Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 315, Issue 6, Pages R1220-R1231Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00458.2017
Keywords
beta-cell; intrauterine growth restriction; islets; mTOR; placenta
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [K01-DK-103823, R21-DK-112144, R03-DK-114465, R01-DK-115720, R03-DK-11446501A1]
- National Heart, Lung, and Blood Institute [2-R15-HL-109843-03]
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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 beta-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 5473) was observed. RUPP offspring showed significantly reduced beta-cell-to-pancreas area and increased beta-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 5473, and pAKT at Thr(308) tended to be reduced in the fetal RUPP pancreas. Altogether, these data show that RUPP offspring demonstrated increased beta-cell death, reduced beta-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.
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