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Different effects of islet transplantation and Detemir treatment on the reversal of streptozotocin-induced diabetes associated with β-cell regeneration

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Abstract

Here we examined whether new β-cell formation occurs when β cells face being severely destroyed and hyperglycemia is restored. Animals were made diabetic by a single i.p. injection of a high dose of streptozotocin, and blood glucose levels were kept in the normal range with twice-daily Detemir (long-acting human insulin analog) injection or islet transplantation for 10 weeks. Although Detemir injection could effectively reverse hyperglycemia and glycemic control was successful, there was no β-cell increase, new formation, or recovery of islet morphology in Detemir-treated mice. In contrast, β-cell regeneration was restored when hyperglycemia was reversed by islet transplantation. The number of β cells and islets was increased, and islet structure was greatly recovered. We further evaluated whether replication or new formation contributes to the recovery. Newly born β cells, as observed as scattered singlets-doublets of insulin-positive cells or clusters of less than 6 β cells across, were frequently seen in transplanted mice, suggesting that neogenesis of β cells was enhanced in transplanted mice. Ki67-positive islets were increased in transplanted mice, suggesting that β-cell proliferation is enhanced. Thus, this recovery involved both increased new formation and replication. Our results suggest that the effects of Detemir on pancreatic β cells were very different from those of islet transplantation and that islet transplantation could be a trigger for the induction of new formation and replication.

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Acknowledgments

We thank Minako Kimura, Rie Matsuoka, and Yo King for excellent technical assistance, and Dr. Gordon C. Weir (Joslin Diabetes Center, Boston, MA, USA) for helpful discussions. We appreciate support from The Kyushu University Research Superstar Program (Drs. Koichi Akashi, Yukitaka Murakami, Hiroshi Gushima, and Kotoku Kurachi), Research Support Center (Dr. Takehiko Yokomizo), and Confocal Core (LSM510META; Dr. Atsushi Takahara). This study was supported by a Grant-in-Aid for Scientific Research (21790285), Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Kyushu University Program Project (P&P), Kyushu University Foundation, Takeda Science Foundation, Astellas Foundation for Research on Metabolic Disorders, and Novo Nordisk Pharma Insulin Award.

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  1. Katsuo Sueishi

    Present address: National Hospital Organization Fukuoka-Higashi Medical Center, Fukuoka, Japan

Authors and Affiliations

  1. Section of Diabetes and Genes, Stem Cell Unit, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Akari Inada & Oogi Inada

  2. Division of Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hiroshi Fujii & Katsuo Sueishi

  3. Medical Shimada Hospital, Fukuoka, Japan

    Tomoyuki Akashi

  4. Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Atsushi Fukatsu

  5. Laboratory of Viral and Molecular Immunology of Diabetes, Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Seiho Nagafuchi

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  1. Akari Inada
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Correspondence to Akari Inada.

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Inada, A., Inada, O., Fujii, H. et al. Different effects of islet transplantation and Detemir treatment on the reversal of streptozotocin-induced diabetes associated with β-cell regeneration. Diabetol Int 1, 49–59 (2010). https://doi.org/10.1007/s13340-010-0005-8

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