Insulin-dependent Diabetes Mellitus Type Research Articles

8090 A Gut Commensal, Parabacteroides distasonis, and Molecular Mimicry in Type 1 Diabetes

Abstract Disclosure: A. Randall: None. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic, insulin-producing beta cells by autoreactive T-cells. The trigger(s) of T1D are unclear and genetics alone cannot explain the recent increase in T1D incidence. The gut microbiome composition in T1D patients is altered and thought to play a key role in T1D pathogenesis. Most longitudinal studies have been descriptive. However, a direct cause-and-effect relationship hasn't been established yet. Insulin is a key autoantigen in T1D autoimmunity, and insulin B-chain amino acids 9-23 (insB:9-23) is an important, commonly recognized T-cell epitope. Molecular mimicry is an autoimmunity mechanism where host-like microbial proteins trigger autoimmune responses. We previously identified a peptide mimic of insB:9-23, amino acids 4-18 of hypoxanthine phosphoribosyl transferase (HPRT:4-18) of Parabacteroides distasonis (Girdhar et al., 2022). HPRT:4-18 stimulated insB:9-23-specific human and non-obese diabetic (NOD) mice T-cells. We hypothesize that P. distasonis HPRT:4-18 is required to accelerate diabetes via molecular mimicry of insB:9-23. By orally gavaging NOD mice (n=40 mice/group), we showed that P. distasonis accelerated diabetes onset. Next, we colonized NOD mice with another common gut commensal, Bacteroides fragilis, as a control, and did not observe any effect on islet infiltration. In addition, P. distasonis colonization increased infiltration of immune cells into the islets of germ-free NOD mice (n=6-8 mice/group), while the diabetes incidence experiment in mice is ongoing. P. distasonis-colonized mice had significantly more splenic CD8 and naïve T-cells, dendritic cells and macrophages but fewer FOXP3 cells (n=3-6 mice/group). To determine whether P. distasonis’s effect is specific to the pancreas, we checked intestinal barrier function and intestinal immune cell composition. Disruption of intestinal barrier function has been associated with diabetes. P. distasonis colonization did not alter gut permeability. Furthermore, P. distasonis did not increase intestinal inflammation. Among the intestinal intraepithelial lymphocytes (IELs), there were fewer naïve, central and effector T-cells and B-cells. The findings indicate that P. distasonis does not stimulate an unspecific immune response and its inflammatory effect is specific to the pancreas, supporting our initial hypothesis. Taken together, our results indicate that exposure to P. distasonis in the first years of life has the potential to stimulate molecular mimicry mechanism and cause T1D onset. Reference: Girdhar, K., Huang, Q., Chow, I. T., Vatanen, T., Brady, C., Raisingani, A., . . . Altindis, E. (2022). A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes. Proc Natl Acad Sci U S A, 119(31), e2120028119. doi:10.1073/pnas.2120028119 Presentation: 6/2/2024

12622 Molecular Physiology And Compensatory Response In Maladapted Pancreatic Islets Of Humanized Mice Model For Type 1 Diabetes

Abstract Disclosure: A. Hussain: None. A. Aldasouqi: None. S. Rafiqi: None. S.S. Khan: None. R. Paparodis: None. J.C. Jaume: None. S. Imam: None. Genetic predisposition linked with specific HLA (DR and DQ) alleles, environmental factors, and other uncharacterized physiological aberrations triggers an autoimmune attack and depletion of β cells in pancreatic islets, leading to decreased insulin secretion and diabetes. Our laboratory has generated humanized mice carrying the antigen-presenting HLA-DQ8 diabetes-linked haplotype and expressing the human autoantigen GAD65 in pancreatic beta cells. These humanized mice spontaneously develop type 1 diabetes (T1D) and represent the full spectrum of pathophysiological conditions experienced in T1D. Using humanized mice as a model of study, we studied the molecular physiology and compensatory response in maladapted pancreas under normal physiological conditions and hyperglycemic stress of T1D. We studied the differential expression of some important genes by quantitative PCR in maladapted islets to identify the physiological processes affected during the initial oxidative stress exerted by autoimmune conditions. Our results confirmed that levels of cyclin B, cMyc, Cyc D, Cyc E, PDGFRA, and NOTCH are reduced during autoimmune insult, reflecting the poor regenerative capacity of islet cells. However, Cyc A has an elevated expression, reflecting that islet cells, particularly the β cells of Type 1 diabetic mice, may have regenerative potential that may be explored. The genes for Desmin and Survivin showed decreased expression, whereas genes for Smad and Synuclein displayed increased expression. The genes for insulin and somatostatin showed elevated expression, whereas the gene for glucagon displayed reduced expression. The results suggest that during autoimmune insults, the β cells moderately whip up the synthesis of insulin-specific RNA to maintain the requirements. Among the endoplasmic reticulum-specific molecular chaperones, Calnexin showed an elevated expression, whereas calreticulin displayed a reduced expression. Among the genes involved with the architecture of the islet, Lamin and Integrin both display increased expression, reflecting the dynamic change in islet architecture during the autoimmune depletion of β cells. We also investigated the expression of ER-specific stress genes both at RNA and protein levels. Our preliminary results have confirmed that ER-specific stress genes showed an elevated expression during oxidative stress mediated by autoimmune T1D conditions. Presentation: 6/3/2024

EXTOD-Immune: a randomised controlled trial to investigate whether a remotely monitored, home-based exercise intervention can reduce disease activity in people with type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease in which the adaptive immune system targets insulin-producing β-cells of pancreatic islets, leading to dependence on exogenous insulin therapy. Cytotoxic (CD8+)...

Quality of Life in Type 1 Diabetes Children with Other Autoimmune Diseases

Abstract The aim of this study was to evaluate and compare the quality of life and glycaemic control in children with type 1 diabetes (T1D) and associated autoimmune diseases with T1D only, using the Pediatric Quality of Life Inventory Generic Core Scale. The study examined differences in health-related quality of life assessments and glycaemic control between children with T1D and associated autoimmune diseases and T1D only. In total, 94 children, aged 2 to 17 years, and their parents participated in the study. The results of the study showed a statistically significantly lower total score of general well-being for children with T1D and associated autoimmune disease (p = 0.016). Children with T1D and associated autoimmune disease reported a lower physical function score (p = 0.034) and lower emotional function score (p = 0.038). Social and school function scores did not differ in those with and without T1D associated autoimmune disease. There were no statistically significant differences in haemoglobin A1c between children with T1D and autoimmune disease and T1D only.

TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes

Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.

Diabetic Ketoalkalosis: A Case Report.

Diabetic ketoacidosis (DKA) is a common diagnosis in the emergency department (ED). However, one must consider other causes for acid-base disturbances when the pattern is not consistent with typical presentation. A 52-year-old female with a history of insulin-dependent diabetes mellitus type 2 presented to the ED with abdominal pain, nausea, and vomiting for three days. Her diagnostic workup revealed diabetic ketoacidosis but with concurrent metabolic alkalosis. Standard treatment for DKA was initiated, and there was improvement of her mentation and resolution of metabolic derangements. Overlooking a diagnosis of DKA because of alkalosis on venous blood gas testing could lead to inappropriate treatment and, therefore, increased risk of morbidity and mortality in the affected patient.

Complete HLA genotyping of type 1 diabetes patients and controls from Mali reveals both expected and novel disease associations.

HLA genotyping was performed on 99 type 1 diabetes (T1D) patients and 200 controls from Mali. Next-generation sequencing of the classical HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, and -DPB1 loci revealed strong T1D association for all loci except HLA-C and -DPA1. Class II association is stronger than class I association, with most observed associations predisposing or protective as expected based on previous studies. For example, HLA-DRB1*03:01, HLA-DRB1*09:01, and HLA-DRB1*04:05 predispose for T1D, whereas HLA-DRB1*15:03 is protective. HLA-DPB1*04:02 (OR = 12.73, p = 2.92 × 10-05 ) and HLA-B*27:05 (OR = 21.36, p = 3.72 × 10-05 ) appear highly predisposing, although previous studies involving multiple populations have reported HLA-DPB1*04:02 as T1D-protective and HLA-B*27:05 as neutral. This result may reflect the linkage disequilibrium between alleles on the extended HLA-A*24:02~HLA-B*27:05~HLA-C*02:02~HLA-DRB1*04:05~HLA-DRB4*01:03~HLA-DQB1*02:02~HLA-DQA1*02:01~HLA-DPB1*04:02~HLA-DPA1*01:03 haplotype in this population rather than an effect of either allele itself. Individual amino acid (AA) analyses are consistent with most T1D association attributable to HLA class II rather than class I in this data set. AA-level analyses reveal previously undescribed differences of the HLA-C locus from the HLA-A and HLA-B loci, with more polymorphic positions, spanning a larger portion of the gene. This may reflect additional mechanisms for HLA-C to influence T1D risk, for example, through expression differences or through its role as the dominant ligand for killer cell immunoglobulin-like receptors (KIR). Comparison of these data to those from larger studies and on other populations may facilitate T1D prediction and help elucidate elusive mechanisms of how HLA contributes to T1D risk and autoimmunity.

Myelomatous Ascitis, a Rare Presenting Symptom of Multiple Myeloma

Abstract Introduction/Objective In 2022, plasma cell neoplasms accounted for approximately 1.8% of all new cancers in the United States with an estimated 34,470 new cases of multiple myeloma. Diagnosis is often straight forward in ~80% of cases by performing serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and/or urine immunofixation (UIFE) with M-spike quantification. The diagnostic challange is in the remainder of asymptomatic myeloma cases (~20%) which are found incidentally. Specialized laboratory technicians are often the first step in identifying plasma cells in body fluids and/or peripheral blood smears. These incidental findings on routine labs, paired with the keen eye of a specialist, are one of the first steps in early detection of multiple myeloma. Methods/Case Report A 62 year-old male, originally from Cambodia, presented to an outside hospital emergency department with abdominal distention and pain. His past medical history was significant for dialysis-dependent end- stage renal disease and insulin-dependent diabetes mellitus type 2. Abdominal CT showed ascites with no other diagnostic findings. Cardiac, renal and hepatic etiologies of ascites were ruled out. Body fluid analysis of the ascites in the Clinical Pathology laboratory revealed numerous plasma cells. Cytologic examination, after consultation with Clinical Pathology, also revealed numerous plasma cells. Subsequent SPEP and SIFE disclosed an IgA lambda monoclonal protein. A diagnosis of multiple myeloma was confirmed by bone marrow biopsy with FISH studies. Results showed several high-risk abnormalities including translocations of 4::14, 14::16, and 14::20, denoting a “triple hit” multiple myeloma. Results (if a Case Study enter NA) NA Conclusion Plasmacytosis in ascites is an extremely rare initial presentation for multiple myeloma. With only a few cases reported in the literature, many technicians and pathologists might easily overlook plasma cells on routine cytology, especially with normal imaging and no previous diagnosis of myeloma. In this case, flagged peritoneal fluid by a skilled medical laboratory technician was key to making a diagnosis. Without any signs of a plasmacytoma or lytic bone lesions on imaging, a normal CBC with non-specific labs, and an unsuspecting surgical pathology report, multiple myeloma was not on the differential. Fast interdepartmental consultation, communication, and teamwork between surgical pathology and clinical pathology, lead to a rapid diagnosis and prompt treatment of this patient.

SAT068 The Golgi Transmembrane Protein GOLM1 Maintains PD-L1 Protein Levels In Islet Beta Cells In Response To Type 1 Diabetic Inflammation

Abstract Disclosure: F. huang: None. J. Nelson: None. C. Muralidharan: None. E. Nakayasu: None. X. Yi: None. D. Eizirik: None. S. May: None. S.A. Tersey: None. R.G. Mirmira: None. In type 1 diabetes (T1D), a dialog between β cells and immune cells results in the dysfunction and autoimmune destruction of β cells. Protein processing pathways in the β cell are critical for the production and processing of immune checkpoint proteins such as PD-L1, which suppress β cell autoimmunity by interacting with receptors (PD-1) on immune cells. We performed unbiased proteomics analysis following proinflammatory cytokine (50 U/ml IL-1β + 1000 U/ml IFN-γ) treatment of the human β cell line EndoC-βH1 to identify potential protein processing molecules. GOLM1, a type II Golgi transmembrane protein involved in the sorting and modification of proteins exported from the endoplasmic reticulum, emerged as a candidate that was increased 33% (p=0.014) in response to cytokines and coordinately upregulated with PD-L1. We hypothesized that GOLM1 is necessary for the posttranscriptional production of PD-L1 in β cells. To test this hypothesis, we performed further quantitative RT-PCR, immunoblot, and flow cytometry studies of GOLM1 and PD-L1 in EndoC-βH1 cells and human islets following cytokine treatment to mimic the inflammatory milieu of T1D. Additional experiments included RNA interference against GOLM1, immunoprecipitation followed by immunoblots, and incubation with an inhibitor of the proteasome (MG132). Treatment of EndoC-βH1 cells with proinflammatory cytokines for 18 h resulted in a 10-fold upregulation of the gene encoding PD-L1. Immunoblot analysis confirmed a >10-fold upregulation of PD-L1 protein, with flow cytometry further indicating that only a subset of β cells (∼60%) exhibit PD-L1 production. GOLM1 protein levels were upregulated nearly 3-fold in response to cytokines in EndoC-βH1 cells and human islets. RNA interference-induced knockdown of GOLM1 in EndoC-βH1 cells abrogated the cytokine-induced increase of PD-L1 protein without altering its corresponding mRNA levels, a finding consistent with a role for GOLM1 in the posttranscriptional regulation of PD-L1 levels. The posttranscriptional effect of GOLM1 on PD-L1 levels appears to involve the proteasome, since proteasome inhibition with MG-132 restored PD-L1 levels in the absence of GOLM1. Direct interaction of GOLM1 with PD-L1 was observed following immunoblot studies in EndoC-βH1 cells. Finally, analysis of the single cell RNA-Seq database of the Human Pancreas Analysis Program revealed a significant increase in GOLM1 in residual β-cells of individuals with T1D compared to controls. Collectively, our data indicate that GOLM1 increases following cytokine-induced inflammation in β cells, stabilizes PD-L1 levels by preventing its proteasomal degradation, and is elevated in residual β cells of individuals with T1D. Our studies provide new insight into the molecular mechanisms by which β cells generate a protective response against autoimmunity in T1D. Presentation: Saturday, June 17, 2023

SAT071 Inhibition Of 12 Lipoxygenase In A Humanized Mouse Model Of Type 1 Diabetes Delays Progression Of Hyperglycemia

Abstract Disclosure: T. Nargis: None. A. Chakraborty: None. K. Figatner: None. D. Maloney: None. M. Boxer: None. S.A. Tersey: None. R.G. Mirmira: None. Type 1 diabetes (T1D) is an autoimmune disorder characterized by islet inflammation (insulitis). We have recently shown that a key mediator of inflammatory signaling in the islet beta cell is the enzyme 12-lipoxygenase (12-LOX), which generates proinflammatory eicosanoids that augment dysfunctional insulin secretion and beta-cell visibility to the immune system. Whereas inhibition of 12-LOX offers an opportunity to modify T1D progression by altering how the beta cell responds to insulitis, a barrier to testing inhibitors in preclinical models is the specificity of next generation inhibitors toward the human enzyme. To generate a preclinical platform for the study of human-specific 12-LOX inhibitors, we developed a mouse model in which the mouse-equivalent Alox15 coding region was replaced with the human ALOX12 gene, while retaining the mouse upstream control region. These mice (hALOX12) were developed on both the C57BL/6J and NOD genetic backgrounds, then subjected to treatment with the human 12-LOX inhibitor VLX-1005 to evaluate diabetes progression. C57BL/6J-wildtype and C57BL/6J-hALOX12 mice were confirmed to express exclusively mouse Alox15 and human ALOX12, respectively, using RNA isolated from islets. To test susceptibility to toxin-induced diabetes, C57BL/6J-wildtype and C57BL/6J-hALOX12 were subjected to multiple low-dose streptozotocin (STZ) to induce diabetes. Both wildtype and humanized mice exhibited gradual and equivalent hyperglycemia (within 25 days) following STZ injection. Following intraperitoneal VLX-1005 therapy (30 mg/kg), whereas C57BL/6J-wildtype mice developed diabetes (with a delay of 10 days) following STZ, C57BL/6J-hALOX12 mice showed complete protection against STZ-induced diabetes and exhibited significantly better glucose tolerance compared to vehicle- or VLX-1005-injected wildtype controls and vehicle-injected C57BL/6J-hALOX12 mice. Next, hALOX12 mice were backcrossed onto the NOD.ShiltJ background model of autoimmune T1D. NOD-hALOX12 mice received either vehicle or VLX-1005 (30 mg/kg) orally during the prediabetic phase (6-10 weeks of age) and were followed for diabetes incidence. Mice receiving VLX-1005 showed a significant delay with only 30% of female and 7% of male mice developing diabetes over 25 weeks of age. Pancreatic sections from the mice treated with VLX-1005 showed reduced insulitis and increased beta cell mass compared to vehicle controls. In summary, the hALOX12 mouse model serves as a preclinical translational platform to interrogate effects of next generation 12-LOX inhibitors and demonstrates the potential of VLX-1005 to modify T1D disease progression. Presentation: Saturday, June 17, 2023

Prevalence, clinical characteristics and HLA genotypes of idiopathic type 1 diabetes: A cross-sectional study.

Idiopathic type 1 diabetes (T1D) is a neglected subtype of T1D. Our aim was to investigate the frequency, clinical characteristics, and human leucocyte antigen (HLA) genotypes of idiopathic T1D. We enrolled 1205 newly diagnosed T1D patients in our analysis. To exclude monogenic diabetes in autoantibody-negative patients, we utilised a custom monogenic diabetes gene panel. Individuals negative for autoantibodies and subsequently excluded for monogenic diabetes were diagnosed with idiopathic T1D. We collected clinical characteristics, measured islet autoantibodies by radioligand assay and obtained HLA data. After excluding 11 patients with monogenic diabetes, 284 cases were diagnosed with idiopathic T1D, accounting for 23.8% (284/1194) of all newly diagnosed T1D cases. When compared with autoimmune T1D, idiopathic T1D patients showed an older onset age, higher body mass index among adults, lower haemoglobin A1c, higher levels of fasting C-peptide and 2-h postprandial C-peptide, and were likely to have type 2 diabetes (T2D) family history and carry 0 susceptible HLA haplotype (all p<0.01). A lower proportion of individuals carrying 2 susceptible HLA haplotypes in idiopathic T1D was observed in the adult-onset subgroup (15.7% vs. 38.0% in child-onset subgroup, p<0.001) and in subgroup with preserved beta-cell function (11.0% vs. 30.1% in subgroup with poor beta-cell function, p<0.001). Multivariable correlation analyses indicated that being overweight, having T2D family history and lacking susceptible HLA haplotypes were associated with negative autoantibodies. Idiopathic T1D represents about 1/4 of newly diagnosed T1D, with adult-onset and preserved beta-cell function patients showing lower HLA susceptibility and more insulin resistance.

Near-miss hypoglycemia—reflections on perioperative glucose management guidelines in diabetics

BackgroundThe American Society of Anesthesiologists (ASA) has an impressive array of professional perioperative guidelines but has not issued a guideline specific to perioperative blood glucose management and does not delve into the topic in their other guidelines.Case reportWe experienced a perioperative case that highlights the potential difficulty of glucose management in this setting. During anesthetic induction for an orthopedic foot surgery, as the medication was infusing, an IDDM 1 (insulin dependent diabetes mellitus type 1) patient expressed feeling that her blood sugar level was low. Her finger stick after induction showed severe hypoglycemia with a blood glucose of 34 mg/dL. The hypoglycemia was treated with intravenous glucose and further closely monitored.ConclusionsThis case led us to revisit the different perioperative guidelines and recommendations for diabetic patients and this manuscript aims to highlight the similarities and discrepancies among the different published recommendations. This case highlights the value of utilizing insulin pump infusions in the perioperative setting when available.

Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes.

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.

No effects of COVID-19 on the development of type 1 diabetes autoimmunity and no evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed type 1 diabetes patients relative to healthy subjects

AimsTo evaluate the relationship between SARS-CoV-2 infection and autoimmunity in type 1 diabetes (T1D) and SARS-CoV-2 antibodies frequency at diagnosis of T1D during pandemic.MethodsThe presence of T1D-specific autoimmunity was evaluated in a cohort of 99 children and adolescents without diabetes that contracted SARS-CoV-2 infection. Moreover, the frequency of IgM- and IgG-SARS-CoV-2 antibodies was evaluated in 41 newly diagnosed T1D patients not yet vaccinated against SARS-CoV-2 disease, collected during the pandemic, compared to healthy subjects (CTRL).ResultsNone of the 99 patients that contracted SARS-CoV-2 infection during the pandemic period was found positive for T1D autoantibodies. The frequency of SARS-CoV-2 antibodies was not significantly different in patients newly diagnosed with T1D (12.2%), compared with CTRL (8.4%). Among SARS-CoV-2 antibody positive T1D patients, 80% were target of diabetes autoantibodies and 60% had another concomitant autoimmune disease. Among the CTRL subjects positive for SARS-CoV-2Abs (n = 10), none was found positive for T1D autoantibodies.ConclusionsThe results of the present study do not confirm, at least in the short term, a role of COVID-19 as a potential trigger of T1D autoimmunity and do not provide evidence of an increased frequency of SARS-CoV-2 antibodies in newly diagnosed T1D patients in comparison with healthy population.

Transit Thrombus in a Patent Foramen Ovale — Time Is Running Out: a Case Report

We report a case of a large thrombus entrapped in a patent foramen ovale after bariatric surgery and pulmonary embolism. The 60-year-old female patient was admitted to hospital as an emergency after syncope. She suffered from metabolic syndrome with obesity (height: 180 cm, weight: 170 kg, BMI: 49.4 kg/m2) and an insulin-dependent diabetes mellitus type 2. She had had bariatric surgery (implantation of a gastric balloon) 4 weeks prior to hospitalization. A transthoracic echocardiography was performed which indicated a large entrapped thrombus in the patent foramen ovale with extensions of approximately 10 cm in both the right and the left heart. Surgical embolectomy was performed to remove the circa 20-cm-long thrombus.At the time of surgery, only 2 cm of the transit thrombus remained in the right atrium. Thus, during the time between diagnosis and emergency surgery, the thrombus had gradually migrated 8 cm. Pulmonary embolectomy and closure of the patent foramen ovale were performed during the same procedure. The patient recovered completely without any complications and was discharged 11 postoperatively. This case demonstrates the importance of urgent medical decision-making with transit thrombi — time is running out.

Revisiting the Pathogenesis of Type 1 Diabetes: Importance of Neural Input to Pancreatic Islets and the Therapeutic Capability of Stem Cell Educator TM Therapy to Restore Their Integrity.

Type 1 diabetes (T1D) is an autoimmune disease with a shortage of islet β cells. To date, the etiology of T1D remains elusive. Increasing clinical evidence and animal studies demonstrate that autoimmune cells are directed against the nervous system of pancreatic islets, contributing to the development of T1D. Therefore, it highlights the necessity to explore novel clinical approaches to fundamentally correct the T1D autoimmunity not only focusing on islet β cells but also on protecting the islet nervous system. This allows the restoration of the integrity of islet innervation and the normal islet β-cell function. To address these issues, we developed a novel technology designated the Stem Cell Educator TM therapy, based on immune education by human cord-blood-derived multipotent stem cells (CB-SC). International amulticenter clinical trials demonstrated its clinical safety and efficacy to treat T1D and other autoimmune diseases. Stem Cell Educator TM therapy may have the potential to revolutionize the treatment of T1D, without the safety and ethical concerns associated with conventional immune and/or stem cell-based therapies.

DETERMINATION OF HEPCIDIN CONCINTRATION AND MANY HEMATOLOGICAL AND BIOCHEMICAL VARIATIONS IN PATIENTS WITH DIABETESTYPE 2 IN BALAD CITY

Introduction: Diabetes is a group of metabolic diseases characterized by excessive blood sugar caused by a defect in insulin secretion or function, there are two main types of diabetes: namely, insulin-dependent diabetes mellitus (Type I) known as childhood diabetes, The second type is non-insulin-dependent diabetes mellitus, and usually affects adults after the age of forty. Hepcidin is the main organizer of the iron metabolism inHuman and in the rest of mammals.&#x0D; The aim of the study:&#x0D; &#x0D; Examine the relationship between the concentrations of each of the hepcidin, glycated hemoglobin HBA1C and ferritin and iron in patients with type II diabetes as well as healthy control.&#x0D; Examine the relationship between these virables with each other and with other virables.&#x0D; &#x0D; Materials and Methods: The concentration of hepcidin hormone and other biochemical variables was examined in (80) patients with diabetes type II, divided into two groups (39) males and (41) females. Age ranged between (34-75) years. Samples have been collected from patients who visited Balad General hospital laboratory and Dijla Private Laboratory in Balad District. At the same time , blood of (25) healthy volunteers was collected. Sample was divided into 2.5 ml in EDTA tube for hematological tests like complete blood count and HbA1C and 2.5 ml in heparin anticoagulated tube for chemical tests like blood sugar, Iron, Total iron binding capacity and Hepcidin.&#x0D; Results and Discussion: The results study showed a significant relationship (P&lt;0.05) between the concentration of Hepcidinin patients with type 2 diabetes and healthy persons for both sexes . Also hepcidin concentration tend to increase in female patients as compared with male patients.&#x0D; It was also noted that there was a statistically significant relationship between hepcidin and ferritin concentration (p&lt;0.05), as well as between iron and Hepcidin concentration (p &lt; 0.05), with no statistical relationship between iron binding capacity (TIBC) and the concentration of hepcidin.&#x0D; The study showed a Positive correlation between the concentration of Hepcidinand count of red blood cells in people with type 2 diabetes when compared with healthy people.&#x0D; Conclusion: The average concentration of hepcidin was found to be higher among females than that among males. Also, there was an increase in the concentration of Hepcidin compared with healthy people.&#x0D;

A diet enriched in omega-3 PUFA and inulin prevents type 1 diabetes by restoring gut barrier integrity and immune homeostasis in NOD mice.

The integrity of the gut barrier (GB) is fundamental to regulate the crosstalk between the microbiota and the immune system and to prevent inflammation and autoimmunity at the intestinal level but also in organs distal from the gut such as the pancreatic islets. In support to this idea, we recently demonstrated that breakage of GB integrity leads to activation of islet-reactive T cells and triggers autoimmune Type 1 Diabetes (T1D). In T1D patients as in the NOD mice, the spontaneous model of autoimmune diabetes, there are alterations of the GB that specifically affect structure and composition of the mucus layer; however, it is yet to be determined whether a causal link between breakage of the GB integrity and occurrence of autoimmune T1D exists. Here we restored GB integrity in the NOD mice through administration of an anti-inflammatory diet (AID- enriched in soluble fiber inulin and omega 3-PUFA) and tested the effect on T1D pathogenesis. We found that the AID prevented T1D in NOD mice by restoring GB integrity with increased mucus layer thickness and higher mRNA transcripts of structural (Muc2) and immunoregulatory mucins (Muc1 and Muc3) as well as of tight junction proteins (claudin1). Restoration of GB integrity was linked to reduction of intestinal inflammation (i.e., reduced expression of IL-1β, IL-23 and IL-17 transcripts) and expansion of regulatory T cells (FoxP3+ Treg cells and IL-10+ Tr1 cells) at the expenses of effector Th1/Th17 cells in the intestine, pancreatic lymph nodes (PLN) and intra-islet lymphocytes (IIL) of AID-fed NOD mice. Importantly, the restoration of GB integrity and immune homeostasis were associated with enhanced concentrations of anti-inflammatory metabolites of the ω3/ω6 polyunsaturated fatty acids (PUFA) and arachidonic pathways and modifications of the microbiome profile with increased relative abundance of mucus-modulating bacterial species such as Akkermansia muciniphila and Akkermansia glycaniphila. Our data provide evidence that the restoration of GB integrity and intestinal immune homeostasis through administration of a tolerogenic AID that changed the gut microbial and metabolic profiles prevents autoimmune T1D in preclinical models.

A Critical Analysis of Relationship and Management of Sweet Bones in Insulin-Dependent Diabetes Mellitus

Due to the increased risk of encountering several bone deformities as a result of insulin-dependent diabetes mellitus (Type 1 diabetes), it has become obligatory to study this relationship among them so that such conditions of skeletal complications might be detected and treated at a much earlier stage. Type 1 diabetic patients have ameliorated bone mineral density and bone turnover, thus increasing the risk of individuals suffering from fractures. The mechanism behind bone deformities is multifactorial and not completely understood yet. The major factors responsible are less amount of osteoclasts and decreased activity of osteoblasts due to deviated insulin signaling pathway. Other eminent factors involved are oxidative stress, elevated levels of calcium and magnesium in urine, and the build-up of advanced glycation end products. These eminent factors lead to the formation of sweet bones. Sweet bone is a name given collectively to the altered structure, strength, and metabolism of bones. This study will help the researchers to understand and maintain good lifestyle practices. Educating the patients about avoiding other diabetic complications, regular consumption of calcium and vitamin D, along with maintaining proper serum glucose levels are the major steps to be taken primarily in treating bone loss due to type 1 diabetes.

Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for InVivo β-Cell Imaging and Islet-Specific Therapies.

Type 1 diabetes (T1D) is a disease in which autoimmune attacks are directed at the insulin-producing β-cell in the pancreatic islet. Autoantigens on the β-cell surface membrane are specific markers for molecular recognition and targets for engagement by autoreactive B lymphocytes, which produce islet cell surface autoantibody (ICSA) upon activation. We report the cloning of an ICSA (mAb43) that recognizes a major T1D autoantigen, ZnT8, with a subnanomolar binding affinity and conformation specificity. We demonstrate that cell-surface binding of mAb43 protects the extracellular epitope of ZnT8 against immunolabeling by serum ICSA from a patient with T1D. Furthermore, mAb43 exhibits invitro and ex vivo specificity for islet cells, mirroring the exquisite specificity of islet autoimmunity in T1D. Systemic administration of mAb43 yields a pancreas-specific biodistribution in mice and islet homing of an mAb43-linked imaging payload through the pancreatic vasculature, thereby validating the invivo specificity of mAb43. Identifying ZnT8 as a major antigenic target of ICSA allows for research into the molecular recognition and engagement of autoreactive B cells in the chronic phase of T1D progression. The invivo islet specificity of mAb43 could be further exploited to develop invivo imaging and islet-specific immunotherapies.