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<p>Compensatory pancreatic islet hyperplasia is an adaptive response to increased systemic insulin demand, although factors meditating this response remain poorly understood. Here, we show that a liver-derived secreted protein, Neuregulin1α, promotes compensatory proliferation of pancreatic β cells in type 2 diabetes. Liver <i>Neuregulin1α</i> expression and serum Neuregulin1α levels increase in male mice fed an obesity-inducing diet. Male mice lacking either <i>Neuregulin1</i> in liver or its receptor, <i>ErbB3</i>, in β cells deteriorate systemic glucose disposal due to impaired β cell expansion with reduced insulin secretion when fed the obesity-inducing diet. Mechanistically, Neuregulin1α activates ERBB2/3-ERK signaling to stimulate β cell proliferation without altering glucose-stimulated insulin secretion potential. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity but without type 2 diabetes serum Neuregulin1α levels increase, while in patient with MASLD and type 2 diabetes show markedly reduced levels of Neuregulin1α. These results suggest that Neuregulin1α serves as a hepatokine that can expand functional β cell mass in type 2 diabetes.</p>

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Liver-derived Neuregulin1α stimulates compensatory pancreatic β cell hyperplasia in insulin resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Takatomo Arai,
  • Eriko Hayashi,
  • Sumie Maeda,
  • Tsutomu Matsubara,
  • Hideki Fujii,
  • Koya Shinohara,
  • Arisu Sogabe,
  • Sadatomo Wainai,
  • Daishi Tanaka,
  • Yutaro Ono,
  • Yumika Ono,
  • Minami Yoshikai,
  • Yuriko Sorimachi,
  • Cindy Yuet-Yin Kok,
  • Masayuki Shimoda,
  • Minoru Tanaka,
  • Norifumi Kawada,
  • Nobuhito Goda

摘要

Compensatory pancreatic islet hyperplasia is an adaptive response to increased systemic insulin demand, although factors meditating this response remain poorly understood. Here, we show that a liver-derived secreted protein, Neuregulin1α, promotes compensatory proliferation of pancreatic β cells in type 2 diabetes. Liver Neuregulin1α expression and serum Neuregulin1α levels increase in male mice fed an obesity-inducing diet. Male mice lacking either Neuregulin1 in liver or its receptor, ErbB3, in β cells deteriorate systemic glucose disposal due to impaired β cell expansion with reduced insulin secretion when fed the obesity-inducing diet. Mechanistically, Neuregulin1α activates ERBB2/3-ERK signaling to stimulate β cell proliferation without altering glucose-stimulated insulin secretion potential. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity but without type 2 diabetes serum Neuregulin1α levels increase, while in patient with MASLD and type 2 diabetes show markedly reduced levels of Neuregulin1α. These results suggest that Neuregulin1α serves as a hepatokine that can expand functional β cell mass in type 2 diabetes.