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

Summary

In db/db mice, Sangzhi alkaloids (SZ-A) improved glycemia and uniquely expanded β-cell area by inducing α-to-β-cell conversion, confirmed by lineage tracing and double immunostaining. Mechanistically, the main component 1-deoxynojirimycin (DNJ) promotes transdifferentiation by inhibiting mitochondrial complex I and reprogramming α- to β-cell gene expression.

Key Findings

• SZ-A improved glycemic control and increased islet and β-cell area in db/db mice, whereas acarbose did not enlarge β-cell area.
• Lineage tracing and double immunostaining confirmed α-to-β-cell conversion after SZ-A treatment.
• DNJ downregulated α-cell markers and upregulated β-cell markers in cultured α-cells.
• RNA-seq implicated mitochondrial protein complexes; DNJ inhibited mitochondrial complex I, and complex I inhibition induced α-to-β conversion.

Clinical Implications

Although preclinical, targeting mitochondrial complex I to induce α-to-β-cell conversion could inspire regenerative therapies for type 2 diabetes and inform optimization of current SZ-A use.

Limitations

• Preclinical mouse and cell models without human islet or clinical validation.
• Potential off-target and safety concerns of mitochondrial complex I inhibition not addressed long-term.

Future Directions

Validate α-to-β conversion and functional insulin secretion in human islets, assess safety/efficacy in large animals, and explore combination regimens optimizing DNJ dosing and delivery.