[Show abstract][Hide abstract] ABSTRACT: The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, α1-syntrophin, annexin A4) in OGDM (n = 6) vs. ONGT (n = 6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (-60-75%) in the OGDM (n = 8) compared with ONGT (n = 10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.
PLoS ONE 09/2014; 9(9):e106872. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Climbing obesity rates in women have propelled the increasing prevalence of type 2 diabetes mellitus (T2DM) in pregnancy, and an increasing number of women with type 1 diabetes mellitus (T1DM) are also affected by obesity. Increasing recognition that an intrauterine environment characterized by obesity, insulin resistance, nutrient excess, and diabetes may be fueling the obesity epidemic in children has created enormous pressure to re-examine the conventional wisdom of our current approaches.
Current opinion in endocrinology, diabetes, and obesity. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Gestational diabetes mellitus (GDM) is a major public health concern because of rising rates and offspring consequences; yet, expert panels are in complete disagreement on how to diagnose and optimally treat GDM. This review underscores why there remains no diagnostic standard, no agreement on whether excess dietary carbohydrate or fat should be reduced, and whether oral hypoglycemic therapy is safe given the unknown offspring effects on hepatic, pancreatic, or fat development.
Current opinion in endocrinology, diabetes, and obesity. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
The conventional diet approach to gestational diabetes mellitus (GDM) advocates carbohydrate restriction, resulting in higher fat (HF), also a substrate for fetal fat accretion and associated with maternal insulin resistance. Consequently, there is no consensus about the ideal GDM diet. We hypothesized that, compared with a conventional, lower carbohydrate/HF diet (40% carbohydrate/45% fat/15% protein), consumption of a higher-complex carbohydrate (HCC)/lower fat (LF) Choosing Healthy Options in Carbohydrate Energy (CHOICE) diet (60/25/15%) would result in 24-h glucose area under the curve (AUC) profiles within therapeutic targets and lower postprandial lipids.RESEARCH DESIGN AND METHODS
Using a randomized, crossover design, we provided 16 GDM women (BMI 34 ± 1 kg/m(2)) with two 3-day isocaloric diets at 31 ± 0.5 weeks (washout between diets) and performed continuous glucose monitoring. On day 4 of each diet, we determined postprandial (5 h) glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) following a controlled breakfast meal.RESULTSThere were no between-diet differences for fasting or mean nocturnal glucose, but 24-h AUC was slightly higher (∼6%) on the HCC/LF CHOICE diet (P = 0.02). The continuous glucose monitoring system (CGMS) revealed modestly higher 1- and 2-h postprandial glucose on CHOICE (1 h, 115 ± 2 vs. 107 ± 3 mg/dL, P ≤ 0.01; 2 h, 106 ± 3 vs. 97 ± 3 mg/dL, P = 0.001) but well below current targets. After breakfast, 5-h glucose and insulin AUCs were slightly higher (P < 0.05), TG AUC was no different, but the FFA AUC was significantly lower (∼19%; P ≤ 0.01) on the CHOICE diet.CONCLUSION
This highly controlled study randomizing isocaloric diets and using a CGMS is the first to show that liberalizing complex carbohydrates and reducing fat still achieved glycemia below current treatment targets and lower postprandial FFAs. This diet strategy may have important implications for preventing macrosomia.
[Show abstract][Hide abstract] ABSTRACT: Elucidating the optimal macronutrient composition for dietary management of gestational diabetes mellitus has enormous potential to improve perinatal outcomes. Diet therapy may result in significant cost savings if effective in deterring the need for expensive medical management within this growing population. In only 6 randomized controlled trials in 250 women, data suggest that a diet higher in complex carbohydrate and fiber, low in simple sugar, and lower in saturated fat may be effective in blunting postprandial hyperglycemia, preventing worsened insulin resistance and excess fetal growth. The use of diet in gestational diabetes mellitus remains an area in grave need for high-quality randomized controlled trials.
Clinical obstetrics and gynecology 09/2013; · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract The power of continuous glucose monitoring system (CGMS) technology to profile glycemic patterns throughout a 24-h period has benefited the care of individuals with diabetes mellitus for over 10 years. Recently, this technology has been utilized to better understand glucose patterns in pregnancy, especially as they relate to abnormal fetal growth given that adiposity at birth is associated with increased risks for childhood obesity and metabolic syndrome. However, the lack of a standardized approach to defining glucose measures associated with maternal outcomes and fetal growth has greatly limited comparison and pooling of CGMS data among pregnancy trials, hindering our ability to take advantage of the enormous amount of data available to explore these relationships. The purpose of this article is to offer a methodical approach to the identification and extraction of CGMS-derived glucose variables for the characterization of glycemic profiles in pregnant women, particularly focusing on women with gestational diabetes or obesity who are at risk for abnormal fetal growth. A review of the properties of CGMS data and examples of how CGMS data in pregnancy have been reported to date are included. We further define several pregnancy-relevant, CGMS-derived glucose variables and directly apply them to unpublished data to illustrate how these measures might be utilized. This approach offers one possible standardized method to define and analyze these time-sensitive glucose measures to facilitate comparisons among studies and to increase our understanding of how glycemic profiles contribute to excess infant adiposity in pregnant women with and without diabetes.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To assess precision magnetic resonance imaging in the neonate and determine whether there is an early maternal influence on the pattern of neonatal fat deposition in the offspring of mothers with gestational diabetes mellitus (GDM) and obesity compared with the offspring of normal-weight women. STUDY DESIGN: A total of 25 neonates born to normal weight mothers (n = 13) and to obese mothers with GDM (n = 12) underwent magnetic resonance imaging for the measurement of subcutaneous and intra-abdominal fat and magnetic resonance spectroscopy for the measurement of intrahepatocellular lipid (IHCL) fat at 1-3 weeks of age. RESULTS: Infants born to obese/GDM mothers had a mean 68% increase in IHCL compared with infants born to normal-weight mothers. For all infants, IHCL correlated with maternal prepregnancy body mass index but not with subcutaneous adiposity. CONCLUSION: Deposition of liver fat in the neonate correlates highly with maternal body mass index. This finding may have implications for understanding the developmental origins of childhood nonalcoholic fatty liver disease.
The Journal of pediatrics 12/2012; · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to define 24-h glycemia in normal-weight and obese pregnant women using continuous glucose monitoring (CGM) while they consumed a habitual and controlled diet both early and late in pregnancy.
Glycemia was prospectively measured in early (15.7 ± 2.0 weeks' gestation) and late (27.7 ± 1.7 weeks' gestation) pregnancy in normal-weight (n = 22) and obese (n = 16) pregnant women on an ad libitum and controlled diet. Fasting glucose, triglycerides (early pregnancy only), nonesterified fatty acids (FFAs), and insulin also were measured.
The 24-h glucose area under the curve was higher in obese women than in normal-weight women both early and late in pregnancy despite controlled diets. Nearly all fasting and postprandial glycemic parameters were higher in the obese women later in pregnancy, as were fasting insulin, triglycerides, and FFAs. Infants born to obese mothers had greater adiposity. Maternal BMI (r = 0.54, P = 0.01), late average daytime glucose (r = 0.48, P < 0.05), and late fasting insulin (r = 0.49, P < 0.05) correlated with infant percentage body fat. However, early fasting triglycerides (r = 0.67, P < 0.001) and late fasting FFAs (r = 0.54, P < 0.01) were even stronger correlates.
This is the first study to demonstrate that obese women without diabetes have higher daytime and nocturnal glucose profiles than normal-weight women despite a controlled diet both early and late in gestation. Body fat in infants, not birth weight, was related to maternal BMI, glucose, insulin, and FFAs, but triglycerides were the strongest predictor. These metabolic findings may explain higher rates of infant macrosomia in obese women, which might be targeted in trials to prevent excess fetal growth.
Diabetes care 07/2011; 34(10):2198-204. · 7.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The rapidly increasing prevalence of gestational diabetes mellitus (GDM) globally places a growing population at risk for developing type 2 diabetes mellitus (T2DM), particularly those with persistent impaired glucose tolerance (IGT) postpartum.
We sought to 1) identify dynamic insulin signaling abnormalities in vivo in a prospective, longitudinal study of GDM women compared to weight-matched pregnant controls both antepartum and postpartum; and 2) determine abnormalities that might distinguish GDM women who normalize their glucose tolerance postpartum from those with persistent IGT.
Skeletal muscle biopsies were obtained before and after a 75-g glucose load in nine overweight to obese GDM women and 10 weight-matched pregnant controls antepartum and postpartum. Postpartum biopsies were collected in five weight-matched GDM women with IGT (GDM/IGT).
GDM women had decreased skeletal muscle insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum. However, GDM/IGT subjects had a persistent impairment in IRS1 activation and increased S6K1 phosphorylation compared to GDM subjects with normal glucose tolerance.
This study reveals that women with GDM demonstrate impaired IRS1 signaling associated with increased S6K1 activation in skeletal muscle in vivo. This defect is maintained postpartum in GDM/IGT subjects, despite similar body weights and cytokine levels. Given that GDM women with persistent IGT are at a high risk of developing T2DM, understanding how the nutrient-sensitive mammalian target of rapamycin/S6K1 pathway is chronically activated in GDM may lead to important therapies that could prevent the progression to T2DM.
The Journal of Clinical Endocrinology and Metabolism 02/2011; 96(5):1431-41. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of obesity and overweight has reached epidemic levels in the United States and developed countries worldwide. Even more alarming is the increasing prevalence of metabolic diseases in younger children and adolescents. Infants born to obese, overweight, and diabetic mothers (even when normal weight) have increased adiposity and are at increased risk of later metabolic disease. In addition to maternal glucose, hyperlipidemia and inflammation may contribute to the childhood obesity epidemic through fetal metabolic programming, the mechanisms of which are not well understood. Pregravid obesity, when combined with normal changes in maternal metabolism, may magnify increases in inflammation and blood lipids, which can have profound effects on the developing embryo and the fetus in utero. Fetal exposure to excess blood lipids, particularly saturated fatty acids, can activate proinflammatory pathways, which could impact substrate metabolism and mitochondrial function, as well as stem cell fate, all of which affect organ development and the response to the postnatal environment. Fetal and neonatal life are characterized by tremendous plasticity and the ability to respond to environmental factors (nutrients, oxygen, hormones) by altering gene expression levels via epigenetic modifications. Given that lipids act as both transcriptional activators and signaling molecules, excess fetal lipid exposure may regulate genes involved in lipid sensing and metabolism through epigenetic mechanisms. Epigenetic regulation of gene expression is characterized by covalent modifications to DNA and chromatin that alter gene expression independent of gene sequence. Epigenetic modifications can be maintained through positive and negative feedback loops, thereby creating stable changes in the expression of metabolic genes and their main transcriptional regulators. The purpose of this article is to review current literature on maternal-fetal lipid metabolism and maternal obesity outcomes and to suggest some potential mechanisms for fetal metabolic programming in key organ systems that regulate postnatal energy balance, with an emphasis on epigenetics and the intrauterine environment.
[Show abstract][Hide abstract] ABSTRACT: Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85alpha regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85alpha levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85alpha subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85alpha mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85alpha protein abundance. We found that p85alpha expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85alpha expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess.
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance is a cardinal feature of normal pregnancy and excess growth hormone (GH) states, but its underlying mechanism remains enigmatic. We previously found a significant increase in the p85 regulatory subunit of phosphatidylinositol kinase (PI 3-kinase) and striking decrease in IRS-1-associated PI 3-kinase activity in the skeletal muscle of transgenic animals overexpressing human placental growth hormone. Herein, using transgenic mice bearing deletions in p85alpha, p85beta, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85alpha is a primary mechanism for skeletal muscle insulin resistance in response to GH. We found that the excess in total p85 was entirely accounted for by an increase in the free p85alpha-specific isoform. In mice with a liver-specific deletion in insulin-like growth factor-1, excess GH caused insulin resistance and an increase in skeletal muscle p85alpha, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85alpha in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85alpha or p85beta, respectively (p85alpha (+/-) and p85beta(-/-)). Wild type and p85beta(-/-) mice developed in vivo insulin resistance and demonstrated overexpression of p85alpha and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85alpha(+/-)mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85alpha expression. These findings demonstrated the importance of increased p85alpha in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.
Journal of Biological Chemistry 12/2005; 280(45):37489-94. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine whether standard therapeutic doses of dalteparin maintain peak therapeutic levels of anticoagulation during pregnancy.
This was a prospective trial in which 13 pregnancies that required therapeutic anticoagulation were treated with dalteparin 100 U/kg every 12 hours; peak and trough (predose) low molecular weight heparin (anti-Xa activity) levels were monitored every 2 weeks. Dosage adjustments were made to maintain peak anti-Xa activity between 0.5 and 1.0 IU/ml. Bone density and bone turnover markers were measured.
A total of 250 peak and trough low-molecular-weight heparin (LMWH) levels were obtained. Eighty-five percent of pregnancies (11/13) required an upward dosage adjustment. Trough levels were in the therapeutic range only 9% of the time, despite the maintenance of therapeutic peak levels. Bone resorption markers and density were unchanged in singleton pregnancies.
Dalteparin dosing, based on weight alone, every 12 hours is inadequate to maintain most pregnant women in the therapeutic range throughout pregnancy as measured by anti-Xa activity. Trough levels are rarely in the therapeutic range, despite maintenance of therapeutic peak levels. These notable changes in low molecular weight heparin peak may explain reported failures in pregnancy.
American Journal of Obstetrics and Gynecology 10/2004; 191(3):1024-9. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The insulin resistance of normal pregnancy is necessary to divert fuels to the fetus to meet fetal growth demands and is mediated by placental hormones. We recently demonstrated that human placental GH (hPGH) can trigger severe insulin resistance in transgenic (TG) mice. In this study we sought to elucidate the cellular mechanisms by which hPGH interferes with insulin signaling in muscle in TG mice. Insulin-stimulated GLUT-4 translocation to the plasma membrane (PM) was reduced in the TG compared with wild-type (WT) mice (P = 0.05). Insulin receptor (IR) levels were modestly reduced by 19% (P < 0.01) in TG mice, but there were no changes in phosphorylation of IR or IR substrate-1 (IRS-1) between WT and TG mice. A singular finding was a highly significant increase in the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase; P < 0.001), yet a reduced ability of insulin to stimulate IRS-1-associated PI 3-kinase activity (P < 0.05). Although the levels of the p110 catalytic subunit protein of PI 3-kinase and IRS-1 were unchanged in the TG mice, insulin's ability to stimulate p110 association with IRS-1 was markedly reduced (P < 0.0001). We demonstrate a unique mechanism of insulin resistance and suggest that hPGH may contribute to the insulin resistance of normal pregnancy by increasing the expression of the p85 alpha monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.
[Show abstract][Hide abstract] ABSTRACT: The insulin resistance of pregnancy is considered to be mediated by human placental lactogen, but the metabolic effects of human placental growth hormone have not been well defined. Our aim was to evaluate the effect of placental growth hormone on insulin sensitivity in vivo using transgenic mice that overexpress the human placental growth hormone gene.
Glucose and insulin tolerance tests were performed on 5 transgenic mice that overexpressed the human placental growth hormone variant gene and 6 normal littermate controls. The body composition of the mice was assessed by dual-energy radiograph absorptiometry, and free fatty acid levels were measured as a marker of lipolysis.
The human placental growth hormone levels in the transgenic mice were comparable to those attained in the third trimester of pregnancy. These mice were nearly twice as heavy as the control mice, and their body composition differed by a significant increase in bone density and a small decrease in percentage of body fat. Fasting insulin levels in the transgenic mice that overexpressed placental growth hormone were approximately 4-fold higher than the control mice (1.57 +/- 0.22 ng/mL vs 0.38 +/- 0.07 ng/mL; P <.001) and 7 times higher 30 minutes after glucose stimulation (4.17 +/- 0.54 ng/mL vs 0.62 +/- 0.10 ng/mL; P <.0001) with no significant difference in either fasting or postchallenge glucose levels. Insulin sensitivity was markedly decreased in the transgenic mice, as demonstrated by an insignificant decline in glucose levels after insulin injection compared with the control mice, which demonstrated more than a 65% reduction in glucose levels (P <.001).
Human placental growth hormone causes insulin resistance as manifested by fasting and postprandial hyperinsulinemia and minimal glucose lowering in response to insulin injection. Human placental growth hormone is a highly likely candidate to mediate the insulin resistance of pregnancy.
American Journal of Obstetrics and Gynecology 03/2002; 186(3):512-7. · 3.88 Impact Factor