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Transcriptomic comparison of hyaluronan-stimulated aTC1-6 cells and type 1 diabetes a cells

ABSTRACT: Type 1 diabetes (T1D) is driven by the immune-mediated destruction of pancreatic b cells. Hyaluronan (HA), an extracellular matrix glycosaminoglycan, accumulates in pancreatic islets in patients with T1D and animal models, and has been implicated in promoting chronic inflammation. Inhibition of HA synthesis in T1D model mice attenuates disease progression, suggesting that HA accumulation contributes to disease deterioration. While b cells are selectively targeted and depleted in T1D, a cells that secrete glucagon are relatively preserved from immune-mediated destruction. Therefore, we hypothesized that accumulated HA may impair a-cell function and thereby contribute to T1D pathophysiology. To investigate this, we performed RNA sequencing on HA-treated a-cell lines and compared the transcriptional profiles to publicly available datasets from a cells isolated from T1D donors. This comparison identified several commonly downregulated genes, potentially reflecting HA-induced -cell dysfunction. These findings provide novel insights into the contribution of the islet microenvironment to the pathogenesis of T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE297634 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Appropriate glucagon secretion from pancreatic alpha cells in response to hypoglycemia is an important component of maintaining glucose homeostasis. Dysregulated glucagon secretion leads to the delayed recovery from a hypoglycemic attack in type 1 diabetes patients which can be lethal. Although elucidating the precise mechanism of glucagon secretion in hypoglycemia is warranted, the underlying mechanism remains poorly understood.The present study provides evidence of the role of autophagy in glucagon secretion in hypoglycemia by demonstrating that autophagy regulates adrenergic stimulation of glucagon secretion downstream of beta2 adrenergic receptor. First, from the analyses of T1D human islets and the published database of scRNA-seq of T1D human alpha cells, we described autophagy pathways altered in T1D alpha cells. Second, we generated alpha cell-specific Atg7KO mice (alphaAtg7KO) and clarified that the lack of autophagy in alpha cells impairs the reactive glucagon secretion in acute hypoglycemia. Third, to interrogate the molecular mechanism of autophagy-mediated glucagon regulation, we analyzed top genes downregulated inT1D and T2D alpha cells and found the expression of beta2 adrenergic receptor showed significant down-regulation in T1D alpha cells. We confirmed the decreased expression of beta2 adrenergic receptor in alpha cells of the T1D pancreas section, the islets of alphaAtg7KO mice, and a murine alpha cell line with stable knockdown of Atg7. Furthermore, in vivo and ex vivo studies of alphaAtg7KO mice exhibited that lack of autophagy led to the loss of stimulatory effect of beta2-adrenergic signaling on glucagon secretion. Finally, we established the Atg7 knockdown model in sorted human alpha cells and confirmed the effect of autophagy on the expression of the beta2 adrenergic receptor. Together, our study provides novel insights into the regulatory role of autophagy in glucagon secretion in response to hypoglycemia and provides therapeutic options to achieve stable glycemic control in T1D patients.

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Transcriptomic comparison of hyaluronan-stimulated aTC1-6 cells and type 1 diabetes a cells

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