Diminished Adenosine A1 Receptor Expression in Pancreatic α-Cells May Contribute to the Pathology of Type 1 Diabetes

Abstract

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.

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

“…Loss of A 1 adenosine receptor expression as a result of alternative splicing in the early stages of T1DM has been reported both in mice and in patients. 12 This alternative splicing, which results in a nonfunctional form of the receptor, is caused by inflammatory processes in diabetic islets. Loss of functional A 1 adenosine receptor expression might contribute to the unrestrained secretion of glucagon and could represent an early intrinsic α-cell defect that contributes to the progression and clinical manifestation of T1DM.…”

“…An increasing amount of evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis 8 and the pathophysiology of diabetes mellitus. [12][13][14] Although adeno sine signalling is known to affect insulin secretion, [15][16][17] new data show that adenosine also regulates β-cell homeostasis by controlling the proliferation and regeneration of β cells, in addition to maintaining their survival in an inflammatory microenvironment. 15,18 Moreover, adenosine is now recognized as a major regulator of cell responsiveness to insulin by controlling insulin signalling in adipose tissue, 13,14,19,20 muscle 14,19,20 and liver; 14,20 adenosine also indirectly mediates actions on inflammatory and/or immune cells in these tissues.…”

Oligofructose as an adjunct in treatment of diabetes in NOD mice

“…However, we did not detect a difference between the group that received aCD3 + OFS and the group that received aCD3 alone (data not shown). Expression of glucagon in alpha cells is known to be elevated in autoimmune T1D3435, but whether the expression of proglucagon in the gut is also elevated is unknown. It is possible that our inability to detect a difference in proglucagon expression between the aCD3 + OFS and the aCD3-alone groups is due to the already up regulated proglucagon levels in the diabetic NOD mouse, such that the addition of OFS cannot increase it further.…”

A run on the biobank

“…Interestingly, a role for adenosine signaling is now emerging in the pathogenesis of diabetes and cellular regeneration of b cells [60]. In a related study, Yip et al [28] looked at the role of the adenosine A1 receptor (Adora1) expression in a cells in the context of T1D pathogenesis. Using pancreatic tissue and RNA samples, gene and protein expression of Adora1 was shown to be gradually reduced in a cells of NOD mice and from both AAbþ diabetes-free and T1D donors.…”