| First Author | Castelblanco E | Year | 2025 |
| Journal | Diabetologia | Volume | 68 |
| Issue | 12 | Pages | 2781-2794 |
| PubMed ID | 40993374 | Mgi Jnum | J:375886 |
| Mgi Id | MGI:8267110 | Doi | 10.1007/s00125-025-06545-w |
| Citation | Castelblanco E, et al. (2025) Restoration of pancreatic beta cell identity and autophagy in K(ATP)-induced diabetes by intermittent fasting. Diabetologia 68(12):2781-2794 |
| abstractText | AIMS/HYPOTHESIS: The loss of pancreatic beta cell mass and identity is a hallmark of diabetes. While factors such as beta cell overwork (insulin hypersecretion) and elevated intracellular calcium have been implicated, beta cell identity loss also occurs in K(ATP) gain-of-function (K(ATP)-GOF) mice, a model of human neonatal diabetes, even in the absence of these factors. This suggests additional underlying mechanisms. Autophagy, a key process for cellular homeostasis, is impaired in the islets and beta cells of both type 1 and type 2 diabetes, but its role in monogenic diabetes with insulin secretory deficiency remains unclear. We hypothesise that autophagy dysfunction contributes to beta cell identity loss in K(ATP)-GOF mice, and that intermittent fasting (IF) can restore autophagic flux, thereby preserving functional beta cell mass. METHODS: To test this, adult tamoxifen-inducible K(ATP)-GOF mice and littermate controls were randomly assigned to two groups: (1) chow diet ad libitum; and (2) chow diet with alternate-day IF. RESULTS: K(ATP)-GOF mice fed ad libitum developed severe hyperglycaemia due to impaired insulin secretion. This was followed by a reduction in insulin content, disruption of beta cell autophagic flux, autophagosome accumulation and, ultimately, the loss of beta cell identity and dedifferentiation. In contrast, K(ATP)-GOF mice subjected to alternate-day IF exhibited lower blood glucose levels, improved mitochondrial morphology, restoration of autophagic flux and reestablishment of beta cell identity. CONCLUSIONS/INTERPRETATION: This study provides the first evidence of autophagy impairment in non-obese, insulin secretory-deficient, K(ATP)-induced diabetes mice and demonstrates that IF restores both autophagic flux and beta cell identity. This finding suggests that similar mechanisms may contribute to beta cell dysfunction in other forms of diabetes. |
