Clinical and immunological features of celiac disease in patients with Type 1 diabetes mellitus

Celiac disease (CD) is one of the most frequent autoimmune disorders occurring in Type 1 diabetes mellitus (T1DM). The prevalence of CD in T1DM varies from 3 to 16%, with a mean prevalence of 8%. The clinical presentation of CD in T1DM is classified as symptomless in approximately half of cases, but a more accurate analysis often discloses a wide array of symptoms suggestive of CD. Both T1DM and CD show the same genetic background and an abnormal small intestinal immune response with inflammation and a variable grade of enteropathy. Serological screening for CD should be performed in all T1DM patients by means of antibodies to tissue transglutaminase at T1DM onset. T1DM patients found to be celiacs must be treated by a gluten-free diet. Potential CD cases (especially when asymptomatic) should be kept on a gluten-containing diet with a careful clinical and antibody follow-up, since many of them will not develop villous atrophy.     

Mechanisms underlying endothelial dysfunction in diabetes mellitus

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabetes was induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N:(G)-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N:-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N:-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.     

Cardiorenal syndrome in type 1 diabetes mellitus: the role of endothelial dysfunction

AIM: To elucidate the role of endothelial dysfunction in formation of cardiorenal syndrome in patients with type 1 diabetes and diabetic nephropathy. MATERIAL AND METHODS: Sixty patients with type 1 diabetes were divided according to severity of nephropathy into the following groups: with normal albuminuria (n=15), microalbuminuria (n=15), proteinuria (n=15), and chronic renal failure (n=15). Control group consisted of 15 healthy subjects of similar age and sex. Methods of investigation included assessment of brachial artery endothelium dependent dilation by duplex scanning during test with reactive hyperemia, measurement of levels of serum markers of endothelial dysfunction (endothelin-1, von-Willebrand factor), and inflammation (C-reactive protein), analysis of parameters of 24-hour blood pressure monitoring and echocardiography data. RESULTS: More severe diabetic nephropathy was associated with higher prevalence of cardiac pathology. Frequency of ischemic heart disease was 13 (2/15), 33 (5/15) and 53% (8/15), frequency of left ventricular concentric hypertrophy and remodeling - 33 (5/15), 40 (6/15) and 60% (9/15) among patients with microalbuminuria, proteinuria and chronic renal failure, respectively. Abnormalities of 24-hour blood pressure rhythm as well as signs of endothelial dysfunction were more pronounced in patients with more severe nephropathy. Correlation analysis revealed significant relationships between markers of endothelial dysfunction, parameters of renal function, blood pressure level and mass of left ventricular myocardium. CONCLUSION: In patients with type 1 diabetes: endothelial dysfunction represents a link integrating processes of progression of nephropathy and development of cardiovascular pathology; close relationship between these processes constitutes a basis of cardiorenal syndrome; active search for cardiac pathology should be initiated on the stage of microalbuminuria.     

Type 1 diabetes and celiac disease in adults: glycemic control and diabetic complications

The prevalence of celiac disease (CD) in patients with type 1 diabetes mellitus (T1DM) is 4.5 %. Objective of the study is to investigate (1) the course of glycemic control at CD diagnosis and after the initiation of a gluten-free diet (GFD) in T1DM patients; (2) the prevalence of diabetic complications in T1DM patients with adult onset of CD. In 20 hospitals in the Netherlands, we identified T1DM patients diagnosed with CD at adult age. We retrospectively collected glycated hemoglobin (HbA1c) levels before CD diagnosis, at CD diagnosis, and the most recent HbA1c levels as well as the presence of nephropathy and retinopathy. The control group consisted of patients with T1DM and negative CD serology matched for age, gender, T1DM duration, and HbA1c levels. Thirty-one patients were eligible with a median duration of T1DM and CD of 27 years (IQR 14–37) and 3 years (IQR 1–8), respectively. The matched control group consisted of 46 patients. HbA1c levels at the moment of CD diagnosis were 7.5 % (IQR 7.1–8) [58 mmol/mol] and at the most recent visit 7.4 % (IQR 6.9–7.9, P = 0.15) [57 mmol/mol] indicating no difference. Prevalence of retinopathy was lower in T1DM + CD group compared with controls, (38.7 vs 67.4 %, P < 0.05), whereas no difference in the prevalence of nephropathy was found between the groups (P = 0.09). In conclusion, T1DM + CD patients have less retinopathy compared to T1DM patients without CD. A GFD possibly favorable affects the development of vascular complications in T1DM patients.     

Common variable immunodeficiency, insulin-dependent diabetes mellitus and celiac disease

Common variable immunodeficiency is a disorder characterised by hypogammaglobulinemia with B-lymphocytes in peripheral blood and repeated infections. We report a child with a diagnosis of diabetes mellitus and celiac disease during lactation, and in whom common variable immunodeficiency was diagnosed at the age of 5. During evolution of the disease he presented multiple respiratory infections in spite of substitution therapy with gamma globulins. He presented pulmonary fibrosis with a pulmonary volume reduced, and a spirometric restrictive patron. Immunologically, he presents reduction in CD4 lymphoid population. He expresses the alleles DQ2 A1 0501 and B1 which are strongly associated with susceptibility to insulin-dependent diabetes mellitus and celiac disease, but don't express antigens HLA class II DR3 and DR4 that are more frequent in these entities. The main disease and all the complications had affected his curve pondostatural.     

Type 1 diabetes mellitus,celiac disease,systemic lupus erythematosus and systemic scleroderma in a 15-year-old girl

We report a case of an association of four autoimmune diseases in a 15-year-old girl and we discuss the etiopathogenic of this association and difficulties of treatment.     

The prevalence of manifest and latent celiac disease in type 1 diabetes mellitus.

BACKGROUND/AIMS: Celiac disease and type 1 diabetes mellitus are both autoimmune diseases which have a common genetic predisposition. The aim of this study was to determine the prevalence of manifest and latent celiac disease in type 1 diabetic patients. METHODS: Anti-endomysium IgA was tested by indirect immunofluorescence using sections of human umbilical cord for screening in 100 adult patients with type 1 diabetes mellitus and in 80 age and sex matched controls with no known disease. Distal duodenal biopsy, human leukocyte antigen typing, urinary D-xylose excretion test, stool analysis, biochemistry profile, blood counts, serum ferritin level and small intestinal radiography were performed in anti-endomysium IgA positive cases. Small bowel biopsy specimens consistent with celiac disease were defined as manifest celiac disease, while positive antiendomysium IgA and normal intestinal histology with the presence of human leukocyte antigen class II antigens consistent with the disease were defined as latent celiac disease. RESULTS: Anti-endomysium IgA was positive in eight diabetic patients, while it was negative in all controls. Celiac disease was found in a total of six (6%) patients, four with manifest and two with latent disease. Only one patient had symptoms. CONCLUSIONS: The prevalence of celiac disease is increased in patients with type 1 diabetes mellitus. Since many patients may be asymptomatic, it is suggested that all diabetic patients should be screened for this disease.     

Acute hyperglycemia and hyperinsulinemia enhance vasodilatation in Type 1 diabetes mellitus without increasing capillary permeability and inducing endothelial dysfunction.

Uncomplicated Type 1 (insulin-dependent) diabetes mellitus is characterized by generalized vasodilatation. Its possible correlates, increased microvascular permeability and endothelial dysfunction, have been associated with long-term complications. The objective was to study the effects of acute hyperglycemia and hyperinsulinemia, both separately and in combination, on skin microvascular flow, capillary permeability, capillary recruitment, and endothelial dysfunction in Type 1 diabetes mellitus. Sixteen Type 1 diabetic patients (all normoalbuminuric, no (pre-)proliferative retinopathy) underwent a euglycemic (glucose target 5.0 mmol/L, insulin infused at 30 mU x kg(-1) x h(-1)), a hyperglycemic (glucose target 12.0 mmol/L, insulin 30 mU x kg(-1) x h(-1)), a hyperinsulinemic (glucose target 5.0 mmol/L, insulin 150 mU x kg(-1) x h(-1)), and a hyperglycemic-hyperinsulinemic (glucose target 12.0 mmol/L, insulin 150 mU x kg(-1) x h(-1)) clamp on separate days, in random order. Skin microvascular flow was measured by laser Doppler flowmetry. Capillary permeability and density were determined by large-window sodium-fluorescein videodensitometry. Increases in serum soluble intercellular adhesion molecule-1 (sICAM-1) and plasma von Willebrand factor antigen (vWF-Ag) were considered to represent abnormal endothelial function. Hyperglycemia (P < 0.01) and hyperinsulinemia (P < 0.05) as well as both interventions combined (P < 0.001) induced an increase in laser Doppler flow, without capillary recruitment. Transcapillary leakage of sodium-fluorescein and sICAM-1 and vWF-Ag levels were unaffected by hyperglycemia or hyperinsulinemia. Microvascular permeability appears to be determined primarily by properties of the capillary wall and not by acute changes in local hemodynamics. The acute hyperglycemia- and hyperinsulinemia-induced vasodilatation is not accompanied by changes in microvascular permeability or endothelial markers.     

Peripheral sensory nerve dysfunction in children and adolescents with Type 1 diabetes mellitus

The aim of the present study was to investigate peripheral sensory nerve function in diabetic children and adolescents without neurological symptoms. Ninety-two children and adolescents with Type 1 (insulin-dependent) diabetes mellitus (mean ± SD age: 14.2 ± 2.1 years, diabetes duration: 5.8 ± 3.0 years) and 80 healthy control subjects (age: 13.8 ± 2.2 years) matched for age, sex, body mass index, and height standard deviation score were involved in the study. Using a sine-wave transcutaneous stimulator, current perception threshold (CPT) testing at 2000, 250 and 5 Hz was performed on the left median and peroneal nerves. Diabetic children had increased CPT at 2000 Hz on both nerves as compared to the control group (median (interquartile range), median nerve: 2.43 (2.20–3.43) vs 1.80 (1.51–2.60) mA, p = 0.02; peroneal nerve: 3.51 (2.81–4.82) vs 2.70 (2.04–3.70) mA, p = 0.01). Twenty-one (23 %) of patients had CPT values higher than that of any healthy individual. Of these, elevated CPT was observed in 9 (9.8 %) patients on the median nerve, in 8 (8.7 %) patients on the peroneal nerve, and in 4 (4.3 %) patients on both median and peroneal nerves. Using multiple logistic regression analysis, worse long-term metabolic control and advanced puberty were independently predictive of peripheral sensory nerve dysfunction as the dependent variable (adjusted OR (95 % CI): 3.4 (1.2–6.2), p = 0.01, and 2.8 (1.1–5.6), p = 0.03, respectively). In conclusion, evidence of peripheral sensory nerve dysfunction is not rare in children and adolescents with diabetes and can be demonstrated by CPT testing in asymptomatic patients. Poor metabolic control is a risk factor for such subclinical neuropathy, and pubertal development may be involved in the pathogenesis of diabetic peripheral neuropathy. © 1998 John Wiley & Sons, Ltd.