Glucocorticoid excess and insulin resistance in aged spontaneously hypertensive rats/stroke-prone

Abstract

Vascular diseases cause chronic cerebral hypoperfusion and neuronal injury and are the second most common cause of dementia. A significant cause of chronic cerebral hypoperfusion is hypertension. Insulin resistance is an important risk factor for hypertension. Aside from age, insulin resistance is also the most important risk factor 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 hypertension could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We hypothesized that hypertension initiates insulin resistance through sustained activation of the hypothalamic-pituitary-adrenal axis. To test this hypothesis, we measured corticosterone and the expression of steroid biosynthetic genes in six-month-old spontaneously hypertensive rat/stroke-prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To measure glycemic control, rats were subjected to glucose tolerance and insulin tolerance tests. SHRSP were hypertensive and cognitively impaired. SHRSPs had increased corticosterone compared to SD (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, SHRSPs had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (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 SHRSPs had decreased clearance of glucose compared to SDs (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). These results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female SHRSP succumbing faster to hyperglycemia than males. Alzheimer's Association Research Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.