Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes

Diabetes Care ◽  
2007 ◽  
Vol 30 (Supplement 2) ◽  
pp. S112-S119 ◽  
Author(s):  
L. A. Barbour ◽  
C. E. McCurdy ◽  
T. L. Hernandez ◽  
J. P. Kirwan ◽  
P. M. Catalano ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Normal Pregnancy ◽  
Cellular Mechanisms

scholarly journals Correlation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes

2002 ◽  
pp. 243-248 ◽  
Author(s):  
L Kalabay ◽  
K Cseh ◽  
A Pajor ◽  
E Baranyi ◽  
GM Csakany ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Pregnant Women ◽  
Normal Pregnancy ◽  
Tnf Alpha ◽  
Control Group ◽  
Anthropometric Parameters ◽  
Necrosis Factor Alpha ◽  
C Peptide ◽  
Glucose Ratio

OBJECTIVE: Human fetuin/alpha(2)-HS-glycoprotein (AHSG) is a 49 kDa serum and tissue protein which is a natural inhibitor of insulin receptor signaling. We investigated serum AHSG levels during pregnancy and whether the protein is involved in insulin resistance observed in healthy pregnant women and patients with gestational diabetes. DESIGN: One hundred and four healthy pregnant women and 23 of their neonates, 30 patients with gestational diabetes and their neonates and 30 healthy age-matched non-pregnant females as a control group were investigated in a case-control cross-sectional study. METHODS: Serum AHSG was determined by radial immunodiffusion. RESULTS: We observed an increase of serum AHSG concentration in the second and third trimesters. Gestational diabetes patients had significantly higher AHSG levels than healthy pregnant women and non-pregnant controls. There was a highly significant positive correlation between serum AHSG concentration and indirect parameters of insulin resistance, i.e. tumor necrosis factor-alpha (TNF-alpha), leptin, C-peptide and C-peptide/blood glucose ratio. There was also a negative correlation between maternal AHSG, TNF-alpha, leptin levels and head circumference, body length and body weight of newborns. CONCLUSION: AHSG, TNF-alpha and leptin may contribute to insulin resistance during normal pregnancy and gestational diabetes. AHSG along with these cytokines may also negatively regulate neonatal skeletal development.

scholarly journals Molecular mechanisms of insulin resistance in normal pregnancy and gestational diabetes

2021 ◽  
Vol 2021 (1) ◽  
pp. 22-30
Author(s):  
L.V. Zhuravlyova ◽  
◽  
N.V. Sokolnikova ◽  
T.A. Rogachova ◽  
◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Molecular Mechanisms ◽  
Normal Pregnancy ◽  
Inflammatory Factors ◽  
Ppar Γ ◽  
Tnf Α ◽  
Therapeutic Measures ◽  
Glut 4 Translocation ◽  
Further Development

The purpose of this review article is to analyze current information on the molecular mechanisms of gestational diabetes and the prospects for their use in the further development of new effective treatments for this common pathology. Decreased ability of insulin to bind to its receptor, decreased IRS-1 expression and GLUT-4 translocation, and increased levels of p85α-PI-3 kinase subunits are involved in the development of insulin resistance during pregnancy. In gestational diabetes, there are not only more significant changes of the above mentioned indicators, but also increased levels of pro-inflammatory factors: TNF-α, IL-6, leptin and decreased insulin-sensitizing factors: adiponectin and PPAR-γ. Therapeutic measures aimed at normalizing the secretion of cytokines and adipokines reduce the risk of gestational diabetes mellitus and its complications and require further development

Absence of pregnancy-induced alterations in tissue insulin sensitivity in the offspring of diabetic rats

1991 ◽  
Vol 131 (3) ◽  
pp. 387-393 ◽  
Author(s):  
K. Holemans ◽  
L. Aerts ◽  
F. A. Van Assche
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Normal Pregnancy ◽  
Diabetic Rats ◽  
Metabolic Clearance ◽  
Response Curves ◽  
Pregnant Rats ◽  
Peripheral Tissues ◽  
Glucose Levels ◽  
Peripheral Insulin Resistance

ABSTRACT We have previously demonstrated insulin resistance in the liver and peripheral tissues of the adult offspring of rats made diabetic with streptozotocin (SDF rats). In this study, a euglycaemic hyperinsulinaemic clamp was used to test the hypothesis that insulin resistance is further aggravated during pregnancy in SDF rats. Normal pregnancy was accompanied by a decrease in the sensitivity of the liver and peripheral tissues to insulin, with a normal responsiveness to insulin. In SDF rats no further decrease in the sensitivity of peripheral tissues to insulin occurred during pregnancy when compared with non-pregnant rats, and the dose–response curves of the glucose metabolic clearance rate during hyperinsulinaemia were similar in pregnant control and pregnant SDF rats. There was, however, a modest decrease in the sensitivity of the liver to insulin during pregnancy in SDF rats. The normal increase in plasma insulin levels during pregnancy was blunted in SDF rats: this resulted in increased glucose levels in maternal and fetal rats and increased fetal insulin concentrations, features compatible with mild 'gestational diabetes'. In conclusion, gestational diabetes develops in pregnant SDF rats, although there is no further deterioration in peripheral insulin resistance. Journal of Endocrinology (1991) 131, 387–393

Downregulated IRS-1 and PPARγ in obese women with gestational diabetes: relationship to FFA during pregnancy

2002 ◽  
Vol 282 (3) ◽  
pp. E522-E533 ◽  
Author(s):  
Patrick M. Catalano ◽  
Steven E. Nizielski ◽  
Jianhua Shao ◽  
Larraine Preston ◽  
Liping Qiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Gestational Diabetes ◽  
Target Genes ◽  
Late Gestation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Obese Women ◽  
Cellular Mechanisms ◽  
Fatty Acid Binding

Gestational diabetes mellitus (GDM) is associated with elevated postprandial 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 insulin suppression of FFA before pregnancy and in early (12–14 wk) and late (34–36 wk) gestation in obese subjects with normal glucose tolerance and in obese GDM subjects. Abdominal subcutaneous adipose tissue biopsies were also obtained during cesarean delivery from normal obese pregnant (Preg-Con), GDM, and nonpregnant obese control (Non-Preg-Con) subjects during gynecological surgery. GDM subjects had higher basal plasma FFA before pregnancy ( P = 0.055). Insulin's ability to suppress FFA levels declined from early to late gestation in both GDM and Preg-Con subjects and was significantly less in GDM subjects compared with Preg-Con subjects over time ( P = 0.025). Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower ( P = 0.02) and p85α subunit of phosphatidylinositol 3-kinase was twofold higher ( P = 0.03) in GDM compared with Preg-Con subjects. The levels of peroxisome proliferator-activated receptor-γ (PPARγ) mRNA and protein were lower by 38% in Preg-Con ( P = 0.006) and by 48% in GDM subjects ( P = 0.005) compared with Non-Preg controls. Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects ( P < 0.002). Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. Decreased PPARγ and its target genes may be part of the molecular mechanism to accelerate fat catabolism to meet fetal nutrient demand in late gestation.

scholarly journals Gestational diabetes: emerging concepts in pathophysiology

2010 ◽  
Vol 3 (4) ◽  
pp. 128-132 ◽  
Author(s):  
Kenneth Hodson ◽  
Stephen Robson ◽  
Roy Taylor
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Normal Pregnancy ◽  
Resonance Spectroscopy ◽  
Muscle Lipid ◽  
Metabolic Substrates ◽  
The United Kingdom ◽  
Type 2 Diabetics ◽  
Skeletal Muscle Lipid

Gestational diabetes affects 3 to 5% of pregnancies in the United Kingdom, contributing to significant maternal and fetal morbidity. Understanding the pathophysiology is important as it guides diagnostic screening and treatment. The insulin resistance of normal pregnancy facilitates provision of metabolic substrates to the fetus and is multifactorial in origin. Recent identification of hepatic and skeletal muscle lipid deposition in Type 2 diabetics, demonstrated by novel magnetic resonance spectroscopy techniques, is likely to be the underlying cause of pathological insulin resistance. Similar mechanisms almost certainly underlie gestational diabetes, although further studies are required to prove this. Women who develop gestational diabetes have demonstrable insulin resistance prior to pregnancy that is part of a chronic process of lipid accumulation ultimately leading to type 2 diabetes later in life. The importance of lifestyle advice and dietary modification and the rationale behind the use of metformin are thus explained.

scholarly journals Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle

Endocrinology ◽  
2004 ◽  
Vol 145 (3) ◽  
pp. 1144-1150 ◽  
Author(s):  
Linda A. Barbour ◽  
Jianhua Shao ◽  
Liping Qiao ◽  
Wayne Leitner ◽  
Marianne Anderson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Normal Pregnancy ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
Cellular Mechanisms ◽  
Severe Insulin Resistance ◽  
Placental Growth Hormone ◽  
Glut 4 Translocation ◽  
Phosphatidylinositol 3

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 &lt; 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 p85α regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase; P &lt; 0.001), yet a reduced ability of insulin to stimulate IRS-1-associated PI 3-kinase activity (P &lt; 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 &lt; 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 p85α monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.

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