Mulberry twig (Sangzhi) alkaloids induce pancreatic α-to-β-cell phenotypic conversion in type 2 diabetic mice

Pancreatic β-cell regeneration represents a promising therapeutic strategy for diabetes, yet safe and effective treatments remain elusive.

We aimed to investigate whether and how mulberry twig (Sangzhi) alkaloids (SZ-A), a newly approved anti-diabetic Chinese medicine, promoted β-cell regeneration.

Diabetic db/db mice and pancreatic α-cell lineage-tracing mice were treated with SZ-A, acarbose, or vehicle daily via intragastric gavage. Blood glucose and plasma insulin levels were measured. The areas of islets, α-cells and β-cells were quantified. Cell transdifferentiation was assessed by double-immunostaining of glucagon or α-cell lineage-tracing marker with β-cell-specific markers. Mouse α-cells were incubated with SZ-A or its three main components, and the mRNA levels of cell transdifferentiation-related genes were detected. RNA-sequencing was performed to screen potential targets. The activities of five mitochondrial complexes were detected following treatment, and specific inhibitor was utilized to validate the involvement.

Both SZ-A and acarbose improved glycemic control, but only SZ-A enlarged islet and β-cell areas in the diabetic mice. SZ-A induced α-to-β-cell conversion, as indicated by glucagon and insulin double-immunostaining and confirmed by α-cell lineage-tracing. In cultured α-cells, SZ-A and its main component 1-deoxynojirimycin (DNJ) downregulated the expressions of α-cell-specific markers, while upregulated the expressions of β-cell-specific markers. DNJ-induced differentially expressed genes were enriched in the mitochondrial protein complex term. DNJ inhibited mitochondrial complex I activity, and the complex inhibitor induced α-to-β-cell conversion.

SZ-A, especially its main component DNJ, induces α-to-β-cell transdifferentiation via inhibiting mitochondrial complex I. Our finding provides a potential strategy for β-cell regeneration and diabetes treatment.