The prevalence, immune profile, and clinical characteristics of children with celiac disease and type 1 diabetes mellitus in the state of Qatar

Objectives Children with antibody positive type 1 diabetes mellitus (type 1 diabetes) are at an increased risk of developing celiac disease (CD) which suggests a common autoimmune basis with both high-risk human lymphocyte antigen (HLA) and non-HLA factors playing a role in the pathophysiology. We aim to describe the prevalence, immune profile, and clinical characteristics of children with CD who have type 1 diabetes mellitus in Qatar. Methods All children (aged 0–18 years) attending a regional diabetes clinic with antibody positive type 1 diabetes were screened for CD. Measurement of tissue transglutaminase IgA and IgG as well as anti-endomysial antibody, was done, clinical details about the birth history, family history of diabetes and CD, age of onset, and ethnicity were collected. Results Out of the 1,325 children with antibody positive type 1 diabetes, 54 were identified to have CD on screening and then confirmed on small bowel biopsy. The prevalence of CD in the type 1 diabetes childhood population in Qatar is 4.07%. CD and type 1 diabetes were more prevalent in the Qatari children (n=32) as compared to non-Qatari (n=22) and occurred mostly in the age group 6–10 years. The most common type 1 diabetes antibodies in children with CD were glutamic acid decarboxylase and insulin autoantibody. Twelve subjects were asymptomatic for CD symptoms and picked up only on screening. Conclusions The prevalence of CD in children with type 1 diabetes in Qatar is comparable to reports from around the world. Many children were asymptomatic and thus routine screening is recommended.

Stress hyperglycemia as first sign of asymptomatic type 1 diabetes: an instructive case

Background Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. A prolonged hyperglycemic duration of more than 48 h was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

A Case of Autoimmune Hypoglycemia (Insulin Autoimmune Syndrome)

Introduction: Insulin Autoimmune Syndrome (IAS) is a condition caused by Insulin Autoantibody (IAA). IAS was initially reported in 1970 by Yukimasa Hirata from Japan. From 1970 to 2009, 380 cases were reported worldwide. We report a case of IAS in an African-American man who had recurrent episodes of syncope secondary to hypoglycemia. Case Report: A 50-year-old African American man with hypertension presented to emergency room after syncope. His initial blood glucose (BG) was 27 mg/dl. After Dextrose and glucagon injection, BG became 270 and he regained consciousness without any deficit. Vital signs and physical examination were unremarkable. He was not on any medication, and had no access to insulin or oral hypoglycemic agents. No family history of endocrine disorders, malignancy or autoimmune diseases were reported. He had been hospitalized two times for syncope secondary to hypoglycemia. During hospitalization, fasting insulin level was >1000 IU/ml with high C-peptide (3.5ng/ml). Hypoglycemic agents assay was negative. During outpatient follow-ups, fasting labs showed C-peptide 1.59 ng/ml, Insulin antibody 37.6 U/ml while venous BG was 65 mg/dl. Random BG at different occasions were 65, 68 and 55 mg/dl. HbA1C was normal. BMI was gradually increased from 32.4 to 34.8 in 6 months. During the third hospitalization, fasting venous BG were 45 and 57 on two different days, Insulin was 2111 IU/ml and C-Peptide was 1.78 ng/ml. Other labs including cortisol and TSH were normal. CT abdomen was unremarkable. Discussion: In IAS, Insulin secreted after meal is bound by IAA. It causes hyperglycemia unchecked which triggers further insulin secretion. When the bound insulin dissociates from antibodies, it causes significant hyperinsulinemia and subsequent hypoglycemia. IAS can occur regardless of previous insulin exposure, as a solitary autoimmune manifestation or in association with other autoimmune disorders. It can be induced by drugs that contain sulfhydryl group. Etiology of IAS is still not fully understood but there are theories that genetic predisposition such as class II Human Leukocyte Antigen (HLA) and environmental triggers such as medications, viruses, hematological diseases etc. might play a role. In our patient, failure to test IAA in past admissions and lack of continuity of care delayed the diagnosis. Conclusion: IAS should be considered especially in those who have no clear etiology of hypoglycemia in order to avoid unnecessary diagnostic and therapeutic procedures. Gold standard test for definitive diagnosis is IAA. As IAS is frequently self-remitting, supportive management is usually recommended. In severe cases, pharmacotherapies that reduce insulin secretion and immunosuppressants are occasionally necessary. But there is still no study that compares different treatment measures.

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension

Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.

Tolerance to Proinsulin-1 Reduces Autoimmune Diabetes in NOD Mice

T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice.

Stress Hyperglycemia as First Sign of Asymptomatic Type 1 Diabetes: An Instructive Case and Literature Review

Background:Stress hyperglycemia (SH) is considered a transient manifestation and routine diagnostic evaluation was thought to be unnecessary due to the lack of definite correlation with diabetes mellitus (DM). Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM). Case presentation:We reported a boy with acute asthma attack presented incidentally with high blood glucose levels exceeding 300 mg/dL and obvious glycemic variability. Sustained hyperglycemic duration lasting longer than 48 hours was also noticed. To elucidate his unique situation, glucagon test and insulin autoantibody survey were done which showed insulinopenia with positive anti-insulin antibody and glutamic acid decarboxylase antibody despite the absence of overt DM symptoms and signs. Conclusions:This case highlights that SH might be a prodromal presentation in T1DM children, especially when accompanied simultaneously with extreme hyperglycemia, apparent glucose variability, as well as prolonged hyperglycemic duration.

Clinical and Laboratory Aspects of Insulin Autoantibody-Mediated Glycaemic Dysregulation and Hyperinsulinaemic Hypoglycaemia: Insulin Autoimmune Syndrome and Exogenous Insulin Antibody Syndrome

Autoimmune glycaemic dysregulation and hyperinsulinaemic hypoglycaemia mediated by insulin autoantibodies is an increasingly recognised but controversial phenomenon described in both exogenous insulin naïve (insulin autoimmune syndrome) and exposed (exogenous insulin antibody syndrome) individuals. There has been a significant proliferation of case reports, clinical studies and reviews in the medical literature in recent years which have collectively highlighted the discrepancy between experts in the field with regard to the nomenclature, definition, proposed pathophysiology, as well as the clinical and biochemical diagnostic criteria associated with the condition. The essential characteristics of the condition are glycaemic dysregulation manifesting as episodes of hyperglycaemia and unpredictable hyperinsulinaemic hypoglycaemia associated with high titres of endogenous antibodies to insulin. Although the hypoglycaemia is often life-threatening and initiation of targeted therapies critical, the diagnosis is often delayed and attributable to various factors including: the fact that existence of the condition is not universally accepted; the need to exclude surreptitious causes of hypoglycaemia; the diverse and often complex nature of the glycaemic dysregulation; and the challenge of diagnostic confirmation. Once confirmed, the available therapeutic options are expansive and the reported responses to these therapies have been variable. This review will focus on our evolving understanding, and the associated diagnostic challenges – both clinical and laboratory – of this complex condition.

Insulin Autoimmune Syndrome After Exposure to Clopidogrel: A Case Report

Background: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. Case report: IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. A review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. Conclusion: SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.

Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort

Introduction Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet beta cells resulting in total loss of insulin production. Recent studies have suggested that the destruction may be interrelated to plasma lipids. Objectives Specific lipids have previously been shown to be decreased in children who develop T1D before four years of age. Disturbances of plasma lipids prior to clinical diagnosis of diabetes, if true, may provide a novel way to improve prediction, and monitor disease progression. Methods A lipidomic approach was utilized to analyze plasma from 67 healthy adolescent subjects (10–15 years of age) with or without islet autoantibodies but all with increased genetic risk for T1D. The study subjects were enrolled at birth in the Diabetes Prediction in Skåne (DiPiS) study and after 10–15 years of follow-up we performed the present cross-sectional analysis. HLA-DRB345, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genotypes were determined using next generation sequencing. Lipidomic profiles were determined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Lipidomics data were analyzed according to genotype. Results Variation in levels of several specific phospholipid species were related to level of autoimmunity but not development of T1D. Five glycosylated ceramides were increased in insulin autoantibody (IAA) positive adolescent subjects compared to adolescent subjects without this autoantibody. Additionally, HLA genotypes seemed to influence levels of long chain triacylglycerol (TG). Conclusion Lipidomic profiling of adolescent subjects in high risk of T1D may improve sub-phenotyping in this high risk population.

Persistent IL-2R signaling by IL-2/CD25 fusion protein controls diabetes in NOD mice by multiple mechanisms

Low-dose IL-2 represents a new therapeutic approach to regulate immune homeostasis to promote immune tolerance in patients with autoimmune diseases, including type 1 diabetes. We have developed a new IL-2-based biologic, an IL-2/CD25 fusion protein, with greatly improved pharmacokinetics and pharmacodynamics when compared to recombinant IL-2 to enhance this type of immunotherapy. Here we show that low-dose mouse IL-2/CD25 (mIL-2/CD25), but not an equivalent amount of IL-2, prevents the onset of diabetes in NOD mice and controls diabetes in hyperglycemic mice. mIL-2/CD25 acts not only to expand regulatory T cells (Tregs) but also by increasing their activation and migration into lymphoid tissues and the pancreas. Lower incidence of diabetes is associated with increased serum levels of IL-10, a cytokine readily produced by activated Tregs. These effects likely act in concert to lower islet inflammation while increasing Tregs in the remaining inflamed islets. mIL-2/CD25 treatment is also associated with lower anti-insulin autoantibody levels in part by inhibition of T follicular helper cells. Thus, long-acting mIL-2/CD25 represents an improved IL-2 analog that persistently elevates Tregs to maintain a favorable Treg:Teff cell ratio that limits diabetes by expansion of activated Tregs that readily migrate into lymphoid tissues and the pancreas while inhibiting autoantibodies.