Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells May Contribute to the Pathology of Type 1 Diabetes
| العنوان: | Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells May Contribute to the Pathology of Type 1 Diabetes |
|---|---|
| المؤلفون: | Linda Yip, C. Garrison Fathman, Chan C. Whiting, Cariel Taylor |
| المصدر: | Diabetes |
| بيانات النشر: | American Diabetes Association, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Inflammation, Nod, Biology, Pathophysiology, Proinflammatory cytokine, Prediabetic State, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Mice, Inbred NOD, Internal medicine, Internal Medicine, medicine, Animals, Humans, Child, Original Research, 030304 developmental biology, NOD mice, 0303 health sciences, Receptor, Adenosine A1, Alternative splicing, Middle Aged, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Endocrinology, Glucagon-Secreting Cells, Female, medicine.symptom, Pancreas, Spleen, Hyperglucagonemia |
| الوصف: | Prediabetic NOD mice exhibit hyperglucagonemia, possibly due to an intrinsic α-cell defect. Here, we show that the expression of a potential glucagon inhibitor, the adenosine A1 receptor (Adora1), is gradually diminished in α-cells of NOD mice, autoantibody-positive (AA+) and overtly type 1 diabetic (T1D) patients during the progression of disease. We demonstrated that islet inflammation was associated with loss of Adora1 expression through the alternative splicing of Adora1. Expression of the spliced variant (Adora1-Var) was upregulated in the pancreas of 12-week-old NOD versus age-matched NOD.B10 (non–diabetes-susceptible) control mice and was detected in the pancreas of AA+ patients but not in control subjects or overtly diabetic patients, suggesting that inflammation drives the splicing of Adora1. We subsequently demonstrated that Adora1-Var expression was upregulated in the islets of NOD.B10 mice after exposure to inflammatory cytokines and in the pancreas of NOD.SCID mice after adoptive transfer of activated autologous splenocytes. Adora1-Var encodes a dominant-negative N-terminal truncated isoform of Adora1. The splicing of Adora1 and loss of Adora1 expression on α-cells may explain the hyperglucagonemia observed in prediabetic NOD mice and may contribute to the pathogenesis of human T1D and NOD disease. |
| تدمد: | 1939-327X 0012-1797 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::298bdfed810ede8b01abdd60e93fb445Test https://doi.org/10.2337/db13-0614Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....298bdfed810ede8b01abdd60e93fb445 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
|---|