Incretin-induced amelioration of type 1 diabetic alpha cell impairmentin an in vitro model based on human islet microtissues

In type 1 diabetes (T1D), counterregulatory glucagon secretion from pancreatic alpha cells in response to low blood glucose is severely impaired. This impairment confers an increased risk of hypoglycemia in the context of both insulin treatment and physical exercise. Hypoglycemia is not only a life-threatening concern but also a major limiting factor for proper glycaemic control, which is essential to prevent diabetic complications. The mechanisms underlying the impaired alpha-cell response to hypoglycemia in T1D are incompletely understood and studies addressing this are therefore highly warranted. Here, we set out to establish an in vitro T1D alpha-cell model using standardized human islet microtissues (MTs) exposed to proinflammatory cytokines.
Human islet MTs from non-diabetic organ donors were exposed to IL-1beta, IFN-gamma, and TNF-alpha for 6 days. Secreted glucagon during low (2.8) and high (16.7) glucose was evaluated using the Meso Scale Discovery (MSD) platform. We found that exposure to cytokines had direct and dose-dependent detrimental effects on low glucose-induced glucagon secretion, reflecting an impaired alpha-cell phenotype similar to that seen in T1D.
Using this model, we then examined if treatment with [D-Ala]2-GIP, a stable glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and Liraglutide, a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist, following cytokine treatment for 6 days could improve alpha-cell function.
Co-treatment with [D-Ala]2-GIP and Liraglutide partially restored low glucose-induced glucagon secretion in T1D islet MTs. This effect was mainly driven by [D-Ala]2-GIP, but Liraglutide, having no effects alone, tended to potentiate [D-Ala]2-GIP-induced glucagon secretion.
Our results corroborate previous clinical findings that GIP increases glucagon secretion at low, but not high, glucose. Furthermore, our findings reveal that dual GIP and GLP-1 receptor agonism ameliorates cytokine-mediated alpha-cell impairment and could therefore be a potential therapeutic way to restore alpha-cell function in T1D.