Effect of diabetes mellitus on levels of insulin-like growth factors and their carrier proteins in Guerin’s carcinoma and it’s perifocal tissue in rats

Purpose of the study. Diabetes mellitus (DM) is considered an independent risk factor for higher cancer incidence and death rates. The system of insulin-like growth factors and their carrier proteins (IGF and IGFBP) and hyperglycemia create favorable conditions for the proliferation and metastasis of cancer cells.

Materials and methods. Outbred male and female rats were divided into groups (n = 8 each): controls - with Guerin's carcinoma; main group - Guerin's carcinoma growing in presence of DM. Experimental DM was reproduces in animals by the single intraperitoneal alloxan injection (150 mg/kg body weight). After 10 days of the carcinoma growth, levels of IGF and IGFBP in the tumor and in it's perifocal area were measured using ELISA.

Results. DM in females upregulated levels of glucose both in the tumor and in perifocal tissues by 1.8 (p < 0.05) and 8.1 times, respectively, but caused opposite changes in IGF-I - it's increase by 6.3 times in the tumor and decrease by 3.2 times in the perifocal area; as a result, such tumors with small primary nodes were more "aggressive" and actively metastasized. In males, induced DM downregulated levels of glucose, IGF-II and IGFBP2 in the carcinoma by 8.4, 3.1 and 1.7 (p < 0.05) times, respectively, and increased levels of IGF-I and IGFBP2 by 1.4 and 1.3 times (p < 0.05) in the perifocal area without changing glucose levels; as a result, tumor volumes exceeded the values in the standard growth, without metastasizing into visceral organs.

Conclusion. We revealed gender differences in changing levels of glucose and IGF both in the tumor and in it's perifocal tissue in rats with Guerin's carcinoma growing in presence of DM; these differences could determine different tumor growth dynamics in male and female rats.

1. Wang M, Yang Y, Liao Z. Diabetes and cancer: Epidemiological and biological links. World J Diabetes. 2020 Jun 15;11(6):227-238. https://doi.org/10.4239/wjd.v11.i6.227

2. Gonzalez-Molina J, Gramolelli S, Liao Z, Carlson JW, Ojala PM, Lehti K. MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues. Cells. 2019 Aug 28;8(9):991. https://doi.org/10.3390/cells8090991

3. Yang Y, Yang T, Liu S, Cao Z, Zhao Y, Su X, et al. Concentrated ambient PM2.5 exposure affects mice sperm quality and testosterone biosynthesis. PeerJ. 2019;7:e8109. https://doi.org/10.7717/peerj.8109

4. Argon Y, Bresson SE, Marzec MT, Grimberg A. Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production. Cells. 2020 Aug 6;9(8):1844. https://doi.org/10.3390/cells9081844

5. Dauber A, Munoz-Calvo MT, Barrios V, Domene HM, Kloverpris S, Serra-Juhe C, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Apr 1;8(4):363-374. https://doi.org/10.15252/emmm.201506106

6. Chanson P, Arnoux A, Mavromati M, Brailly-Tabard S, Massart C, Young J, et al. Reference Values for IGF-I Serum Concentrations: Comparison of Six Immunoassays. J Clin Endocrinol Metab. 2016 Sep;101(9):3450-3458. https://doi.org/10.1210/jc.2016-1257

7. Collins KK. The diabetes-cancer link. Diabetes Spectr. 2014 Nov;27(4):276-280. https://doi.org/10.2337/diaspect.27.4.276

8. Kit OI, Frantsiyants EM, Bandovkina VA, Shatova YS, Komarova EF, Vereskunova MI, et al. The sex hormone's and prolactin's level in the tissue of breast cancer among the patients of different age. Fundamental Research. 2013;(7-3):560-564. (In Russ.).

9. Zhukova GV, Shikhliarova AI, Sagakyants AB, Protasova TP. about expanding options for using BALB/c nude mice for experimental study of human malignant tumors in vivo. South Russian Journal of Cancer. 2020;1(2):28-35. (In Russ.). https://doi.org/10.37748/2687-0533-2020-1-2-4

10. Sarfstein R, Pasmanik-Chor M, Yeheskel A, Edry L, Shomron N, Warman N, et al. Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells. J Biol Chem. 2012 Jan 20;287(4):2766-2776. https://doi.org/10.1074/jbc.M111.281782

11. Dyshlovoy SA, Pelageev DN, Hauschild J, Sabutskii YE, Khmelevskaya EA, Krisp C, et al. Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer. Mar Drugs. 2020 May 11;18(5):251. https://doi.org/10.3390/md18050251

12. Pant K, Richard S, Peixoto E, Gradilone SA. Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcino-ma. Front Med (Lausanne). 2020;7:113. https://doi.org/10.3389/fmed.2020.00113

13. Poreba E, Durzynska J. Nuclear localization and actions of the insulin-like growth factor 1 (IGF-1) system components: Transcriptional regulation and DNA damage response. Mutat Res Rev Mutat Res. 2020 Jun;784:108307. https://doi.org/10.1016Zj.mrrev.2020.108307

14. Allard JB, Duan C. IGF-Binding Proteins: Why Do They Exist and Why Are There So Many? Front Endocrinol (Lausanne). 2018;9:117. https://doi.org/10.3389/fendo.2018.00117

15. Vassilakos G, Lei H, Yang Y, Puglise J, Matheny M, Durzynska J, et al. Deletion of muscle IGF-I transiently impairs growth and progressively disrupts glucose homeostasis in male mice. FASEB J. 2019 Jan;33(1):181-194. https://doi.org/10.1096/fj.201800459R