Ins2-KO Mouse

Ins2, the insulin 2 gene, is crucial for insulin production. In rats, it is one of two genes (along with Ins1) coding for insulin on chromosome 1 [8]. Insulin is essential for regulating glucose metabolism, and the Ins2-related insulin secretion pathway is fundamental for maintaining normal blood glucose levels. Genetic mouse models are valuable tools for studying Ins2 function [3,4,6,9].

In Ins2GFP knockin mice, live-cell imaging and other techniques showed that Ins2 gene activity is dynamic in β-cells. About 25% of β-cells had higher Ins2 activity at a given time, with some cells oscillating in activity, and glucose stimulation increased oscillation and average gene activity. Also, Ins2(GFP)HIGH β-cells were enriched for β-cell maturity markers but less viable under stress [1]. In Ins2Akita/wt mice, GSK3β inhibition reduced vascular calcification by redirecting endothelial-derived osteoblast-like cells back to the endothelial lineage [2]. In Ins2+/- Akita (T1DM) mice, overexpression of cardiac-specific miR-133a was proposed to prevent the progression of diabetic cardiomyopathy (DMCM) [3]. In Ins2+/Akita mice (a diabetes model), there was impaired mechanical and thermal nociception, loss of intraepidermal nerve fibers, and reduced heat responsiveness in dorsal root ganglion neurons, which could be reversed by islet transplantation [4]. Genetic deletion of Ins2 in retinal pigment epithelium (RPE) cells decreased retinal glucose uptake, dysregulated retinal physiology, and exacerbated photoreceptor loss, as RPE-derived Ins2 is stimulated by phagocytosis of photoreceptor outer segments [5]. NOD.Ins2(-/-) mice showed accelerated disease and increased CD8+ T cell responses to preproinsulin, and NOD.β2m(-/-).HHD.Ins2(-/-) mice were proposed as an improved humanized disease model for type 1 diabetes [6]. In Wnt/β-catenin signaling knockout mice, there was a notable increase in INS2 expression in adulthood, especially near the oral cavity, indicating that this pathway may affect Ins2 cell migration [7]. In the insulinoma cell line Rin-5F, overexpression of the PTEN gene increased Ins2 gene mRNA expression [8]. The KINGS Ins2 +/G32S mouse, with a mutation in Ins2, developed spontaneous hyperglycemia, had β-cell endoplasmic reticulum stress, and may be useful for studying β-cell responses to ER stress [9].

In conclusion, Ins2 is essential for insulin production and glucose metabolism. Studies using Ins2-related mouse models, such as knockout and mutant models, have revealed its role in various biological processes and disease conditions, including diabetes, vascular calcification, diabetic cardiomyopathy, sensory neuropathy, retinal physiology, and type 1 diabetes immunopathology. These models contribute significantly to understanding the mechanisms underlying these diseases and developing potential therapeutic strategies.

References:

1. Chu, Chieh Min Jamie, Modi, Honey, Ellis, Cara, Lynn, Francis C, Johnson, James D. . Dynamic Ins2 Gene Activity Defines β-Cell Maturity States. In Diabetes, 71, 2612-2631. doi:10.2337/db21-1065. https://pubmed.ncbi.nlm.nih.gov/36170671/

2. Boström, Kristina I, Qiao, Xiaojing, Zhao, Yan, Cai, Xinjiang, Yao, Yucheng. 2023. GSK3β Inhibition Reduced Vascular Calcification in Ins2Akita/+ Mice. In International journal of molecular sciences, 24, . doi:10.3390/ijms24065971. https://pubmed.ncbi.nlm.nih.gov/36983045/

3. Shahshahan, Hamid R, Kambis, Tyler N, Kar, Sumit, Yadav, Santosh K, Mishra, Paras K. . Generating Ins2+/-/miR-133aTg Mice to Model miRNA-Driven Cardioprotection of Human Diabetic Heart. In Methods in molecular biology (Clifton, N.J.), 2224, 113-121. doi:10.1007/978-1-0716-1008-4_8. https://pubmed.ncbi.nlm.nih.gov/33606210/

4. Vastani, Nisha, Guenther, Franziska, Gentry, Clive, Bevan, Stuart, Andersson, David A. 2018. Impaired Nociception in the Diabetic Ins2+/Akita Mouse. In Diabetes, 67, 1650-1662. doi:10.2337/db17-1306. https://pubmed.ncbi.nlm.nih.gov/29875100/

5. Iker Etchegaray, J, Kelley, Shannon, Penberthy, Kristen, Ambati, Jayakrishna, Ravichandran, Kodi S. 2023. Phagocytosis in the retina promotes local insulin production in the eye. In Nature metabolism, 5, 207-218. doi:10.1038/s42255-022-00728-0. https://pubmed.ncbi.nlm.nih.gov/36732622/

6. Jarchum, Irene, DiLorenzo, Teresa P. 2009. Ins2 deficiency augments spontaneous HLA-A*0201-restricted T cell responses to insulin. In Journal of immunology (Baltimore, Md. : 1950), 184, 658-65. doi:10.4049/jimmunol.0903414. https://pubmed.ncbi.nlm.nih.gov/19966211/

7. Xiang, Ke-Zhen, Yan, Luan, Yang, De-Qin. 2025. INS2 lineage cell tracking and insulin expression in the related organs of mice. In Scientific reports, 15, 9164. doi:10.1038/s41598-025-92993-8. https://pubmed.ncbi.nlm.nih.gov/40097501/

8. Kiba, T. 2024. OVEREXPRESSION OF PTEN GENE INCREASES INS2 GENE MRNA EXPRESSION, NOT INS1 GENE MRNA EXPRESSION, IN INSULINOMA CELL LINE RIN-5F. In Acta endocrinologica (Bucharest, Romania : 2005), 19, 277-280. doi:10.4183/aeb.2023.277. https://pubmed.ncbi.nlm.nih.gov/38356984/

9. Austin, Amazon L F, Daniels Gatward, Lydia F, Cnop, Miriam, Jones, Peter M, King, Aileen J F. 2020. The KINGS Ins2 +/G32S Mouse: A Novel Model of β-Cell Endoplasmic Reticulum Stress and Human Diabetes. In Diabetes, 69, 2667-2677. doi:10.2337/db20-0570. https://pubmed.ncbi.nlm.nih.gov/32994272/