New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2

1994 ◽  
Vol 131 (4) ◽  
pp. 431-437 ◽  
Author(s):  
Alberto Signore ◽  
Marco Chianelli ◽  
Elisabetta Ferretti ◽  
Anna Toscano ◽  
Keith E Britton ◽  
...  
Keyword(s):  
Gamma Camera ◽  
Type I Diabetes ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Insulin Dependent Diabetes ◽  
Type I ◽  
New Approach ◽  
In Vivo Detection ◽  
Insulin Dependent

Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozzilli P. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2. Eur J Endocrinol 1994;131:431–7. ISSN 0804–4643 Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the nonobese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin (p < 0.003 at 20 min; p< 0.001 at 40 min; p< 0.0001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p< 0.05 at 40 min; p< 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22–45 min in NOD mice vs Balb/c mice). Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration (p < 0.01 for pancreas radioactivity counted in vitro and p< 0.004 for pancreas radioactivity counted in vivo by gamma camera). This study demonstrates that 123I-labelled interleukin 2 administered iv accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus. A Signore, Servizio Speciale di Medicina Nucleare, II Clinica Medica, Policlinico Umberto I, 00161 Roma, Italy

NOD Hematopoietic Stem Cells Exhibit Autonomous Behavior and a Competitive Advantage in Allogeneic Recipients That Maps to the Idd9 Locus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2676-2676
Author(s):  
Paula M. Chilton ◽  
Francine Rezzoug ◽  
Janina Ratajczak ◽  
Mariusz Ratajczak ◽  
Yiming Huang ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Cell Phenotype ◽  
Type I ◽  
Hematopoietic Stem ◽  
Autonomous Behavior ◽  
Insulin Dependent

Abstract Multiple hematopoietic defects have been defined in NOD mice and in humans with type I diabetes, including defects in myeloid cells and antigen presenting cells that correlate with diabetes progression. Since the replacement of HSC in NOD mice can eliminate the progression of autoimmunity and control on-going autoimmune responses, we characterized the function of HSC from NOD mice. We found that purified HSC from NOD mice have an autonomous behavior when transplanted in allogeneic recipient strains as reflected by significantly enhanced engraftment in allogeneic recipients. NOD HSC were able to compete for engraftment with syngeneic HSC even when the NOD and syngeneic HSC were given at a 1:1 ratio. NOD BMC produced a higher number of splenic colonies compared to B10.BR BMC in the allogeneic day 12 CFU-S assay. We also demonstrated that NOD HSC had a high resistance to irradiation, as reflected by the cell survival 20 hours after irradiation and in the in vitro CFC assay. These data suggest that NOD HSC escape alloreactivity and compete with normal HSC. The enhanced engraftment ability in allogeneic recipients of NOD HSC was not due to an increase in frequency of primitive HSC, enumerated by day 35 cobblestone area forming cells (CAFC). This finding was further confirmed by the fact that there was no difference in the long-term repopulating cell phenotype (CD49e+/CD49ddim) between HSC obtained from NOD, B10.BR or C57BL/10 mice. Notably, NOD bone marrow cells exhibit significantly enhanced chemotaxis to SDF-1 in vitro and significantly increased HSC adhesion to primary stroma. This was associated with an increase in the expression of VCAM-1, ICAM-1 and ICAM-2 on NOD HSC. Using NOD mice congenic at selected Idd loci with C57BL/10, we determined that the enhanced engraftment potential of NOD HSC mapped to the Idd9 (insulin-dependent diabetes) locus and, as such, the TNF receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSC. In conclusion, NOD HSC exhibit increased autonomy in vivo and in vitro compared to non-diabetic strains, and engraft better in allogeneic recipients, possibly due to enhanced migration and adherence to the microenvironment. This finding may be of interest for a better understanding of disease pathogenesis and in developing cell-based strategies to cure diabetes.

scholarly journals The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

2021 ◽  
Author(s):  
Ariel Galindo-Albarrán ◽  
Sarah Castan ◽  
Jérémy C. Santamaria ◽  
Olivier P. Joffre ◽  
Bart Haegeman ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Nod Mice ◽  
Vital Role ◽  
Nod Mouse ◽  
Type I ◽  
Antigen Specificity ◽  
Regulatory T Lymphocytes ◽  
Winged Helix Transcription Factor ◽  
Complementarity Determining Region

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

scholarly journals Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in a Rat Model of Streptozotocine-Induced Insulin-Dependent Diabetes Mellitus

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Yu-Chen Lee ◽  
Te-Mao Li ◽  
Chung-Yuh Tzeng ◽  
Ying-I Chen ◽  
Wai-Jane Ho ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Insulin Signaling ◽  
Type I Diabetes ◽  
Insulin Dependent Diabetes ◽  
Type I ◽  
Signaling Proteins ◽  
Glucose Levels ◽  
Before And After ◽  
Insulin Dependent ◽  
Adrenalectomized Rats

Animal studies have shown that electroacupuncture (EA) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints reduces plasma glucose concentrations in rats with type II diabetes. However, whether EA reduces plasma glucose levels in type I diabetes is still unknown. In this study, we explore the various non-insulin-dependent pathways involved in EA-induced lowering of plasma glucose. Streptozotocin (STZ) (60 mg kg−1, i.v.) was administered via the femoral vein to induce insulin-dependent diabetes in non-adrenalectomized and in adrenalectomomized rats. EA (15 Hz) was applied for 30 min to bilateral ST-36 acupoints after administration of Atropine (0.1 mg kg−1i.p.), Eserine (0.01 mg kg−1i.p.), or Hemicholinium-3 (5 μg kg−1i.p.) in non-adrenalectomized rats. Rats administered acetylcholine (0.01 mg kg−1i.v.) did not undergo EA. Adrenalectomized rats underwent EA at bilateral ST-36 acupoints without further treatment. Blood samples were drawn from all rats before and after EA to measure changes in plasma glucose levels. Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. Atropine and hemicholinium-3 completely blocked the plasma glucose lowering effects of EA, whereas eserine led to a significant hypoglycemic response. In addition, plasma glucose levels after administration of acetylcholine were significantly lower than the fasting glucose levels. In STZ-adrenalectomized rats, EA did not induce a hypoglycemic response. EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. Taken together, EA at the ST-36 acupoint reduces plasma glucose concentrations by stimulating the cholinergic nerves.

scholarly journals The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

2008 ◽  
Vol 198 (3) ◽  
pp. 581-589 ◽  
Author(s):  
Jon G Mabley ◽  
Pal Pacher ◽  
Kanneganti G K Murthy ◽  
William Williams ◽  
Garry J Southan ◽  
...  
Keyword(s):  
Animal Models ◽  
Type I Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Diabetes Incidence ◽  
Type I ◽  
Protective Effects ◽  
Naturally Occurring ◽  
Anti Inflammatory

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-α, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1α. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes.

Reduced number of angiotensin II receptors on platelets in insulin-dependent diabetes

1986 ◽  
Vol 71 (2) ◽  
pp. 217-220 ◽  
Author(s):  
J. M. C. Connell ◽  
Yu-An Ding ◽  
B. M. Fisher ◽  
B. M. Frier ◽  
P. F. Semple
Keyword(s):  
Angiotensin Ii ◽  
Type I Diabetes ◽  
Plasma Concentrations ◽  
Normal Subjects ◽  
Insulin Dependent Diabetes ◽  
Angiotensin Ii Receptors ◽  
Diabetic Patients ◽  
Type I ◽  
Angiotensin Ii Receptor ◽  
Insulin Dependent

1. Angiotensin II receptors on platelets were studied in 13 patients with uncomplicated type I diabetes mellitus and in 15 age-matched normal subjects. 2. Receptor density on cells from the diabetic patients was 15% lower than the normal subjects (5.2 ± 0.8 sd sites/platelet in diabetic patients and 6.4 ± 0.8 in normals, P < 0.001), but there were no differences in receptor affinity as measured by Kd (4.9 ± 1.5 × 10−10 mol/l in diabetic patients and 5.4 ± 1.4 × 10−10 mol/l in normals). 3. Plasma concentrations of renin and angiotensin II were similar in both groups. 4. The reduced density of angiotensin II receptors on platelets from patients with insulin-dependent diabetes may reflect a generalized abnormality of angiotensin II receptor regulation.

Sulfonylureas in Insulin-Dependent (Type I) Diabetes: Evidence for an Extrapancreatic Effect in Vivo*

1985 ◽  
Vol 61 (2) ◽  
pp. 247-251 ◽  
Author(s):  
A. PERNET ◽  
E. R. TRIMBLE ◽  
F. KUNTSCHEN ◽  
J.-Ph. ASSAL ◽  
C. HAHN ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Type I ◽  
Insulin Dependent ◽  
Dependent Type

scholarly journals Hepatobiliary function in children with insulin-dependent diabetes mellitus

1995 ◽  
Vol 41 (4) ◽  
pp. 15-17
Author(s):  
Ye. B. Kravets ◽  
Ye. A. Biryulina ◽  
Z. G. Mironova
Keyword(s):  
Diabetes Mellitus ◽  
Type I Diabetes ◽  
Diagnostic Methods ◽  
Insulin Dependent Diabetes ◽  
Dependent Diabetes Mellitus ◽  
Main Role ◽  
Type I ◽  
Hepatobiliary System ◽  
Insulin Dependent ◽  
Bile Excretion

The hepatobiliary system plays the crucial role in the development of metabolic disorders in diabetics. Involvement of the hepatobiliary system may develop at the early stages of diabetes mellitus. The present study was aimed at elucidation of the specific features of bile excretion and production in children with type I diabetes making use of present-day diagnostic methods. Fifty-two patients with type 1 diabetes aged 6 to 15 and 20 healthy controls were examined. Besides common clinical studies, fractionated duodenal probing followed by biochemical analysis of the bile, ultrasonic examination of the hepatobiliary system, and dynamic hepatobiliscintigraphy were carried out. Typical changes in liver parenchyma developing after fatty hepatosis type were found to play the main role in the structure of hepatobiliary involvement occurring in insulin-dependent diabetes. Disorders of bile excretion are caused by dyskinetic disorders of extrahepatic bile duct and choleresis changes. Bile excretion arrhythmia manifests most frequently as hypertensive dyskinesia. In patients with a longstanding disease bile excretion changes are mainly due to increased tone of the sphincter of Oddi and decelerated contractility of the gallbladder. Biochemical composition of the bile was characterized by decreased concentration of bile acids, phospholipids, and bilirubin, by a lower cholate-cholesterol coefficient, and increased levels of cholesterol and total lipids.

scholarly journals The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

2021 ◽  
Author(s):  
Ariel Galindo-Albarrán ◽  
Sarah Castan ◽  
Jérémy C. Santamaria ◽  
Olivier P. Joffre ◽  
Bart Haegeman ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Nod Mice ◽  
Vital Role ◽  
Nod Mouse ◽  
Type I ◽  
Antigen Specificity ◽  
Regulatory T Lymphocytes ◽  
Winged Helix Transcription Factor ◽  
Complementarity Determining Region

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

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