Pancreatic β cell TRAPδ deficiency reduces insulin production but improves insulin sensitivity

Abstract

The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β cells. However, its pathophysiological significance in maintaining islet β cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β cell-specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that, while TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin/proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues.

Article Highlights

l TRAPδ plays a pivotal role in insulin biosynthesis and potentially contributes to β cell survival in type 2 diabetes mellitus. Nevertheless, its specific function in preserving islet β cell function in vivo has yet to be fully explored and elucidated.

l Specific knockout of TRAPδ in pancreatic β cells leads to a decrease in proinsulin and insulin content within the islets, subsequently resulting in a slight reduction of serum insulin levels. Remarkably, despite this insulin decrease, euglycemia is preserved.

l The moderate decrease in circulating insulin levels may potentially enhance insulin sensitivity in insulin target tissues.