Young Adult LEW.1WR1 Rats Develop Dysregulated Islet Function and Impaired Liver Insulin Responses

Abstract Obesity in humans can lead to metabolic problems such as glucose intolerance and insulin resistance, which may result from pancreatic islet dysregulation and reduced insulin sensitivity in the liver. LEW.1WR1 (1WR1) rats became more glucose intolerant than LEW/SsNHsd (SsNHsd) rats after 12 weeks on a moderate sucrose diet.1 We hypothesize that the 1WR1 rats develop decreased insulin sensitivity due to impaired islet function and liver responses to insulin. To test this hypothesis we measured blood hormone levels and islet and liver gene expression. The terminal blood insulin (14988+/- 4024 vs. 22703+/-5101 pg/mL; p=0.0085; n=7,7) and glucagon (127.3+/-73.31 vs. 188.6+/-46.87 pg/mL; p=0.0537; n=7,7) were higher in the the 1WR1 rats. Using qRT-PCR, we determined the islets of 1WR1 rats had 3 fold increased insulin (p<0.0001; n=3,3) and glucagon (p<0.0001; n=3,2) relative gene expression. Yet, the β-cell area (22.05+/-6.408 vs. 2.276 +/-1.284mm2; p=0.0016; n=3,4) was significantly reduced in 1WR1 rats. Islet Plin5 expression was upregulated in 1WR1 rats (5.388+/-0.3806 F.C.; p<0.0001; n=3,3) indicating increased lipid droplet production, while Cyclin D (0.5726+/-0.08797 F.C.; p=0.0035; n=3,2) was downregulated indicating decreased cell cycle proliferation. These results indicate that the islets of the 1WR1 rats were insensitive to insulin signaling, which may have been caused by increased lipid droplets and a decrease in compensatory islet area. We also measured the relative expression of insulin-sensitive genes in the liver tissue to determine if there were alterations in liver insulin signaling. Downregulation of Irs-2 (0.5840+/-0.001045 F.C.; p<0.0001; n=7,7) expression was likely caused by the upregulated fat10 gene in 1WR1 rats.2 Fat10 (2315+/-0.01380 F.C.; p<0.0001; n=4,6) expression in the liver was significantly increased. Foxo1 (2.644+/- 0.001211 F.C.; p<0.0001; n=7,7) expression, which is normally reduced by insulin, was upregulated which indicates reduced insulin sensitivity. Upregulated expression of Fgf21 (2.260+/-0.002376 F.C.; p<0.0001; n=6,7), which improves glucose homeostasis, in the liver is why the fasting blood glucose of 1WR1 rats were not significantly different from the SsNHsd rats.1 In conclusion, 1WR1 rats show increasingly impaired metabolism over time. These rats have increased insulin and glucagon levels coupled with liver fat10 overexpression leading to impaired gene regulation of insulin-responsive genes in the liver. These changes synergistically increase susceptibility to pathological obesity and metabolic disease. References: (1) Collins et al., Journal of the Endocrine Society. 2019 3(S1). (2) Ge, Q. et al., Frontiers in Physiology. 2018; 9(1051): 1–16.