Outbred Mice with Streptozotocin-Induced Diabetes Show Sex Differences in Glucose Metabolism

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Mar 29

PMID 36982285

Authors

Boyoung Kim

Eun-Sun Park

Jong-Sun Lee

Jun-Gyo Suh

Affiliations

Soon will be listed here.

Abstract

Outbred mice (ICR) with different genotypes and phenotypes have been reported to be more suitable for scientific testing than inbred mice because they are more similar to humans. To investigate whether the sex and genetic background of the mice are important factors in the development of hyperglycemia, we used ICR mice and divided them into male, female, and ovariectomized female (FOVX) groups and treated them with streptozotocin (STZ) for five consecutive days to induce diabetes. Our results show that fasting blood glucose and hemoglobin A (HbA) levels were significantly higher in diabetes-induced males (M-DM) and ovariectomized diabetes-induced females (FOVX-DM) than in diabetes-induced females (F-DM) at 3 and 6 weeks after STZ treatment. Furthermore, the M-DM group showed the most severe glucose tolerance, followed by the FOVX-DM and F-DM groups, suggesting that ovariectomy affects glucose tolerance in female mice. The size of pancreatic islets in the M-DM and FOVX-DM groups was significantly different from that of the F-DM group. The M-DM and FOVX-DM groups had pancreatic beta-cell dysfunction 6 weeks after STZ treatment. Urocortin 3 and somatostatin inhibited insulin secretion in the M-DM and FOVX-DM groups. Overall, our results suggest that glucose metabolism in mice is dependent on sex and/or genetic background.

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References

Le May C, Chu K, Hu M, Ortega C, Simpson E, Korach K . Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci U S A. 2006; 103(24):9232-7. PMC: 1482595. DOI: 10.1073/pnas.0602956103. View

Li C, Chen P, Vaughan J, Lee K, Vale W . Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. Proc Natl Acad Sci U S A. 2007; 104(10):4206-11. PMC: 1820733. DOI: 10.1073/pnas.0611641104. View

Li C, Chen P, Vaughan J, Blount A, Chen A, Jamieson P . Urocortin III is expressed in pancreatic beta-cells and stimulates insulin and glucagon secretion. Endocrinology. 2003; 144(7):3216-24. DOI: 10.1210/en.2002-0087. View

Mauvais-Jarvis F, Le May C, Tiano J, Liu S, Kilic-Berkmen G, Kim J . The Role of Estrogens in Pancreatic Islet Physiopathology. Adv Exp Med Biol. 2017; 1043:385-399. DOI: 10.1007/978-3-319-70178-3_18. View

Taylor K, Gordon N, Langley G, Higgins W . Estimates for worldwide laboratory animal use in 2005. Altern Lab Anim. 2008; 36(3):327-42. DOI: 10.1177/026119290803600310. View

Remedi M, Emfinger C . Pancreatic β-cell identity in diabetes. Diabetes Obes Metab. 2016; 18 Suppl 1:110-6. PMC: 5021188. DOI: 10.1111/dom.12727. View

Festing M . Evidence should trump intuition by preferring inbred strains to outbred stocks in preclinical research. ILAR J. 2014; 55(3):399-404. DOI: 10.1093/ilar/ilu036. View

van der Meulen T, Xie R, Kelly O, Vale W, Sander M, Huising M . Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS One. 2012; 7(12):e52181. PMC: 3522648. DOI: 10.1371/journal.pone.0052181. View

Festing M . Phenotypic variability of inbred and outbred mice. Nature. 1976; 263(5574):230-2. DOI: 10.1038/263230a0. View

10.

Enriquez J, Mims B, Trasti S, Furr K, Grisham M . Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery. BMC Immunol. 2020; 21(1):50. PMC: 7464063. DOI: 10.1186/s12865-020-00380-x. View

11.

Wang S, Chen L, Wang Q, He Z, Chen S, Zhang H . Strain differences between CD-1 and C57BL/6 mice in expression of metabolic enzymes and DNA methylation modifications of the primary hepatocytes. Toxicology. 2018; 412:19-28. DOI: 10.1016/j.tox.2018.11.011. View

12.

Blum B, Roose A, Barrandon O, Maehr R, Arvanites A, Davidow L . Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway. Elife. 2014; 3:e02809. PMC: 4204634. DOI: 10.7554/eLife.02809. View

13.

Tuttle A, Philip V, Chesler E, Mogil J . Comparing phenotypic variation between inbred and outbred mice. Nat Methods. 2018; 15(12):994-996. PMC: 6518396. DOI: 10.1038/s41592-018-0224-7. View

14.

Bryda E . The Mighty Mouse: the impact of rodents on advances in biomedical research. Mo Med. 2013; 110(3):207-11. PMC: 3987984. View

15.

Furman B . Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol. 2015; 70:5.47.1-5.47.20. DOI: 10.1002/0471141755.ph0547s70. View

16.

van der Meulen T, Donaldson C, Caceres E, Hunter A, Cowing-Zitron C, Pound L . Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat Med. 2015; 21(7):769-76. PMC: 4496282. DOI: 10.1038/nm.3872. View

17.

van der Meulen T, Huising M . Role of transcription factors in the transdifferentiation of pancreatic islet cells. J Mol Endocrinol. 2015; 54(2):R103-17. PMC: 4373662. DOI: 10.1530/JME-14-0290. View

18.

De Paoli M, Werstuck G . Role of Estrogen in Type 1 and Type 2 Diabetes Mellitus: A Review of Clinical and Preclinical Data. Can J Diabetes. 2020; 44(5):448-452. DOI: 10.1016/j.jcjd.2020.01.003. View

19.

Martin M, Danahy D, Hartwig S, Harty J, Badovinac V . Revealing the Complexity in CD8 T Cell Responses to Infection in Inbred C57B/6 versus Outbred Swiss Mice. Front Immunol. 2017; 8:1527. PMC: 5702636. DOI: 10.3389/fimmu.2017.01527. View