Scholarlink

Aims/hypothesis <p>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 <i>K</i><sub><i>ATP</i></sub><i> gain-of-function</i> (<i>K</i><sub><i>ATP</i></sub><i>-GOF</i>) 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 <i>K</i><sub><i>ATP</i></sub><i>-GOF</i> mice, and that intermittent fasting (IF) can restore autophagic flux, thereby preserving functional beta cell mass.</p> Methods <p>To test this, adult tamoxifen-inducible <i>K</i><sub><i>ATP</i></sub><i>-GOF</i> mice and littermate controls were randomly assigned to two groups: (1) chow diet ad libitum; and (2) chow diet with alternate-day IF.</p> Results <p><i>K</i><sub><i>ATP</i></sub><i>-GOF</i> 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, <i>K</i><sub><i>ATP</i></sub><i>-GOF</i> mice subjected to alternate-day IF exhibited lower blood glucose levels, improved mitochondrial morphology, restoration of autophagic flux and reestablishment of beta cell identity.</p> Conclusions/interpretation <p>This study provides the first evidence of autophagy impairment in non-obese, insulin secretory-deficient, <i>K</i><sub><i>ATP</i></sub>-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.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Restoration of pancreatic beta cell identity and autophagy in KATP-induced diabetes by intermittent fasting

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月25日

查看全文
  • Esmeralda Castelblanco,
  • Zeenat A. Shyr,
  • Irving Ramirez-Sotero,
  • Zihan Yan,
  • Sophia X. Chen,
  • Abhinav Diwan,
  • Maria S. Remedi

摘要

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 KATP gain-of-function (KATP-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 KATP-GOF mice, and that intermittent fasting (IF) can restore autophagic flux, thereby preserving functional beta cell mass.

Methods

To test this, adult tamoxifen-inducible KATP-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

KATP-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, KATP-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, KATP-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.

Graphical Abstract