Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes
Abstract Background To evaluate the effect of insulin treatment on the incidence and/or severity of hepatocellular carcinoma (HCC) in a mouse model of HCC based on diabetes. Methods We recently reported that neonatal streptozotocin (STZ) treatment causes type 1 diabetes and subsequent HCC in ddY, In...
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| Format: | Article |
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BMC
2017-09-01
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| Series: | BMC Research Notes |
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| Online Access: | http://link.springer.com/article/10.1186/s13104-017-2783-6 |
| _version_ | 1811218468156997632 |
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| author | Hayato Baba Makoto Kurano Takeshi Nishida Hideki Hatta Ryoji Hokao Koichi Tsuneyama |
| author_facet | Hayato Baba Makoto Kurano Takeshi Nishida Hideki Hatta Ryoji Hokao Koichi Tsuneyama |
| author_sort | Hayato Baba |
| collection | DOAJ |
| description | Abstract Background To evaluate the effect of insulin treatment on the incidence and/or severity of hepatocellular carcinoma (HCC) in a mouse model of HCC based on diabetes. Methods We recently reported that neonatal streptozotocin (STZ) treatment causes type 1 diabetes and subsequent HCC in ddY, Institute for Animal Reproduction (DIAR) mice. Newborn male DIAR mice were divided into three groups based on STZ and insulin (INS) treatment. STZ was subcutaneously injected (60 mg/g) into the STZ-treated group (DIAR-nSTZ mice, N = 13) and the STZ/insulin-treated group (DIAR-nSTZ/INS mice, N = 20). A physiologic solution was injected into the control group (DIAR-control mice, N = 8) 1.5 days after birth. Insulin was subcutaneously injected into the DIAR-nSTZ/INS mice according to the following protocol: 2 IU/day at 4–5 weeks of age, 3 IU/day at 5–7 weeks of age, and 4 IU/day at 7–12 weeks of age. All mice were fed a normal diet and were subjected to physiological and histopathological assessments at 12 weeks of age. Results DIAR-nSTZ mice had significantly lower body weight and higher blood glucose levels than DIAR-control mice, whereas no significant differences were observed between DIAR-nSTZ/INS mice and control mice. At 12 weeks of age, lower weight of paratesticular fat and higher levels of total cholesterol, triglyceride, and free fatty acids were observed in DIAR-nSTZ mice compared to DIAR-control mice, whereas there were no significant differences between DIAR-nSTZ/INS mice and DIAR-control mice. In the livers of DIAR-nSTZ mice, HCC was observed in 15% of cases, and dysplastic nodules were observed in 77% of cases. In the livers of DIAR-nSTZ/INS mice, HCC was observed in 39% of cases and dysplastic nodules were observed in 61% of cases (p = 0.011). Moreover, the average tumor size was significantly larger in STZ/INS-treated mice than in STZ-treated mice. Immunohistochemical analysis demonstrated that the expression of ERK1/2, downstream substrates of insulin signaling that activate cell proliferation, was significantly higher in STZ/INS-treated mice compared to STZ-treated mice. Conclusions Insulin treatment promoted, rather than inhibited, the progression of liver carcinogenesis in DIAR-nSTZ mice. Hyperinsulinemia rather than hyperglycemia can accelerate the progression of HCC via insulin signaling. |
| first_indexed | 2024-04-12T07:09:24Z |
| format | Article |
| id | doaj.art-51c1d86c3e154215bbe0906c1b4a1fe3 |
| institution | Directory Open Access Journal |
| issn | 1756-0500 |
| language | English |
| last_indexed | 2024-04-12T07:09:24Z |
| publishDate | 2017-09-01 |
| publisher | BMC |
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| spelling | doaj.art-51c1d86c3e154215bbe0906c1b4a1fe32022-12-22T03:42:40ZengBMCBMC Research Notes1756-05002017-09-011011710.1186/s13104-017-2783-6Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetesHayato Baba0Makoto Kurano1Takeshi Nishida2Hideki Hatta3Ryoji Hokao4Koichi Tsuneyama5Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate SchoolDepartment of Clinical Laboratory Medicine, The University of TokyoDepartment of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of ToyamaDepartment of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of ToyamaInstitute for Animal ReproductionDepartment of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate SchoolAbstract Background To evaluate the effect of insulin treatment on the incidence and/or severity of hepatocellular carcinoma (HCC) in a mouse model of HCC based on diabetes. Methods We recently reported that neonatal streptozotocin (STZ) treatment causes type 1 diabetes and subsequent HCC in ddY, Institute for Animal Reproduction (DIAR) mice. Newborn male DIAR mice were divided into three groups based on STZ and insulin (INS) treatment. STZ was subcutaneously injected (60 mg/g) into the STZ-treated group (DIAR-nSTZ mice, N = 13) and the STZ/insulin-treated group (DIAR-nSTZ/INS mice, N = 20). A physiologic solution was injected into the control group (DIAR-control mice, N = 8) 1.5 days after birth. Insulin was subcutaneously injected into the DIAR-nSTZ/INS mice according to the following protocol: 2 IU/day at 4–5 weeks of age, 3 IU/day at 5–7 weeks of age, and 4 IU/day at 7–12 weeks of age. All mice were fed a normal diet and were subjected to physiological and histopathological assessments at 12 weeks of age. Results DIAR-nSTZ mice had significantly lower body weight and higher blood glucose levels than DIAR-control mice, whereas no significant differences were observed between DIAR-nSTZ/INS mice and control mice. At 12 weeks of age, lower weight of paratesticular fat and higher levels of total cholesterol, triglyceride, and free fatty acids were observed in DIAR-nSTZ mice compared to DIAR-control mice, whereas there were no significant differences between DIAR-nSTZ/INS mice and DIAR-control mice. In the livers of DIAR-nSTZ mice, HCC was observed in 15% of cases, and dysplastic nodules were observed in 77% of cases. In the livers of DIAR-nSTZ/INS mice, HCC was observed in 39% of cases and dysplastic nodules were observed in 61% of cases (p = 0.011). Moreover, the average tumor size was significantly larger in STZ/INS-treated mice than in STZ-treated mice. Immunohistochemical analysis demonstrated that the expression of ERK1/2, downstream substrates of insulin signaling that activate cell proliferation, was significantly higher in STZ/INS-treated mice compared to STZ-treated mice. Conclusions Insulin treatment promoted, rather than inhibited, the progression of liver carcinogenesis in DIAR-nSTZ mice. Hyperinsulinemia rather than hyperglycemia can accelerate the progression of HCC via insulin signaling.http://link.springer.com/article/10.1186/s13104-017-2783-6Diabetes mellitusHepatocellular carcinomaInsulinHyperinsulinemiaHyperglycemia |
| spellingShingle | Hayato Baba Makoto Kurano Takeshi Nishida Hideki Hatta Ryoji Hokao Koichi Tsuneyama Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes BMC Research Notes Diabetes mellitus Hepatocellular carcinoma Insulin Hyperinsulinemia Hyperglycemia |
| title | Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| title_full | Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| title_fullStr | Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| title_full_unstemmed | Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| title_short | Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| title_sort | facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes |
| topic | Diabetes mellitus Hepatocellular carcinoma Insulin Hyperinsulinemia Hyperglycemia |
| url | http://link.springer.com/article/10.1186/s13104-017-2783-6 |
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