Maternal hypertension during pregnancy is a major risk factor for intrauterine growth restriction (IUGR), which increases susceptibility to cardiovascular and metabolic disease in adulthood through unclear mechanisms. The aim of this study was to characterize the pancreatic β-cell area and function in the fetal rat offspring of a reduced uterine perfusion pressure (RUPP) model of gestational hypertension. At embryonic day 19.5, RUPP dams exhibited lower body weight, elevated mean blood pressure, reduced litter size, and higher blood glucose compared with sham-operated controls. In RUPP placental lysates, a nonsignificant change in mammalian target of rapamycin (mTOR) activity markers, phosphorylated S6 at serine 240, and phosphorylated AKT (at S473) was observed. RUPP offspring showed significantly reduced β-cell-to-pancreas area and increased β-cell death but normal insulin levels in serum. Isolated islets had normal insulin content and secretory function in response to glucose and palmitate. Fetal pancreatic lysates showed a tendency for reduced insulin levels, with a significant reduction in total mTOR protein with RUPP surgery. In addition, its downstream complex 2 targets phosphorylation of AKT at S473, and pAKT at Thr308 tended to be reduced in the fetal RUPP pancreas. Altogether, these data show that RUPP offspring demonstrated increased β -cell death, reduced β-cell area, and altered nutrient-sensor mTOR protein level in the pancreas. This could represent a mechanistic foundation in IUGR offspring’s risk for enhanced susceptibility to type 2 diabetes and other metabolic vulnerabilities seen in adulthood.
|Original language||English (US)|
|Journal||American Journal of Physiology - Regulatory Integrative and Comparative Physiology|
|State||Published - Dec 2018|
Bibliographical noteFunding Information:
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants (K01-DK-103823, R21-DK-112144, R03-DK-114465, and R01-DK-115720) to E. U. Alejandro, R03-DK-11446501A1 to B. Akhaphong, and National Heart, Lung, and Blood Institute Grant 2-R15-HL-109843–03 to J. F. Regal.
- Intrauterine growth restriction