Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.

Summary

Across human and mouse islets and β-cells, BCKAs suppress GSIS and divert glucose flux from the TCA cycle toward LDHA‑mediated lactate production by directly binding/activating LDHA. Circulating BCKAs inversely correlate with insulin secretory capacity in humans, and lowering BCKAs improves glucose tolerance and GSIS in diabetic mice; β‑cell LDHA ablation rescues BCKA‑induced dysfunction.

Key Findings

• BCKAs inhibit GSIS and glucose flux in human islets, mouse islets, and β-cell lines.
• Circulating BCKAs inversely correlate with insulin secretory capacity in diabetic humans.
• Reducing BCKAs improves glucose tolerance and GSIS in diabetic mice; impaired BCKA catabolism worsens GSIS.
• BCKAs bind LDHA, promote dimerization and activity, redirecting glucose to lactate; β-cell LDHA ablation restores GSIS despite BCKA exposure.

Clinical Implications

Suggests BCKAs as candidate biomarkers of β-cell secretory dysfunction and supports therapeutic strategies to reduce BCKAs or modulate LDHA activity in type 2 diabetes. Nutritional guidance regarding BCAA/BCKA load may merit investigation.

Limitations

• Translational relevance requires clinical interventional studies targeting BCKAs/LDHA.
• Potential sex differences and long-term metabolic consequences need further evaluation.

Future Directions

Prospective human studies to validate BCKAs as biomarkers and test dietary/pharmacologic BCKA lowering or LDHA modulation on β-cell function and glycemic outcomes.