GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells

Shilleh, Ali H.; Viloria, Katrina; Broichhagen, Johannes; Campbell, Jonathan E.; Hodson, David J.

doi:10.1016/j.peptides.2024.171179

Cited by 7 publications

(1 citation statement)

References 120 publications

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“…Furthermore, liraglutide alone did not inhibit glucagon secretion. GLP-1 effects on alpha cells are complex and have mainly been considered indirect, as GLP-1R expression is thought to be limited or absent in human alpha cells, although uncertainty exists [59, 61, 62]. However, there is some evidence that GLP-1 can act directly on alpha cells, as glucagonostatic effects are independent of insulin and somatostatin, as evidenced by INSR and SSTR2 blockage [59].…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory cytokine-induced alpha-cell impairment in human islet microtissues is partially restored by dual incretin receptor agonism

Henriksen,

Rufer,

Title

et al. 2024

Preprint

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Aims/hypothesisIn type 1 diabetes, the counterregulatory glucagon response to low plasma glucose is impaired. The resulting increased risk of hypoglycaemia necessitates novel strategies to ameliorate alpha-cell impairment. Here, we aimed to establish an in vitro model of alpha-cell impairment in type 1 diabetes using human islet microtissues (MTs) exposed to proinflammatory cytokines. Additionally, we investigated the therapeutic potential of incretin receptor agonists in improving alpha-cell responses to low glucose.MethodsHuman islet MTs were exposed to proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) for 1 day (short-term) and 6 days (long-term). Alpha-cell function was assessed by sequential glucose-dependent secretion assays at 2.8 and 16.7 mmol/l glucose, followed by glucagon measurements. Additional evaluations included ATP content, caspase-3/7 activity, chemokine secretion, and expression of islet transcription factors and hormones. The effects of incretin receptor agonist treatment (glucose-dependent insulinotropic polypeptide (GIP) analogue [D-Ala2]-GIP ± liraglutide) alongside or after cytokine exposure were also investigated, focusing on low glucose-dependent glucagon secretion.ResultsShort-term cytokine exposure increased glucagon secretion at both 2.8 and 16.7 mmol/l glucose. In contrast, long-term cytokine exposure caused dose-dependent suppression of glucagon secretion at 2.8 mmol/l glucose, resembling a type 1 diabetes phenotype. Long-term cytokine exposure also diminished somatostatin secretion, reduced ATP content, increased caspase 3/7 activity, and decreased islet transcription factor and hormone expression. Despite cytokine-induced impairment, alpha cells partially retained secretory capacity to L-arginine stimulation. Treatment with incretin receptor agonists during long-term cytokine exposure did not prevent alpha-cell impairment. However, acute treatment with [D-Ala2]-GIP ± liraglutide or the single-molecule dual agonist tirzepatide partially restored glucagon secretion at low glucose.Conclusions/interpretationLong-term cytokine exposure of human islet MTs impaired glucagon secretion to low glucose, creating a type 1 diabetes alpha-cell phenotype. This cytokine-induced alpha-cell impairment was partially restored by [D-Ala2]-GIP ± liraglutide and tirzepatide, respectively.Research in contextWhat is already known about this subject?The counterregulatory alpha-cell response to low glucose is impaired in type 1 diabetes, increasing the risk of hypoglycaemia.Limited translatability of rodent islet findings highlights the need for human islet models.Actions of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have mainly been studied in the context of type 2 diabetes and hyperglycaemia but less in type 1 diabetes and hypoglycaemia.What is the key question?Can alpha-cell impairment in type 1 diabetes be modelled in vitro by exposing human islet microtissues (MTs) to proinflammatory cytokines, and could incretins protect against this?What are the new findings?Long-term (6-day) exposure to proinflammatory cytokines produces a type 1 diabetes phenotype of alpha-cell impairment to low glucose in islet MTsAcute dual treatment with incretin receptor agonists partially restored glucose-dependent glucagon secretion in cytokine-exposed islet MTs — an effect mainly carried by GIP receptor agonism and not opposed by GLP-1 receptor agonism.How might this impact on clinical practice in the foreseeable future?Investigating incretin receptor agonists in a preclinical in vitro model of alpha-cell impairment may reveal their potential and fast-track their use as safeguards against hypoglycaemia in type 1 diabetes.

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