Gestational diabetes mellitus (GDM) is a common obstetric complication. Half of women who have GDM will go on to develop type 2 diabetes. Understanding the mechanisms by which this occurs requires an animal model of GDM without ongoing diabetes at conception. C57Bl/6J mice react acutely to a high-fat, high-sucrose (HFHS) challenge. Here, we hypothesized that a periconceptional HFHS challenge will induce glucose intolerance during gestation. C57Bl/6J female mice were placed on an HFHS either 1 or 3 weeks prior to mating and throughout pregnancy. Intraperitoneal glucose tolerance tests, insulin measurements, and histological analysis of pancreatic islets were used to assess the impact of acute HFHS. C57Bl/6J females fed HFHS beginning 1 week prior to pregnancy became severely glucose intolerant, with reduced insulin response to glucose, and decreased pancreatic islet expansion during pregnancy compared to control mice. These GDM characteristics did not occur when the HFHS diet was started 3 weeks prior to mating, suggesting the importance of acute metabolic stress. Additionally, HFHS feeding resulted in only mild insulin resistance in nonpregnant females. When the diet was discontinued at parturition, symptoms resolved within 3 weeks. However, mice that experienced glucose intolerance in pregnancy became glucose intolerant more readily in response to a HFHS challenge later in life than congenic females that experienced a normal pregnancy, or that were fed the same diet outside of pregnancy. Thus, acute HFHS challenge in C57Bl/6 mice results in a novel, nonobese, animal model that recapitulates the long-term risk of developing type 2 diabetes following GDM.

During pregnancy several maternal adaptations occur in order to support the growing fetus which are further exacerbated by gestational diabetes mellitus (GDM). Previously we developed a mouse model of GDM, however we did not evaluate alterations to energy and fat metabolism. We have also shown that alterations in lipid metabolism are mediated by adrenomedullin (ADM) in normal and GDM pregnancies. Our objectives were: (1) evaluate energy and fat homeostasis in our GDM mouse model and (2) determine if ADM may play a role in these changes. Female mice were placed on either control (P-CD) or high fat, high sucrose diet (P-HFHS) 1 week prior to and throughout pregnancy. Mice were placed into comprehensive lab animal monitoring system (CLAMS) chambers throughout pregnancy. Visceral adipose tissue (VAT) was collected at d17.5 of pregnancy for analysis. Energy Expenditure was significantly increased (p < 0.05) in P-HFHS dams compared to all other groups. VAT ex-vivo lipolysis was increased (p < 0.05) in P-HFHS compared to P-CD dams. VAT gene expression of ADM receptors Crlr, Ramp2, and Ramp3 was increased (p < 0.05) in P-HFHS dams. ADM dose dependently increased ex vivo lipolysis. This data further validates our animal model of GDM and is usefulness in investigating the pathophysiology of GDM.

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OBJECTIVE: Despite recommendations, compliance with postpartum screening in women diagnosed with gestational diabetes (GDM) is low. Identification of persistent impaired glucose tolerance provides the opportunity for early preventative interventions or treatment for Type 2 diabetes. Therefore, identification of a biomarker that can risk stratify those women at greatest risk may increase testing compliance and ultimately, long term women's health. We sought to evaluate whether maternal serum adiponectin and high-sensitivity C-reactive protein (hsCRP) levels at the time of GDM diagnosis are associated with persistent glucose intolerance in GDM women at 6-12 weeks postpartum. STUDY DESIGN: This is a secondary analysis of prospective randomized trial of GDM women enrolled in a behavior education program. Women with a GDM diagnosis ! 20 week were included. At the time of randomization (22-34 wks), serum adiponectin and hsCRP levels were drawn. After delivery, women underwent a 2hr 75g OGTT at 6-12 weeks postpartum. Persistent impaired glucose tolerance (P-IGT) was defined by: impaired fasting glucose, impaired glucose tolerance, or a diagnosis of Type 2 diabetes based on American Diabetes Association criteria. Regression models and receiver operator curves were used to evaluate the association between both midpregnancy adiponectin and hsCRP and P-IGT. RESULTS: Of 100 women in the trial, 63 completed postpartum glucose testing. 20 (31.7%) of the women had P-IGT. With the exception of gestational age at randomization, clinical characteristics including age, race, initial BMI, total weight gain, prior GDM history and fasting glucose during pregnancy were similar between women with normal glucose testing (N-GT) and those with P-IGT (p>0.05 for all). Median hsCRP levels were higher in women with P-IGT compared with N-GT women (5.1 vs. 3.8, p¼0.01). Overall, hsCRP was associated with threefold increased odds of P-IGT (OR: 3.38, 95% CI: 1.31-8.71, p¼0.01) and an AUC ¼0.72 (Figure). There was no difference in median adiponectin levels between groups (44.8 vs. 52.0, p¼0.57) or in odds of P-IGT (OR: 1.08, 95% CI: 0.39-2.98, p¼0.89) and AUC¼ 0.45. CONCLUSION: Midpregnancy hsCRP is a strong predictor of persistent impaired glucose tolerance diagnosed on the postpartum 2hr 75 gram OGTT in GDM women. Validation of this biomarker for clinical use is warranted.