Pancreatic ß-Cell Mass Is Determined by ß-Cell Size after Parturition in Mice

Abstract

During pregnancy, β-cell mass is increased through β-cell hypertrophy and proliferation to adapt to insulin resistance. While β-cell mass is known to return toward non-pregnant levels after parturition, the cellular mechanisms by which β-cell mass is regulated during this period remains unclear. To address this issue in mice, we first quantified β-cell mass throughout the perinatal period using C57BL/6J female mice, and found that increased β-cell mass at gestational day 18 (G18) was significantly reduced at postpartum days 7 (P7), to comparable level with that in age-matched, non-pregnant (NP) female mice. Co-immunostaining for insulin and E-cadherin, which enabled us to precisely measure individual β-cell size, revealed that the mean β-cell size was significantly increased during perinatal periods at G18 and P1 than during non-pregnant state, and robustly decreased at P7. Intriguingly, the mean β-cell size at P7 was slightly but significantly smaller than that in the non-pregnant mice, and then returned to the non-pregnant levels until P21. On the other hand, quantification of apoptosis by TUNEL assay demonstrated that there was no significant difference in the number of apoptotic cells among the groups. To further investigate the contribution of dedifferentiation or transdifferentiation in reduced β-cell mass after parturition, we performed genetic lineage tracing using Ins1-Cre; ROSA26lacZ mice, which resulted in no evidence for transition into other cell types. Taken together, these findings demonstrate that the reduction of β-cell mass after parturition is mainly through reduced β-cell size rather than increased apoptosis or β-to-non-β transition. Disclosure M. Takahashi: None. T. Miyatsuka: Research Support; Self; Eli Lilly and Company, Japan Society for the Promotion of Science, Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Astellas Pharma Inc., MSD K.K., Takeda Pharmaceutical Company Limited.. M. Himuro: None. L. Suzuki: None. M. Miura: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Kowa Pharmaceuticals America, Inc.. T. Katahira: None. Y. Nishida: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, AstraZeneca. A. Itakura: None. S. Takeda: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.