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Articles in PresS, published online ahead of print November 5, 2001
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00124.2001
Submitted on March 16, 2001
Accepted on October 31, 2001
in Obese Women with GDM: Relationship to Free Fatty Acids during Pregnancy
1 Reproductive Biology and Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
2 Nutrition, Texas A&M University, College Station, Texas, USA
* To whom correspondence should be addressed. E-mail: jed.friedman{at}uchsc.edu.
Gestational Diabetes Mellitus (GDM) is associated with elevated post-prandial free fatty acids (FFA) and insulin resistance, however little is known about the cellular mechanisms underlying insulin resistance to suppress lipolysis during gestation. We evaluated the longitudinal changes in basal maternal FFA concentration and insulin suppression of FFA prior to pregnancy, and in early (12-14 wks), and late (34-36 wks) gestation in four obese subjects with normal glucose tolerance and in five obese GDM subjects. In addition, abdominal subcutaneous adipose tissue biopsies were obtained at the time of cesarean delivery from normal obese pregnant (Preg-Con, n= 8), GDM (n = 7), and in non-pregnant obese control subjects during gynecologic surgery (Non-Preg Con, n = 7). GDM subjects tended to have higher starting basal plasma FFA prior to pregnancy (p =0.055). Insulin's ability to suppress FFA levels (based on percent suppression) declined from early to late gestation in both GDM and Preg-Con subjects, and was significantly less in GDM subjects compared to Preg-Con subjects over time (P=0.025). Normal pregnancy was not associated with decreased insulin signaling protein levels in adipose tissue compared to non-pregnant controls, indicating that declining insulin regulation of lipolysis over time could be due to a change in protein activity. In contrast, despite no differences in hormonal milieau, GDM subjects' adipose tissue IRS-1 protein levels were 43% lower (P=0.02) and p85
subunit of PI 3-kinase was 2 fold higher (p =0.03) in adipocytes compared with Preg-Con subjects. The steady-state levels of PPAR mRNA were lower by 38% in Preg-Con (P= 0.006) and by 48% in GDM subjects (P=0.005) compared to Non-Preg controls. UCP2 mRNA levels were lower by 38% in Preg-Con and by 48% in GDM subjects compared to Non-Preg Con, while GDM subjects demonstrated a 73% and 52% reduction LPL and aP2 mRNA levels compared with Preg-Con subjects (p<0.002). These results demonstrate that GDM women, matched for obesity, have decreased IRS-1 as well as increased p85a protein content, both of which may contribute to their greater insulin resistance and reduced ability of insulin to suppress lipolysis with advancing gestation. The down-regulation of PPAR mRNA expression and related genes in late pregnancy is consistent with insulin resistance and could be an important mechanism underlying the changes in lipid storage during the transition from early to late pregnancy.
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