Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells
IntroductionThe enhanced β-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks includin...
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| Format: | Article |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1203534/full |
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| author | Kanako Iwasaki Kanako Iwasaki Benjamin Lalani Jiho Kahng Priscila Carapeto Stephanie Sanjines Francesko Hela Cristian Abarca Tadataka Tsuji Justin Darcy Andrzej Bartke Yu-Hua Tseng Rohit N. Kulkarni Cristina Aguayo-Mazzucato |
| author_facet | Kanako Iwasaki Kanako Iwasaki Benjamin Lalani Jiho Kahng Priscila Carapeto Stephanie Sanjines Francesko Hela Cristian Abarca Tadataka Tsuji Justin Darcy Andrzej Bartke Yu-Hua Tseng Rohit N. Kulkarni Cristina Aguayo-Mazzucato |
| author_sort | Kanako Iwasaki |
| collection | DOAJ |
| description | IntroductionThe enhanced β-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in β-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human β-cells is a marker of older β-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined.MethodsIn this study, we explored the direct role of IGF1R in β-cell function and senescence using two independent mouse models with decreased IGF1/IGF1R signaling: a) Ames Dwarf mice (Dwarf +/+), which lack growth hormone and therefore have reduced circulating levels of IGF1, and b) inducible β-cell-specific IGF1R knockdown (βIgf1rKD) mice.ResultsCompared to Dwarf+/- mice, Dwarf+/+ mice had lower body and pancreas weight, lower circulating IGF1 and insulin levels, and lower IGF1R and p21Cip1 protein expression in β-cells, suggesting the suppression of senescence. Adult βIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in β-cells. RNA-Seq of islets isolated from these βIgf1rKD mice revealed the restoration of three signaling pathways known to be downregulated by aging: sulfide oxidation, autophagy, and mTOR signaling. Additionally, deletion of IGF1R in mouse β-cells increased transcription of genes important for maintaining β-cell identity and function, such as Mafa, Nkx6.1, and Kcnj11, while decreasing senescence-related genes, such as Cdkn2a, Il1b, and Serpine 1. Decreased senescence and improved insulin-secretory function of β-cells were also evident when the βIgf1rKD mice were fed a high-fat diet (HFD; 60% kcal from fat, for 5 weeks).DiscussionThese results suggest that IGF1R signaling plays a causal role in aging-induced β-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic β-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore β-cell function and identity, therefore preventing the progression to T2D. |
| first_indexed | 2024-03-13T02:59:54Z |
| format | Article |
| id | doaj.art-a9c12083d3e244c1aa69f5f508cb46b4 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-13T02:59:54Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-a9c12083d3e244c1aa69f5f508cb46b42023-06-27T15:28:37ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-06-011410.3389/fendo.2023.12035341203534Decreased IGF1R attenuates senescence and improves function in pancreatic β-cellsKanako Iwasaki0Kanako Iwasaki1Benjamin Lalani2Jiho Kahng3Priscila Carapeto4Stephanie Sanjines5Francesko Hela6Cristian Abarca7Tadataka Tsuji8Justin Darcy9Andrzej Bartke10Yu-Hua Tseng11Rohit N. Kulkarni12Cristina Aguayo-Mazzucato13Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesMedical Research Institute, Kitano Hospital, Osaka, JapanSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesDepartment of Internal Medicine, Division of Geriatrics Research, Department of Medicine, Southern Illinois University School of Medicine, Springfield, IL, United StatesSection on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesSection on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United StatesIntroductionThe enhanced β-cell senescence that accompanies insulin resistance and aging contributes to cellular dysfunction and loss of transcriptional identity leading to type 2 diabetes (T2D). While senescence is among the 12 recognized hallmarks of aging, its relation to other hallmarks including altered nutrient sensing (insulin/IGF1 pathway) in β-cells is not fully understood. We previously reported that an increased expression of IGF1R in mouse and human β-cells is a marker of older β-cells; however, its contribution to age-related dysfunction and cellular senescence remains to be determined.MethodsIn this study, we explored the direct role of IGF1R in β-cell function and senescence using two independent mouse models with decreased IGF1/IGF1R signaling: a) Ames Dwarf mice (Dwarf +/+), which lack growth hormone and therefore have reduced circulating levels of IGF1, and b) inducible β-cell-specific IGF1R knockdown (βIgf1rKD) mice.ResultsCompared to Dwarf+/- mice, Dwarf+/+ mice had lower body and pancreas weight, lower circulating IGF1 and insulin levels, and lower IGF1R and p21Cip1 protein expression in β-cells, suggesting the suppression of senescence. Adult βIgf1rKD mice showed improved glucose clearance and glucose-induced insulin secretion, accompanied by decreased p21Cip1 protein expression in β-cells. RNA-Seq of islets isolated from these βIgf1rKD mice revealed the restoration of three signaling pathways known to be downregulated by aging: sulfide oxidation, autophagy, and mTOR signaling. Additionally, deletion of IGF1R in mouse β-cells increased transcription of genes important for maintaining β-cell identity and function, such as Mafa, Nkx6.1, and Kcnj11, while decreasing senescence-related genes, such as Cdkn2a, Il1b, and Serpine 1. Decreased senescence and improved insulin-secretory function of β-cells were also evident when the βIgf1rKD mice were fed a high-fat diet (HFD; 60% kcal from fat, for 5 weeks).DiscussionThese results suggest that IGF1R signaling plays a causal role in aging-induced β-cell dysfunction. Our data also demonstrate a relationship between decreased IGF1R signaling and suppressed cellular senescence in pancreatic β-cells. Future studies can further our understanding of the interaction between senescence and aging, developing interventions that restore β-cell function and identity, therefore preventing the progression to T2D.https://www.frontiersin.org/articles/10.3389/fendo.2023.1203534/fullsenescenceSASPIGF-1insulinDwarfdiabetes mellitus |
| spellingShingle | Kanako Iwasaki Kanako Iwasaki Benjamin Lalani Jiho Kahng Priscila Carapeto Stephanie Sanjines Francesko Hela Cristian Abarca Tadataka Tsuji Justin Darcy Andrzej Bartke Yu-Hua Tseng Rohit N. Kulkarni Cristina Aguayo-Mazzucato Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells Frontiers in Endocrinology senescence SASP IGF-1 insulin Dwarf diabetes mellitus |
| title | Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells |
| title_full | Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells |
| title_fullStr | Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells |
| title_full_unstemmed | Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells |
| title_short | Decreased IGF1R attenuates senescence and improves function in pancreatic β-cells |
| title_sort | decreased igf1r attenuates senescence and improves function in pancreatic β cells |
| topic | senescence SASP IGF-1 insulin Dwarf diabetes mellitus |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1203534/full |
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