Around the morning of the OGTT, a cannula (BD Intracath no

Around the morning of the OGTT, a cannula (BD Intracath no. more suppressed (5.5 6.1 vs. 7.8 2.8 mg100 g liver1min1,P< 0.05) in P than in P-HFF dogs. In conclusion, in the 2nd trimester the canine pancreas does not exhibit islet hypertrophy, Lazabemide hyperplasia, or neogenesis. Combined with the lack of pancreatic adaptation, a HFF diet during late pregnancy produces a canine model of IGT and GDM without hyperinsulinemia but exhibiting liver and muscle mass insulin resistance. Keywords:hyperinsulinemic euglycemic clamp, insulin resistance, oral glucose tolerance, pancreatic islet, pregnancy gestational diabetes(GDM), or diabetes manifested during pregnancy, affects 210% of pregnancies in the U.S. (15). Women with GDM are seven occasions more likely to develop type 2 diabetes at some point in life than women who do not have GDM (4). Metabolic risk is not limited to women with overt diabetes; instead, the impact of altered glucose tolerance lies on a continuum such that impaired glucose tolerance (IGT) Lazabemide during pregnancy is also associated with an increased risk of metabolic syndrome, cardiovascular disease, prediabetes, and diabetes after pregnancy (4447). Animal models of IGT in pregnancy and GDM are needed to examine the pathophysiology associated with the human disorders. There are several small animal models of diabetes in pregnancy. These include the streptozotocin-treated mouse or rat. This model is usually poorly suited for the study of GDM, because large doses of streptozotocin produce a model more closely resembling type 1 diabetes, whereas smaller doses result in varying levels of hyperglycemia and lack of fetal macrosomia (9). In addition, these models are associated with high rates of reproductive failure (infertility and resorption of fetuses) (31,57). Human GDM has a strong genetic and familial component, being more prevalent in particular minority ethnic groups; common variants in several genes (KCNJ11,GCK, andHNF4a) increase the risk of GDM (48). Similarly, several genetic models of IGT and GDM have been developed in mice. Most recently, our group has exhibited, using conditional gene inactivation (58), that this FoxM1 transcription factor is critical for -cell proliferation and -cell mass growth during pregnancy in mice. This OBSCN model is similar to human GDM in that a phenotype is usually manifested specifically at midgestation, whereas virgin and postpartum mutant females show no phenotype. Human GDM patients likely have an underlying undetected -cell defect that becomes apparent only under the physiological stress of pregnancy. In addition to pharmacological and genetic models, rats and mice fed a high-fat diet have been shown to be hyperinsulinemic and hyperglycemic during pregnancy and to provide a useful model of GDM (28,34). Despite the improvements in establishing rodent models of the disease, a suitable large animal model would allow more extensive study of metabolism in GDM, including interorgan balance measurements, and would permit the assessment of pharmacological interventions on maternal hepatic and whole body glucose metabolism. The chronically catheterized doggie model has a near-unique advantage in the study of nutrient metabolism, because it is one of the very few models in which it is possible to assess hepatic substrate uptake directly. Hepatic glucose uptake (HGU) is usually a key variable, because it helps to determine postprandial glycemia. Glucose intolerance in pregnancy not only predicts a number of complications during pregnancy but also is a predictor of future metabolic dysfunction in both the mother and child (e.g., Refs.27,45,46). Thus an appropriate canine model can provide a basis for further studies defining the pathology of IGT/GDM when the liver is in uptake mode and for examining interventions aimed at alleviating the pathology. The dog is usually well suited to this purpose and has been used extensively as a model of glucose metabolism in health and disease (e.g., Refs.10,21). This project was undertaken to compare glucose tolerance and hepatic and peripheral insulin sensitivity in pregnant dogs Lazabemide (3rd trimester) receiving a normal chow and meat diet and those fed a high-fat and high-fructose diet. In view of the fact that even normal pregnant dogs exhibited little rise in plasma insulin following ingestion of an oral glucose load compared with normal nonpregnant animals, islet Lazabemide size and proliferation were assessed late in the 2nd trimester to examine the potential for -cell adaptation in pregnancy. == MATERIALS AND METHODS == == Animals, Animal Care, and Surgical Procedures == The protocol was approved by the Vanderbilt University or college Animal Care and Use Committee, and the animals were housed in an American Association for the Lazabemide Accreditation of Laboratory Animal Care-approved facility. Healthy adult timed-pregnant purpose-bred.