Aaron Poole

Adipose Tissue Insulin Resistance in Gestational Diabetes

BACKGROUND Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance (IR) and altered glucose-lipid metabolism. We propose that ectonucleotide pyrophosphate phosphodiesterase-1 (ENPP1), a protein known to induce adipocyte IR, is a determinant of GDM. Our objective was to study ENPP1 expression in adipose tissue (AT) of obese pregnant women with or without GDM, as well as glucose tolerance in pregnant transgenic (Tg) mice with AT-specific overexpression of human ENPP1. METHODS AT biopsies and blood were collected from body mass index-matched obese pregnant women non-GDM (n = 6), GDM (n = 7), and nonpregnant controls (n = 6) undergoing cesarian section or elective surgeries, respectively. We measured the following: (1) Expression of key molecules involved in insulin signaling and glucose-lipid metabolism in AT; (2) Plasma glucose and insulin levels and calculation of homeostasis model assessment of IR (HOMA-IR); (3) Intraperitoneal glucose tolerance test in AtENPP1 Tg pregnant mice. RESULTS We found that: (1) Obese GDM patients have higher AT ENPP1 expression than obese non-GDM patients, or controls (P = 0.01-ANOVA). (2) ENPP1 expression level correlated negatively with glucose transporter 4 (GLUT4) and positively with insulin receptor substrate-1 (IRS-1) serine phosphorylation, and to other adipocyte functional proteins involved in glucose and lipid metabolism (P < 0.05 each), (3) AT ENPP1 expression levels were positively correlated with HOMA-IR (P = 0.01-ANOVA). (4) Pregnant AT ENPP1 Tg mice showed higher plasma glucose than wild type animals (P = 0.046-t test on area under curve [AUC]glucose). CONCLUSIONS Our results provide evidence of a causative link between ENPP1 and alterations in insulin signaling, glucose uptake, and lipid metabolism in subcutaneous abdominal AT of GDM, which may mediate IR and hyperglycemia in GDM.

Long-Term Effect of Lactation on Maternal Cardiovascular Function and Adiposity in a Murine Model

Objective Epidemiological studies suggest that lactation is associated with long‐term maternal health benefits. To avoid confounders in human studies, we used a previously characterized murine model to investigate the long‐term effect of lactation on both cardiovascular function and adiposity. Study Design After the delivery of the pups, CD‐1 female mice were randomly divided into two groups: lactated and nonlactated (NL). Before pregnancy and at 9 months postdelivery, blood pressure was measured using a tail cuff, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed by computed tomography (CT), echocardiography was performed using microultrasound, and cholesterol panels and fasting blood glucose were measured. The data were analyzed using Students t ‐test (significance at p < 0.05). Results There were no differences in baseline parameters between the two groups. At 9 months postdelivery, the NL group weighed significantly more (p = 0.03) and demonstrated a significantly lower cardiac output (p = 0.05) and ejection fraction (p = 0.03). The mice in the NL group also had higher VAT (p < 0.01) and SAT percentiles (p = 0.03). Fasting glucose (p = 0.01) and low‐density lipoprotein (p = 0.01) were significantly higher in the NL group at 9 months. Conclusion Our results show the benefit of lactation is not just limited to the immediate postpartum period but it also extends into midlife in a murine model.