent with cerebellar ataxia. The patient exhibited high titers of anti-glutamic acid decarboxylase (anti-GAD) in both serum (619 IU/mL) and cerebrospinal fluid. Brain MRI was unremarkable. After a 5-day intravenous immunoglobulin (IVIG) therapy, the patient showed notable improvement in tandem gait and speech fluency. Her glycemic control also improved significantly, with the glycated hemoglobin (HbA1c) dropping from 9.7 to 6.8% over two months. Follow-up testing showed a steady decline in serum anti-GAD levels to 229 IU/mL. This case represents one of the youngest reported patients with anti-GAD-CA in the context of long-standing T1DM. The case emphasizes the importance of considering anti-GAD-CA in patients with unexplained cerebellar signs and autoimmune diabetes, even in younger individuals. Furthermore, the observed parallel improvements in neurological and glycemic parameters following immunotherapy may provide insight into the interplay between anti-GAD autoimmunity and metabolic control. Further studies are required to better understand the pathophysiological mechanisms and optimize management strategies.
2026-03-16 | PLA2R-positive primary membranous nephropathy in an adolescent with type 1 diabetes mellitus and autoimmune hypothyroidism: a case report.
Membranous nephropathy (MN) is an uncommon cause of nephrotic syndrome in children, accounting for fewer than 5% of cases. Primary MN mediated by antibodies against the phospholipase A2 receptor (PLA2R) is particularly rare in the paediatric population. We report the case of a 14-year-old girl with type 1 diabetes mellitus and autoimmune hypothyroidism who presented with nephrotic syndrome and was subsequently diagnosed with PLA2R-positive primary MN. She presented with periorbital oedema, abdominal distension, and bilateral pitting pedal oedema. Laboratory investigations demonstrated severe hypoalbuminemia (serum albumin 1.2 g/dL), nephrotic-range proteinuria (24-hour urine protein excretion of 3.5 g/day), and preserved renal function (serum creatinine 0.3 mg/dL). Renal biopsy findings, supported by immunohistochemistry, confirmed PLA2R positivity. The patient was treated with four weekly doses of rituximab (375 mg/m2), resulting in complete clinical remission at 6 months. Serum albumin normalised to 4 g/dL, 24-hour urine protein excretion decreased to 250 mg/day, and serum PLA2R antibody levels fell below the normal range. This case highlights the importance of considering PLA2R-mediated MN in adolescents with nephrotic syndrome and the presence of multiple autoimmune comorbidities. It also underscores the diagnostic value of tissue PLA2R testing and demonstrates the efficacy of early rituximab-based B-cell-directed therapy in achieving complete remission while avoiding corticosteroid exposure.
2025-11-12 | Use of Teplizumab to Modulate Stage 2 Type 1 Diabetes in Two Individuals With Autoimmune Polyendocrine Syndrome 1.
Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic autoimmune disorder that may manifest as type 1 diabetes (T1D). Teplizumab, an anti-CD3 monoclonal antibody, delays progression of stage 2 T1D, but its effects in APS-1-associated diabetes are unknown. We report clinical responses of two adolescents with APS-1 and stage 2 T1D who received 14-day courses of teplizumab. In one patient, pancreatic MRI and spectral immune cell phenotyping were performed before and after treatment. Both patients exhibited improved glycemia. One who briefly required insulin recovered insulin independence 2 weeks after therapy. Pancreatic volume transiently increased, and circulating lymphocytes showed changes in homing receptors and senescence markers in the individual who underwent those studies. Nonpancreatic APS-1 manifestations were unchanged. Teplizumab may preserve β-cell function in APS-1-associated T1D. Larger studies are needed to define efficacy, durability, and immunologic and tissue mechanisms in this rare context.
2025-07-23 | Development of type 1 diabetes mellitus after nivolumab dose escalation: A case report.
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare but serious immune-related adverse event associated with programmed cell death-1 inhibitors such as nivolumab. While previous reports have documented its occurrence, the relationship between nivolumab dosing and the onset of ICI-T1DM remains unclear. This study presents a case of ICI-T1DM following a nivolumab dose and includes a literature review. A man in his 50s (weight: 49.4 kg, body mass index: 17.65 kg/m2) with advanced esophageal cancer had been receiving nivolumab (240 mg every 14 days) for over 2 years without adverse effects. Because of treatment adjustments, the dose was increased to 480 mg and administered every 28 days. Ninety-six days after the dose increase, he developed acute-onset fatigue, anorexia, and thirst. Laboratory tests confirmed diabetic ketoacidosis with hyperglycemia (582 mg/dL), low C-peptide levels, and negative islet-associated antibodies, leading to the diagnosis of nivolumab-induced fulminant type 1 diabetes mellitus. The patient was treated with insulin and discharged after stabilization. This case suggests that higher dose nivolumab may increase the risk of ICI-T1DM, especially in low body-weight individuals. Given that nivolumab remains effective at lower doses, dose optimization may help mitigate immune-related adverse events while maintaining therapeutic efficacy.
2025-03-12 | Early expansion of TIGIT+PD1+ effector memory CD4 T cells via agonistic effect of alefacept in new-onset type 1 diabetes.
The CD2-depleting drug alefacept (LFA3-Ig) preserved beta cell function in new-onset type 1 diabetes (T1D) patients. The most promising biomarkers of response were late expansion of exhausted CD8 T cells and rare baseline inflammatory islet-reactive CD4 T cells, neither of which can be used to measure responses to drug in the weeks after treatment. Thus, we investigated whether early changes in T cell immunophenotypes could serve as biomarkers of drug activity. We characterized T cell responses by flow cytometry and identified an exhausted-like population of CD2low CD4 effector memory T cells coexpressing TIGIT and PD1 that expanded by 11 wk after the start of treatment. This population was not entirely spared from alefacept-mediated depletion in vivo or in vitro but recovered through homeostatic proliferation of CD2low cells in vivo. Proliferation of TIGIT+PD1+ effector memory CD4 T cells increased with treatment, with a concomitant reduction of proinflammatory cytokine production. The persistent increase of TIGIT+PD1+ effector memory CD4 T cells was specific to alefacept treatment; 2 other T cell depleting therapies, teplizumab and anti-thymocyte globulin, induced only a transient increase in this CD4 population. Our data suggest that the expanding TIGIT+PD1+ effector memory CD4 T cell population represents a promising biomarker of early treatment effects of alefacept. The nondepleting effects on proliferation and cytokine production also suggest agonistic activity by this CD2 targeted therapy.
other
2026-01-26 | Pulmonary mucormycosis with bacterial coinfection in an adolescent with poorly controlled type 1 diabetes: a case report.
Pulmonary Mucormycosis (PM), a severe fungal infection affecting mainly immunocompromised individuals, is often caused by fungi like Rhizopus and Mucor. This report details a 12-year-old diabetic girl with pulmonary mucormycosis from an unusual Rhizopus species. Successful treatment involved stabilizing her blood glucose and managing multiple co-infections. This case provides important insights into diagnosing and treating rare fungal infections in diabetic children. A 12-year-old girl with a two-year history of type 1 diabetes, inconsistently monitored, was hospitalized. She had a persistent cough for over ten days and a six-day high fever. Previous treatments with dexamethasone and antibiotics were ineffective. She showed symptoms of a productive cough, right-sided pleuritic chest pain, and a fever of 40°C. Examination revealed reduced breath sounds and moist rales in the right lung. Tests confirmed a severe infection, and imaging showed inflammatory consolidation, multiple cavitations, and pleural effusion in the right lung. Metagenomic next-generation sequencing (mNGS) analyzes all nucleic acids from a patient's bronchoalveolar lavage fluid to identify various pathogens without traditional cultures. The analysis identified Rhizopus species and Streptococcus pneumoniae, confirming pulmonary mucormycosis with a bacterial infection. Additionally, the glycated hemoglobin (HbA1c) level was 14.3%, indicating poorly controlled diabetes. A comprehensive treatment regimen was employed. The bacterial co-infection was addressed with intravenous administration of meropenem and linezolid, while nebulized amphotericin B was utilized to treat the pulmonary mucormycosis. To mitigate the underlying risk factor, intensive glycemic control was achieved through the use of an insulin pump. Furthermore, bronchoscopy was conducted to clear respiratory secretions. After 11 days in the hospital, the patient stabilized and was discharged. At a follow-up 1.5 months later, infection markers and blood glucose levels were normal. This case highlights the high risk of severe infections like pulmonary mucormycosis in adolescents with poorly managed type 1 diabetes. Metagenomic sequencing was crucial for quickly identifying co-infections. Successful treatment required a comprehensive approach, including targeted antimicrobial therapy, strict glycemic control, and bronchoscopic support, leading to a positive outcome.
2025-06-18 | The role and mechanism of mesenchymal stem cells in immunomodulation of type 1 diabetes mellitus and its complications: recent research progress and challenges: a review.
Mesenchymal stem cells are of great interest because of their multipotency, immune modulation capacity, and tissue and vascular regeneration effects. They are used in treating type 1 diabetes mellitus, helping improve the pancreatic environment and insulin secretion. Type 1 diabetes mellitus predominantly affects children and adolescents, with early onset and a prolonged course that can lead to multiorgan complications and related disorders. Studies using mesenchymal stem cells to treat type 1 diabetes mellitus have yielded promising results. This review discusses the common animal models of type 1 diabetes mellitus, mesenchymal stem cell immunotherapy mechanisms, and combined diabetes treatments. Its purpose is to summarize the current evidence on mesenchymal stem cell use in type 1 diabetes, providing insights for further research directions. Current studies show that mesenchymal stem cells play an active role in the treatment of type 1 diabetes; however, clinical trials remain rare, necessitating more basic and preclinical research to identify optimal treatments. Mesenchymal stem cells can treat type 1 diabetes through a variety of immune mechanisms and also play a positive role in the treatment of type 1 diabetes complications. At the same time, it can be combined with other therapies to play a better therapeutic role.
2025-04-16 | The Last Mile in Beta-Cell Replacement Therapy for Type 1 Diabetes: Time to Grow Up.
Beta cell replacement therapy for type 1 diabetes (T1D) is undergoing a transformative shift, driven by advances in stem cell biology, gene editing, and tissue engineering. While islet transplantation has demonstrated proof-of-concept success in restoring endogenous insulin production, its clinical impact remains limited by donor scarcity, immune rejection, and procedural complexities. The emergence of stem cell-derived beta-like cells represents a paradigm shift, with initial clinical trials showing promising insulin secretion in vivo. However, translating these breakthroughs into scalable, widely accessible treatments poses significant challenges. Drawing parallels to space exploration, this paper argues that while scientific feasibility has been demonstrated, true accessibility remains elusive. Without a strategic shift, beta cell therapy risks becoming an elite intervention, restricted by cost and infrastructure. Lessons from gene and cell therapies for rare diseases highlight the dangers of unsustainable pricing and limited market viability. To bridge the "last mile" a Quality by Design approach is proposed, emphasizing scalability, ease of use, and economic feasibility from the outset. By emphasizing practical implementation over academic achievements, corporate interests, market economics, or patent constraints, beta cell therapy can progress from proof-of-concept to a viable, widely accessible treatment.
2025-01-27 | P-30 ROLE OF PLASMAPHERESIS IN TREATING A RARE CASE OF EXOGENOUS INSULIN ANTIBODY SYNDROME (EIAS) IN A YOUNG PATIENT WITH TYPE 1 DIABETES MELLITUS IN BABYLON GOVERNORATE: A CASE REPORT
Abstract Clinical Case A 17-year old female patient who was diagnosed with type 1 diabetes mellitus (DM) seven years ago, and she had continuously very high blood glucose readings with recurrent admissions to the emergency unit due to attacks of DKA. In addition to a planned diet, she was on more than 250 units of insulin per day (while her weight was 75 kilograms). She was initially on human insulin in the form of twice NPH insulin injections, and pre-meal regular insulin injections, in addition to repeated regular insulin correction doses without any reduction of her blood glucose. Then she was shifted to insulin analogues (to eliminate the possibility of insulin immunogenicity which have been encountered with the use of human insulin), in form of basal insulin Glargine OD, plus pre-meal rapid acting insulin Glulisine without any noticeable response. Continuous switching of her injection sites, with an in-hospital observed insulin injections (to avoid noncompliance), even the use of intravenous route did not help to achieve a glycemic control. Later on, metformin 1000 mg XR BID was added to her daily treatment without any benefit. A screen of anti-insulin antibodies was done and found to be elevated (which should be negative after all these years after her initial diabetes diagnosis). A presumptive diagnosis of EIAS (Exogenous Insulin Antibody Syndrome) was put. A small dose of steroids was administered with close observation (to avoid exacerbation ketosis) without any improvement. Then Cellcept (Mycophenolate mofetil), an immune modulator was added at a dose of 500 mg BID and increased 48 hrs. later to 1000 mg BID and resulted in a minimal reduction of her blood glucose levels. Finally the decision of plasmapheresis was made and an informed consent was obtained from the family after explaining the condition. A good response was recorded after the 1st session, with a minimal decrease of her total daily insulin doses. Later on, an additional excellent response was received during the next 2 sessions with a rapid decline of her glucose readings and her total daily insulin doses. She had recurrent attacks of hypoglycemia during her third and last plasmapheresis session. Her total daily dose of insulin was successfully reduced by more than 50%, and her general condition was improved noticeably without any recorded adverse reactions, as shown in the blood glucose logbook photos attached below.Figure 1:Glucose logbook after the 3rd and last session of Plasmapheresis Table 1:Response parameters to three sessions plasampheresis therapy
2024-08-07 | Efficacy and safety of gut microbiota-based therapies in autoimmune and rheumatic diseases: a systematic review and meta-analysis of 80 randomized controlled trials.
Previous randomized controlled trials (RCTs) suggested that gut microbiota-based therapies may be effective in treating autoimmune diseases, but a systematic summary is lacking. Pubmed, EMbase, Sinomed, and other databases were searched for RCTs related to the treatment of autoimmune diseases with probiotics from inception to June 2022. RevMan 5.4 software was used for meta-analysis after 2 investigators independently screened literature, extracted data, and assessed the risk of bias of included studies. A total of 80 RCTs and 14 types of autoimmune disease [celiac sprue, SLE, and lupus nephritis (LN), RA, juvenile idiopathic arthritis (JIA), spondyloarthritis, psoriasis, fibromyalgia syndrome, MS, systemic sclerosis, type 1 diabetes mellitus (T1DM), oral lichen planus (OLP), Crohn's disease, ulcerative colitis] were included. The results showed that gut microbiota-based therapies may improve the symptoms and/or inflammatory factor of celiac sprue, SLE and LN, JIA, psoriasis, PSS, MS, systemic sclerosis, Crohn's disease, and ulcerative colitis. However, gut microbiota-based therapies may not improve the symptoms and/or inflammatory factor of spondyloarthritis and RA. Gut microbiota-based therapies may relieve the pain of fibromyalgia syndrome, but the effect on fibromyalgia impact questionnaire score is not significant. Gut microbiota-based therapies may improve HbA1c in T1DM, but its effect on total insulin requirement does not seem to be significant. These RCTs showed that probiotics did not increase the incidence of adverse events. Gut microbiota-based therapies may improve several autoimmune diseases (celiac sprue, SLE and LN, JIA, psoriasis, fibromyalgia syndrome, PSS, MS, T1DM, Crohn's disease, and ulcerative colitis).
small molecules
2026-06-22 | β-Hydroxybutyrate Improves Glucose Metabolism in Streptozotocin-Induced Type 1 Diabetes by Inhibiting Gut and Liver Glucose Transporters via GPR109A.
Ketone bodies, particularly β-hydroxybutyrate (3HB), are often elevated in type 1 diabetes (T1D); however, their physiological roles remain unclear. In a low-carbohydrate diet study, patients with insulin-deficient diabetes exhibited reduced fasting blood glucose and increased fasting blood ketone levels, negatively correlated. Another clinical study using continuous glucose and ketone monitoring confirmed inverse glucose-ketone fluctuations. To test causality, we conducted animal and cellular studies. In streptozotocin-induced T1D mice, 7-week oral 3HB administration improved glucose metabolism and alleviated glycogenic hepatopathy. Imaging with 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography/computed tomography demonstrated reduced hepatic and intestinal glucose uptake. Western blotting confirmed 3HB suppressed glucose transporter (sodium-glucose cotransporter 1, GLUT2, GLUT5) overexpression and normalized glycogen metabolism. In vitro, 3HB dose-dependently inhibited glucose transporter expression and glucose uptake in primary hepatocytes and IEC-6 cells. G protein-coupled receptor 109A (GPR109A) serves as the primary receptor for 3HB. Mechanistic studies using the GPR109A inhibitor mepenzolate bromide, the mTOR inhibitor rapamycin, and siRNA-mediated gene silencing revealed that these effects were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. Overall, this study provides new insights into the role of ketone bodies in T1D, establishing 3HB as a modulator of glucose homeostasis through GPR109A-mediated suppression of glucose transporters in the liver and intestine.
2026-06-19 | Phenylketonuria and type 1 diabetes: a clinical and nutritional challenge in a young adult-a case report.
Phenylketonuria and type 1 diabetes are lifelong metabolic disorders requiring complex and potentially conflicting nutritional strategies. Their coexistence is rare, yet management may become particularly challenging during transition from pediatric to adult care. We describe the case of a young adult with phenylketonuria who developed type 1 diabetes. A 27-year-old man with longstanding phenylketonuria was referred to an adult metabolic-diabetes center after the diagnosis of type 1 diabetes. Clinical, biochemical, nutritional, and continuous glucose monitoring data were reviewed. The intervention included structured therapeutic education, transition from fixed insulin doses to a dynamic regimen based on carbohydrate counting, and revision of medical nutrition therapy using phenylketonuria-adapted low-protein foods and sugar-free phenylalanine-free amino acid supplements. At diagnosis, HbA1c was 11.5%, with markedly reduced C-peptide levels and high titer anti-GAD antibodies. Initial diabetes management was associated with poor adherence to the phenylketonuria diet, increased intake of conventional protein sources, and elevated phenylalanine levels. After individualized insulin titration and nutritional intervention, HbA1c improved from 11.5% to 7.8%, phenylalanine levels decreased from 842 to 705 μmol/L, insulin requirement declined from 0.55 to 0.3 IU/kg/day, and continuous glucose monitoring showed improved glycemic control without increased hypoglycemia. The Glycemia Risk Index improved from high-risk Zone E to low-intermediate-risk Zone B. This case highlights the need for personalized multidisciplinary care integrating continuous glucose monitoring, carbohydrate counting, and phenylketonuria specific nutrition to optimize both metabolic conditions.
2026-06-01 | Insulin Resistance Unveiled: Cushing's Disease in a Patient With Type 1 Diabetes Mellitus and Worsening Glycemic Control.
Type 1 diabetes mellitus is an autoimmune disease often characterized by endogenous insulin deficiency and often sensitivity to exogenous insulin administration. Cushing's disease, though rare, should be considered as a cause of insulin resistance and increased insulin requirements in individuals with type 1 diabetes mellitus. A 21-year-old female with type 1 diabetes mellitus presented with steadily increasing insulin requirements via her hybrid closed-loop insulin pump. She subsequently developed hypertension, weight gain, violaceous striae, and cystic acne. Laboratory evaluation revealed unsuppressed cortisol of 16.6 μg/dL after a 1-mg dexamethasone suppression test, with a simultaneous adrenocorticotropin hormone level of 73.3 pg/mL. Pituitary MRI showed a 1.9 cm sellar mass with local invasion. She underwent transsphenoidal hypophysectomy. Postoperative cortisol was 8.9 μg/dL after intraoperative dexamethasone exposure. Residual hypercortisolism was confirmed, necessitating gamma knife radiation and pharmacologic treatment with a steroidogenesis inhibitor. We present a case of Cushing's disease due to a corticotropin-secreting pituitary macroadenoma in a young woman with type 1 diabetes. Her initial presentation included rising insulin requirements, followed by overt hypercortisolism. Despite surgery, persistent hypercortisolism required further intervention with gamma knife radiation and osilodrostat. She experienced reductions in both weight and insulin needs, with normalization of cortisol levels on maintenance osilodrostat. Cushing's syndrome should be considered in the differential diagnosis of patients with type 1 diabetes and increasing insulin requirements. This case underscores the importance of regular review of automated insulin delivery data and consideration of endocrine causes of insulin resistance and increased insulin requirements in those with type 1 diabetes.
2026-02-06 | Pelvic Gastrointestinal Stromal Tumor (GIST) Mimicking Ovarian Cancer in a Kidney-Liver Transplant Recipient Under Chronic Immunosuppression.
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that predominantly originate in the gastrointestinal tract. Extra-gastrointestinal GISTs can occur in atypical locations such as the pelvis, which may mimic gynecologic malignancies, creating diagnostic challenges. This case report presents a 39-year-old female with a history of Type 1 diabetes mellitus and prior kidney and liver transplantation who presented with progressive abdominal bloating and discomfort. Initial pelvic ultrasound revealed a large right adnexal mass (18.8 × 12.8 × 9.8 cm), suggestive of an ovarian mass. CT imaging confirmed a complex pelvic tumor exerting mass effect on surrounding organs, initially concerning for gynecologic malignancy. Following an unrevealing endoscopic evaluation, the patient underwent exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking. Intraoperative findings included a large right pelvic mass with extensive adhesions, friable tumor implants, and mesenteric lymphadenopathy. Postoperative pathology confirmed a high-grade GIST with epithelioid features, positive for DOG1 and CD117, with a Ki-67 index exceeding 30%. Molecular testing identified a KIT Exon 9 mutation, leading to initiation of imatinib therapy. Overall, this case represents an extra-GI/pelvic GIST that mimicked a primary ovarian neoplasm. We achieved a complete macroscopic cytoreduction (no gross residual disease) but explicitly note pT4 (due to intraoperative rupture), informing adjuvant KIT inhibition. This case emphasizes the diagnostic challenge of extra-GI/pelvic GISTs mimicking ovarian tumors. Studies show that GISTs mimicking primary ovarian tumors (GIST-OTs) typically occur in younger women, have lower recurrence rates (6.8% vs. 54.5% in metastatic ovarian GISTs), and achieve complete resection more frequently (> 90% vs. 57% in metastatic cases). Immunohistochemical profiling (DOG1 and CD117) and molecular testing are crucial for accurate diagnosis and treatment planning. Although imatinib remains the cornerstone of GIST management, dose adjustments based on specific mutations may be necessary, as patients with KIT Exon 9 mutations might benefit from higher dosing. Multidisciplinary approaches combining imaging, histology, and molecular profiling are essential for optimizing outcomes in these complex cases. This extra-GI/pelvic GIST occurred under chronic posttransplant immunosuppression after renal and liver transplantation; as such, we highlight the transplant-oncology interface, notably, an elevated posttransplant cancer risk, rare but documented GIST after kidney transplant, and TKI-calcineurin-inhibitor interactions that require coordinated management.
2026-02-02 | Successful rapid desensitization to multiple insulin preparations in an adult with type 1 diabetes: a case report and literature review.
Insulin allergy, although rare in type 1 diabetes (T1DM), poses a significant clinical challenge due to the indispensable role of insulin therapy. Rapid induction of insulin tolerance is critical for affected individuals, especially in acute complications such as diabetic ketoacidosis (DKA). We report a case of a 50-year-old male with newly diagnosed T1DM who developed type I hypersensitivity reactions to multiple insulin analogs, manifesting as localized erythema, pruritus, and induration. After conventional management, including switching insulin preparations, proved ineffective, a rapid desensitization protocol was initiated using continuous subcutaneous insulin infusion (CSII). Preceding the pump initiation, half of the estimated basal dose of insulin glargine was administered subcutaneously. CSII with insulin aspart was then started at an extremely low initial rate, with increments every 30 minutes. The target basal infusion rate was successfully achieved within 5 hours without the use of antihistamines or corticosteroids. The procedure was well-tolerated, with no systemic or local allergic reactions. Following desensitization, the patient successfully transitioned to daily injections of glargine and pre-meal aspart insulin, with no recurrence of allergic reactions during long-term follow-up. A CSII-based rapid desensitization protocol is a safe, effective, and efficient strategy for managing insulin allergy in T1DM, including cases with sensitivities to multiple insulin preparations. This approach is particularly suitable for patients requiring urgent insulin therapy.
gene therapies
2024-12-19 | Monogenic Type 1 Diabetes: A High Yield Pool in Which to Discover New Mechanisms and Candidate Therapeutics for Type 1 Diabetes.
Rare monogenic forms of disease provide a unique opportunity to understand novel pathways in human biology. With the rapid advances in genomics and next-generation sequencing, we now have the tools to interrogate the genomes of patients on a large scale to identify candidate genes in patients with rare monogenic forms of type 1 diabetes (T1D). These cases are more likely to represent genetic defects in critical pathways of immune tolerance, and the study of these patients provides a high-yield pool in which to discover new mechanisms of disease in T1D. These studies are also expected to have high translational impact for the T1D community by helping to identify at-risk individuals and provide compelling candidate targets for prevention and treatment.
2024-11-13 | A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.
Wolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene's mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype-phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7. Bioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays. We showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316-460del), and two open reading frame-conserving mRNAs (c.271-513del and c.316-456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316-460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells. This study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype-phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease. The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).
2024-10-04 | Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.
Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High-resolution HLA class II haplotyping, SNP genotyping, and T1D-genetic risk score (T1D-GRS) were also evaluated. Results: Eight of the ninety-nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C-peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C-peptide compared to EOT1D without MODY rare variants. They also carried at least one high-risk DR3-DQ2 or DR4-DQ8 haplotype and exhibited a T1D-GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β-cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes.
2024-06-14 | CRISPR: An Elixir for Autoimmune Diseases? A Systematic Review
Genetic studies have linked the gene polymorphisms and autoimmune disorders. In response, the Clustered Regularly Interspaced Short Palindromic Repeats and its associated protein 9 (CRISPR-Cas9) has become a promising tool for treating these diseases. The broad acceptance of CRISPR, due to its simplicity, precision, and adaptability, has significantly rushed scientificresearch, and fostered radical discoveries in both model species and human cells. CRISPR-Cas9 offers versatile applications for rare diseases like urea cycle disorders or hepatorenal tyrosinemia and in reducing cholesterol by targeting Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). It can also immunomodulate the autoimmune diseases by specifically targeting genes associated with these conditions. This targeted approach holds the potential to modify the immune response, leading to the potential alleviation of disease progression. Our review underscores the ongoing exploration of CRISPR-Cas9 therapy for autoimmune disorders, emphasizing its transformative possibilities in this field. We specifically highlight the potential target genes for CRISPR-Cas9 immunomodulation in prevalent autoimmune disorders such as systemic lupus erythematosus, multiple sclerosis, insulin-dependent diabetes mellitus, psoriasis, type 1 coeliac disease, and rheumatoid arthritis. The future holds immense promise as the remarkable advances in CRISPR-Cas9 therapies pave the way for a revolutionary transformation in the treatment of various autoimmune disorders
2022-08-26 | Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines.
Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1aC825X and wfs1bW493X. We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS.
proteins
2026-08-14 | Evaluating the use of GLP-1 receptor agonists in Wolfram syndrome patients.
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - properties of particular therapeutic relevance to Wolfram syndrome. We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study, with additional longitudinal data for participants co-enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study. We characterized the prevalence of GLP-1 RA use and the documented rationale for initiation, and evaluated within-participant pre-post changes in glycemic (HbA1c, body mass index) and visual (LogMAR best-corrected visual acuity, retinal nerve fiber layer thickness) parameters, along with adverse effects and reasons for discontinuation. Thirty of the 84 participants (35.7%) had received a GLP-1 RA in addition to insulin. No statistically significant changes in HbA1c or body mass index were observed at one or two years. Best-corrected visual acuity (LogMAR) declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common (56.7% of users) and were the leading cause of discontinuation. In this largest reported evaluation of GLP-1 RA use in Wolfram syndrome, these agents were already integrated into clinical care and were generally tolerated, but showed no glycemic or visual benefit over one to two years. Given the retrospective, uncontrolled design, the small number of participants with paired pre-post measurements, and the absence of a longitudinally followed comparator group, these findings are preliminary and hypothesis-generating rather than definitive, and provide a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.
2026-06-08 | DIABETES MELLITUS IN WOLFRAM SYNDROME 1: CHARACTERISTICS AND PERSPECTIVES IN TREATMENT
Wolfram syndrome 1 is a rare autosomal recessive disorder caused by mutations in the WFS1 gene related to endoplasmic reticulum (ER) function. The course of the disease most often begins with diagnosis of insulin-dependent non-autoimmune diabetes mellitus with an early onset. Its clinical character is presented with an acronym DIDMOAD: diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D). This article focuses on the clinical features of diabetes mellitus in Wolfram syndrome. We also describe current approach to its therapy and discuss possible treatment options placing the main emphasis on the GLP1 receptor agonists and cell regenerative therapy. Methods and materials: A qualitative synthesis of the data focusing on GLP-1 agonists, cell regenerative therapy and diabetes mellitus in Wolfram syndrome was performed. This literature review of GLP-1 receptor agonists and cell regenerative therapy effect on metabolic control, and current perspectives of treatment in patients with Wolfram syndrome, a monogenic type of diabetes, included recent publications, primarily from the past 10 years, and was conducted from November 2025 to April 2026 using the PubMed database. A systematic search was performed using specific keywords and medical subject headings (MeSH terms) related to GLP-1 agonists and Wolfram syndrome. The primary search terms included: “diabetes mellitus”, “GLP-1 agonists”, “Wolfram syndrome”, “WFS1”, “monogenic diabetes”, “islet transplantation”, and “cell regenerative therapy”. The criteria for inclusion of articles were as follows: published before April 2026, written in English, peer-reviewed original research articles. Exclusion criteria included publications not available in full text, articles in languages other than English. Editorials, commentaries, and conference abstracts without full data were also excluded. Titles and abstracts of the retrieved articles were screened to determine eligibility based on the inclusion and exclusion criteria.
2026-06-08 | Delayed Hypersensitivity Reaction to Insulin: A Case Report.
Advances in the purification of animal insulin preparations and the introduction of recombinant human insulin have markedly reduced the frequency of insulin hypersensitivity reactions. However, preservatives such as metacresol and other excipients contained in insulin formulations may still induce hypersensitivity reactions, which may be immediate, corresponding to type I hypersensitivity, or delayed, suggesting type III or, more commonly, type IV hypersensitivity according to the Gell and Coombs classification. We report the case of a 25-year-old woman with a 2-year history of type 1 diabetes mellitus who was initially treated with insulin detemir and insulin glulisine. Fifteen months after the initiation of insulin therapy, she developed delayed erythematous skin lesions associated with mild headaches and abdominal pain. Several alternative insulin preparations were subsequently tried, but all reproduced the same symptoms despite antihistamine therapy. Dose splitting and rotation of injection sites failed to improve the reaction. Specific IgE antibodies to human insulin, porcine insulin, protamine, and latex were negative. Skin prick tests performed with different insulin preparations were negative on immediate reading; however, 12 hours later, the patient developed a diffuse and extensive cutaneous reaction, including facial involvement. Because all tested insulin preparations triggered a reaction, their excipient profiles were reviewed, and metacresol was identified as the only common excipient among them. As no metacresol-free insulin preparation was available in Morocco, tolerance induction with insulin was undertaken in an attempt to induce tolerance despite probable hypersensitivity to metacresol. The procedure was successful and resulted in sustained tolerance to all insulin preparations. Insulin allergy remains a rare yet challenging condition that requires careful diagnostic evaluation. Identification of the causative mechanism, including possible hypersensitivity to excipients such as metacresol, is crucial to guide appropriate management.
2026-05-19 | Simultaneous Pancreas and Kidney Transplantation in a Patient With Congenital Hemophilia A: A rare Case Report and Management Insights.
Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for end-stage kidney disease (ESKD) and type 1 diabetes mellitus. However, even with careful perioperative control of hemostasis, SPK carries a high risk of postoperative bleeding, which is exacerbated in patients with hemophilia A. Here, we report the first known successful SPK in a patient with congenital hemophilia A. A 52-year-old man was diagnosed with hemophilia A at 2 years of age. He developed type 1 diabetes mellitus at 25 years of age, which progressed to ESKD at 43 years of age. A comprehensive preoperative FVIII replacement protocol was applied during the perioperative period, using continuous infusion with bolus supplementation to maintain target VIII activity levels (100% intraoperatively, 80% during the first postoperative week, and ≥30% thereafter). This case demonstrates that SPK transplantation can be safely performed in patients with congenital hemophilia A, by implementing appropriate FVIII replacement strategies and close multidisciplinary collaboration.
2025-10-08 | Continuous Subcutaneous Insulin Infusion (CSII)-Associated Granulomatous Suppurative Reaction in Four Children With Type 1 Diabetes.
With the increasing use of continuous glucose monitors and continuous subcutaneous insulin infusion (CSII) devices in pediatric patients with type 1 diabetes (T1DM), dermatologic complications are being reported more frequently. We describe four children with T1DM who developed persistent erythematous nodules with suppurative granulomatous inflammation at prior CSII injection sites. Treatment responses varied: one child improved after transitioning to subcutaneous insulin injections, another with oral dapsone, a third after switching CSII devices and limiting placement to the abdomen, and a fourth with topical corticosteroids and antibiotic ointment. This rare complication appears unrelated to specific device models or insulin types, highlighting the need for further studies to identify risk factors and guide optimal management.
antibodies
2026-08-12 | Anti-GAD65 antibody-associated cerebellar ataxia in a young adult with type 1 diabetes: a case report and literature review.
Anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia (anti-GAD-CA) is a rare autoimmune neurological disorder. Although frequently associated with latent autoimmune diabetes in adults (LADA), it can occasionally coexist with type 1 diabetes mellitus (T1DM). We report a 27-year-old woman with a 14-year history of T1DM who presented with subacute onset of balance impairment, vertigo, and hypophonic speech. Neurological examination and laboratory investigations were consistent with cerebellar ataxia. The patient exhibited high titers of anti-glutamic acid decarboxylase (anti-GAD) in both serum (619 IU/mL) and cerebrospinal fluid. Brain MRI was unremarkable. After a 5-day intravenous immunoglobulin (IVIG) therapy, the patient showed notable improvement in tandem gait and speech fluency. Her glycemic control also improved significantly, with the glycated hemoglobin (HbA1c) dropping from 9.7 to 6.8% over two months. Follow-up testing showed a steady decline in serum anti-GAD levels to 229 IU/mL. This case represents one of the youngest reported patients with anti-GAD-CA in the context of long-standing T1DM. The case emphasizes the importance of considering anti-GAD-CA in patients with unexplained cerebellar signs and autoimmune diabetes, even in younger individuals. Furthermore, the observed parallel improvements in neurological and glycemic parameters following immunotherapy may provide insight into the interplay between anti-GAD autoimmunity and metabolic control. Further studies are required to better understand the pathophysiological mechanisms and optimize management strategies.
2026-03-16 | PLA2R-positive primary membranous nephropathy in an adolescent with type 1 diabetes mellitus and autoimmune hypothyroidism: a case report.
Membranous nephropathy (MN) is an uncommon cause of nephrotic syndrome in children, accounting for fewer than 5% of cases. Primary MN mediated by antibodies against the phospholipase A2 receptor (PLA2R) is particularly rare in the paediatric population. We report the case of a 14-year-old girl with type 1 diabetes mellitus and autoimmune hypothyroidism who presented with nephrotic syndrome and was subsequently diagnosed with PLA2R-positive primary MN. She presented with periorbital oedema, abdominal distension, and bilateral pitting pedal oedema. Laboratory investigations demonstrated severe hypoalbuminemia (serum albumin 1.2 g/dL), nephrotic-range proteinuria (24-hour urine protein excretion of 3.5 g/day), and preserved renal function (serum creatinine 0.3 mg/dL). Renal biopsy findings, supported by immunohistochemistry, confirmed PLA2R positivity. The patient was treated with four weekly doses of rituximab (375 mg/m2), resulting in complete clinical remission at 6 months. Serum albumin normalised to 4 g/dL, 24-hour urine protein excretion decreased to 250 mg/day, and serum PLA2R antibody levels fell below the normal range. This case highlights the importance of considering PLA2R-mediated MN in adolescents with nephrotic syndrome and the presence of multiple autoimmune comorbidities. It also underscores the diagnostic value of tissue PLA2R testing and demonstrates the efficacy of early rituximab-based B-cell-directed therapy in achieving complete remission while avoiding corticosteroid exposure.
2025-11-12 | Use of Teplizumab to Modulate Stage 2 Type 1 Diabetes in Two Individuals With Autoimmune Polyendocrine Syndrome 1.
Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic autoimmune disorder that may manifest as type 1 diabetes (T1D). Teplizumab, an anti-CD3 monoclonal antibody, delays progression of stage 2 T1D, but its effects in APS-1-associated diabetes are unknown. We report clinical responses of two adolescents with APS-1 and stage 2 T1D who received 14-day courses of teplizumab. In one patient, pancreatic MRI and spectral immune cell phenotyping were performed before and after treatment. Both patients exhibited improved glycemia. One who briefly required insulin recovered insulin independence 2 weeks after therapy. Pancreatic volume transiently increased, and circulating lymphocytes showed changes in homing receptors and senescence markers in the individual who underwent those studies. Nonpancreatic APS-1 manifestations were unchanged. Teplizumab may preserve β-cell function in APS-1-associated T1D. Larger studies are needed to define efficacy, durability, and immunologic and tissue mechanisms in this rare context.
2025-07-23 | Development of type 1 diabetes mellitus after nivolumab dose escalation: A case report.
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare but serious immune-related adverse event associated with programmed cell death-1 inhibitors such as nivolumab. While previous reports have documented its occurrence, the relationship between nivolumab dosing and the onset of ICI-T1DM remains unclear. This study presents a case of ICI-T1DM following a nivolumab dose and includes a literature review. A man in his 50s (weight: 49.4 kg, body mass index: 17.65 kg/m2) with advanced esophageal cancer had been receiving nivolumab (240 mg every 14 days) for over 2 years without adverse effects. Because of treatment adjustments, the dose was increased to 480 mg and administered every 28 days. Ninety-six days after the dose increase, he developed acute-onset fatigue, anorexia, and thirst. Laboratory tests confirmed diabetic ketoacidosis with hyperglycemia (582 mg/dL), low C-peptide levels, and negative islet-associated antibodies, leading to the diagnosis of nivolumab-induced fulminant type 1 diabetes mellitus. The patient was treated with insulin and discharged after stabilization. This case suggests that higher dose nivolumab may increase the risk of ICI-T1DM, especially in low body-weight individuals. Given that nivolumab remains effective at lower doses, dose optimization may help mitigate immune-related adverse events while maintaining therapeutic efficacy.
2025-03-12 | Early expansion of TIGIT+PD1+ effector memory CD4 T cells via agonistic effect of alefacept in new-onset type 1 diabetes.
The CD2-depleting drug alefacept (LFA3-Ig) preserved beta cell function in new-onset type 1 diabetes (T1D) patients. The most promising biomarkers of response were late expansion of exhausted CD8 T cells and rare baseline inflammatory islet-reactive CD4 T cells, neither of which can be used to measure responses to drug in the weeks after treatment. Thus, we investigated whether early changes in T cell immunophenotypes could serve as biomarkers of drug activity. We characterized T cell responses by flow cytometry and identified an exhausted-like population of CD2low CD4 effector memory T cells coexpressing TIGIT and PD1 that expanded by 11 wk after the start of treatment. This population was not entirely spared from alefacept-mediated depletion in vivo or in vitro but recovered through homeostatic proliferation of CD2low cells in vivo. Proliferation of TIGIT+PD1+ effector memory CD4 T cells increased with treatment, with a concomitant reduction of proinflammatory cytokine production. The persistent increase of TIGIT+PD1+ effector memory CD4 T cells was specific to alefacept treatment; 2 other T cell depleting therapies, teplizumab and anti-thymocyte globulin, induced only a transient increase in this CD4 population. Our data suggest that the expanding TIGIT+PD1+ effector memory CD4 T cell population represents a promising biomarker of early treatment effects of alefacept. The nondepleting effects on proliferation and cytokine production also suggest agonistic activity by this CD2 targeted therapy.
other
2026-01-26 | Pulmonary mucormycosis with bacterial coinfection in an adolescent with poorly controlled type 1 diabetes: a case report.
Pulmonary Mucormycosis (PM), a severe fungal infection affecting mainly immunocompromised individuals, is often caused by fungi like Rhizopus and Mucor. This report details a 12-year-old diabetic girl with pulmonary mucormycosis from an unusual Rhizopus species. Successful treatment involved stabilizing her blood glucose and managing multiple co-infections. This case provides important insights into diagnosing and treating rare fungal infections in diabetic children. A 12-year-old girl with a two-year history of type 1 diabetes, inconsistently monitored, was hospitalized. She had a persistent cough for over ten days and a six-day high fever. Previous treatments with dexamethasone and antibiotics were ineffective. She showed symptoms of a productive cough, right-sided pleuritic chest pain, and a fever of 40°C. Examination revealed reduced breath sounds and moist rales in the right lung. Tests confirmed a severe infection, and imaging showed inflammatory consolidation, multiple cavitations, and pleural effusion in the right lung. Metagenomic next-generation sequencing (mNGS) analyzes all nucleic acids from a patient's bronchoalveolar lavage fluid to identify various pathogens without traditional cultures. The analysis identified Rhizopus species and Streptococcus pneumoniae, confirming pulmonary mucormycosis with a bacterial infection. Additionally, the glycated hemoglobin (HbA1c) level was 14.3%, indicating poorly controlled diabetes. A comprehensive treatment regimen was employed. The bacterial co-infection was addressed with intravenous administration of meropenem and linezolid, while nebulized amphotericin B was utilized to treat the pulmonary mucormycosis. To mitigate the underlying risk factor, intensive glycemic control was achieved through the use of an insulin pump. Furthermore, bronchoscopy was conducted to clear respiratory secretions. After 11 days in the hospital, the patient stabilized and was discharged. At a follow-up 1.5 months later, infection markers and blood glucose levels were normal. This case highlights the high risk of severe infections like pulmonary mucormycosis in adolescents with poorly managed type 1 diabetes. Metagenomic sequencing was crucial for quickly identifying co-infections. Successful treatment required a comprehensive approach, including targeted antimicrobial therapy, strict glycemic control, and bronchoscopic support, leading to a positive outcome.
2025-06-18 | The role and mechanism of mesenchymal stem cells in immunomodulation of type 1 diabetes mellitus and its complications: recent research progress and challenges: a review.
Mesenchymal stem cells are of great interest because of their multipotency, immune modulation capacity, and tissue and vascular regeneration effects. They are used in treating type 1 diabetes mellitus, helping improve the pancreatic environment and insulin secretion. Type 1 diabetes mellitus predominantly affects children and adolescents, with early onset and a prolonged course that can lead to multiorgan complications and related disorders. Studies using mesenchymal stem cells to treat type 1 diabetes mellitus have yielded promising results. This review discusses the common animal models of type 1 diabetes mellitus, mesenchymal stem cell immunotherapy mechanisms, and combined diabetes treatments. Its purpose is to summarize the current evidence on mesenchymal stem cell use in type 1 diabetes, providing insights for further research directions. Current studies show that mesenchymal stem cells play an active role in the treatment of type 1 diabetes; however, clinical trials remain rare, necessitating more basic and preclinical research to identify optimal treatments. Mesenchymal stem cells can treat type 1 diabetes through a variety of immune mechanisms and also play a positive role in the treatment of type 1 diabetes complications. At the same time, it can be combined with other therapies to play a better therapeutic role.
2025-04-16 | The Last Mile in Beta-Cell Replacement Therapy for Type 1 Diabetes: Time to Grow Up.
Beta cell replacement therapy for type 1 diabetes (T1D) is undergoing a transformative shift, driven by advances in stem cell biology, gene editing, and tissue engineering. While islet transplantation has demonstrated proof-of-concept success in restoring endogenous insulin production, its clinical impact remains limited by donor scarcity, immune rejection, and procedural complexities. The emergence of stem cell-derived beta-like cells represents a paradigm shift, with initial clinical trials showing promising insulin secretion in vivo. However, translating these breakthroughs into scalable, widely accessible treatments poses significant challenges. Drawing parallels to space exploration, this paper argues that while scientific feasibility has been demonstrated, true accessibility remains elusive. Without a strategic shift, beta cell therapy risks becoming an elite intervention, restricted by cost and infrastructure. Lessons from gene and cell therapies for rare diseases highlight the dangers of unsustainable pricing and limited market viability. To bridge the "last mile" a Quality by Design approach is proposed, emphasizing scalability, ease of use, and economic feasibility from the outset. By emphasizing practical implementation over academic achievements, corporate interests, market economics, or patent constraints, beta cell therapy can progress from proof-of-concept to a viable, widely accessible treatment.
2025-01-27 | P-30 ROLE OF PLASMAPHERESIS IN TREATING A RARE CASE OF EXOGENOUS INSULIN ANTIBODY SYNDROME (EIAS) IN A YOUNG PATIENT WITH TYPE 1 DIABETES MELLITUS IN BABYLON GOVERNORATE: A CASE REPORT
Abstract Clinical Case A 17-year old female patient who was diagnosed with type 1 diabetes mellitus (DM) seven years ago, and she had continuously very high blood glucose readings with recurrent admissions to the emergency unit due to attacks of DKA. In addition to a planned diet, she was on more than 250 units of insulin per day (while her weight was 75 kilograms). She was initially on human insulin in the form of twice NPH insulin injections, and pre-meal regular insulin injections, in addition to repeated regular insulin correction doses without any reduction of her blood glucose. Then she was shifted to insulin analogues (to eliminate the possibility of insulin immunogenicity which have been encountered with the use of human insulin), in form of basal insulin Glargine OD, plus pre-meal rapid acting insulin Glulisine without any noticeable response. Continuous switching of her injection sites, with an in-hospital observed insulin injections (to avoid noncompliance), even the use of intravenous route did not help to achieve a glycemic control. Later on, metformin 1000 mg XR BID was added to her daily treatment without any benefit. A screen of anti-insulin antibodies was done and found to be elevated (which should be negative after all these years after her initial diabetes diagnosis). A presumptive diagnosis of EIAS (Exogenous Insulin Antibody Syndrome) was put. A small dose of steroids was administered with close observation (to avoid exacerbation ketosis) without any improvement. Then Cellcept (Mycophenolate mofetil), an immune modulator was added at a dose of 500 mg BID and increased 48 hrs. later to 1000 mg BID and resulted in a minimal reduction of her blood glucose levels. Finally the decision of plasmapheresis was made and an informed consent was obtained from the family after explaining the condition. A good response was recorded after the 1st session, with a minimal decrease of her total daily insulin doses. Later on, an additional excellent response was received during the next 2 sessions with a rapid decline of her glucose readings and her total daily insulin doses. She had recurrent attacks of hypoglycemia during her third and last plasmapheresis session. Her total daily dose of insulin was successfully reduced by more than 50%, and her general condition was improved noticeably without any recorded adverse reactions, as shown in the blood glucose logbook photos attached below.Figure 1:Glucose logbook after the 3rd and last session of Plasmapheresis Table 1:Response parameters to three sessions plasampheresis therapy
2024-08-07 | Efficacy and safety of gut microbiota-based therapies in autoimmune and rheumatic diseases: a systematic review and meta-analysis of 80 randomized controlled trials.
Previous randomized controlled trials (RCTs) suggested that gut microbiota-based therapies may be effective in treating autoimmune diseases, but a systematic summary is lacking. Pubmed, EMbase, Sinomed, and other databases were searched for RCTs related to the treatment of autoimmune diseases with probiotics from inception to June 2022. RevMan 5.4 software was used for meta-analysis after 2 investigators independently screened literature, extracted data, and assessed the risk of bias of included studies. A total of 80 RCTs and 14 types of autoimmune disease [celiac sprue, SLE, and lupus nephritis (LN), RA, juvenile idiopathic arthritis (JIA), spondyloarthritis, psoriasis, fibromyalgia syndrome, MS, systemic sclerosis, type 1 diabetes mellitus (T1DM), oral lichen planus (OLP), Crohn's disease, ulcerative colitis] were included. The results showed that gut microbiota-based therapies may improve the symptoms and/or inflammatory factor of celiac sprue, SLE and LN, JIA, psoriasis, PSS, MS, systemic sclerosis, Crohn's disease, and ulcerative colitis. However, gut microbiota-based therapies may not improve the symptoms and/or inflammatory factor of spondyloarthritis and RA. Gut microbiota-based therapies may relieve the pain of fibromyalgia syndrome, but the effect on fibromyalgia impact questionnaire score is not significant. Gut microbiota-based therapies may improve HbA1c in T1DM, but its effect on total insulin requirement does not seem to be significant. These RCTs showed that probiotics did not increase the incidence of adverse events. Gut microbiota-based therapies may improve several autoimmune diseases (celiac sprue, SLE and LN, JIA, psoriasis, fibromyalgia syndrome, PSS, MS, T1DM, Crohn's disease, and ulcerative colitis).
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Drug Discovery Landscape
22 orphan drug designations for Rare diabetes mellitus type 1, including 2 approved therapies.
22 orphan drug designations for Rare diabetes mellitus type 1, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous, engineered regulatory T-cell immunotherapy, designed to express an islet antigen-specific T cell receptor, stable Forkhead box P3 (FOXP3) protein, and a chemically induced signaling complex that promotes selective interleukin 2-pathway signaling | cell therapies | FDA | 2025-06-10 | — | GentiBio Inc. |
Purified Human Allogeneic Pancreatic Islets of Langerhans | cell therapies | FDA | 2020-03-09 | — | University of Minnesota |
Allogeneic Human Pancreatic Islets of Langerhans | cell therapies | FDA | 2019-07-22 | — | Hospital of the University of Pennsylvania (Penn Medicine) |
Allogeneic Human Pancreatic Islets of Langerhans | cell therapies | FDA | 2019-06-04 | — | University of California, San Francico |
Purified Allogeneic Human Pancreatic Islets of Langerhans | cell therapies | FDA | 2019-05-01 | — | University of Chicago |
allogeniec Human Pancreatic Islets of Langerhans | cell therapies | FDA | 2019-05-01 | — | Diabetes Research Institute & Cell Transplant Center, Univ of Miami |
donislecel-jujn [Lantidra] | cell therapies | FDA | 2017-02-01 | 2023-06-28 | CellTrans Inc. |
anti-interleukin 21 (NNC0114-0006) in combination with liraglutide | antibodies | FDA | 2017-01-12 | — | Novo Nordisk, Inc. |
methyldopa | small molecules | FDA | 2017-01-12 | — | IM Therapeutics LLC |
autologous ex vivo expanded polyclonal CD4+CD25+CD1271o/-FOXP3+ Regulatory T cells | cell therapies | FDA | 2016-05-10 | — | Caladrius Biosciences |
alpha1-proteinase inhibitor (human) | proteins | FDA | 2015-03-03 | — | Grifols Therapeutics, Inc. |
CD40/CD80/CD86 modified autologous dendritic cell therapy | cell therapies | FDA | 2013-12-20 | — | DiaVacs, Inc. |
abatacept | proteins | FDA | 2013-05-30 | — | Orban Biotech LLC |
human insulin beta chain peptide with incomplete Freund's adjuvant vaccine | peptides | FDA | 2013-02-11 | — | Orban Biotech, LLC |
Heat Shock Protein (hsp60) antigen | peptides | FDA | 2012-05-21 | — | AndromedA Biotech, LTD |
ustekinumab | antibodies | FDA | 2010-11-29 | — | Johnson & Johnson Pharmaceutical & Development LLC |
anti-TCR murine monoclonal antibody (MAb, type IgM) | antibodies | FDA | 2010-06-07 | — | Tolera Therapeutics, Inc. |
ex-vivo cultered adult human mesenchymal stem cells | cell therapies | FDA | 2010-04-30 | — | Mesoblast, Inc. |
Recombinant human glutamic acid decarboxylase 65KDa isoform | proteins | FDA | 2010-03-22 | — | Diamyd Therapeutics AB |
teplizumab-mzwv [Tzield] | antibodies | FDA | 2006-09-29 | 2022-11-17 | Provention Bio, Inc. |
otelixizumab | antibodies | FDA | 2006-02-06 | — | GlaxoSmithKline |
Encapsulated porcine islet preparation | cell therapies | FDA | 1995-07-05 | — | VivoRx |
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