Glucocorticoid excess and insulin resistance in rat models of vascular contributions to cognitive impairment and dementia

Abstract Background Hypertension and insulin resistance are major risk factors for the development of dementia. While insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that vascular disease could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We previously showed that bilateral carotid artery stenosis results in HPA‐axis dysfunction and insulin resistance (Lansdell et al., 2022). We hypothesized that hypertension would also cause glucocorticoid excess and insulin resistance. Method To test this hypothesis, we measured fecal corticosterone and the expression of steroid biosynthetic genes in the adrenal glands of six‐month‐old spontaneously hypertensive rat/stroke‐prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To assess glycemic control, rats were subjected to glucose and insulin tolerance tests. Result SHRSP were hypertensive and cognitively impaired. Corticosterone was elevated in hypertensive compared to normotensive rats (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P<0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P = 0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P = 0.0009; Females 710±59, P = 0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P = 0.0028). Female, but not male, hypertensive rats had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (female SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P = 0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P = 0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P = 0.0368). When fasting rats were challenged with insulin, both male and female hypertensive rats had decreased clearance of glucose compared to normotensive rats (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P< 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P = 0.0007). Conclusion These results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female hypertensive rats developing hyperglycemia at an earlier age than males.