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      Effects of dynamic change in fetuin-A levels from the first to the second trimester on insulin resistance and gestational diabetes mellitus: a nested case–control study

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          To examine the effects of dynamic change in fetuin-A levels before the diagnosis of gestational diabetes mellitus (GDM) on insulin resistance and GDM.

          Research design and methods

          A total of 135 women with GDM and 135 normal glucose tolerance (NGT) women with matched age (±2 years old) and gestational age at taking the oral glucose tolerance test (OGTT) were included in this nested case–control study. Fasting venous blood samples were collected at the prenatal visit of the first trimester and during OGTT of the second trimester. Plasma concentration of fetuin-A and insulin was determined.


          The plasma fetuin-A concentration in women with GDM was significantly higher than NGT controls in both the first trimester (medians: 403.0 pg/mL vs 273.4 pg/mL; p<0.05) and the second trimester (medians: 475.7 pg/mL vs 290.8 pg/mL; p<0.05) and notably increased from the first to the second trimester. Multivariate linear regression analysis showed that the change in fetuin-A concentration was associated with the changes in fasting insulin, homeostasis model assessment (HOMA) of insulin resistance, and HOMA of β-cell function (HOMA-β) (p<0.05). The highest quartile of the increase in fetuin-A concentration from the first to the second trimester was associated with a higher risk of developing GDM compared with the lowest quartile (OR 2.14; 95% CI 1.05 to 4.37).


          The dynamic change in fetuin-A levels was associated with the changes in insulin resistance and β-cell function from the first to the second trimester, and was associated with an increased risk of the development of GDM, indicating that fetuin-A could be a biomarker to predict the risk of GDM.

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          Most cited references 15

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          Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance.

          Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes.
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            Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene.

            Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.
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              Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity.

              Amino acid sequence of the precursor of the phosphorylated N-glycoprotein (pp63) secreted by rat hepatocytes was deduced from the cDNA sequence. This polypeptide (Mr = 40,586) was rich in both cysteine and proline and contained three potential N-glycosylation sites. A single pp63 mRNA species (approximately 2000 bp), found in normal hepatocytes but not in FaO hepatoma cells, appeared to result from transcription of a single gene. pp63 purified by affinity chromatography inhibited insulin receptor tyrosine kinase and receptor autophosphorylation. Only the phosphorylated form of the protein was active. In additon, pp63 antagonized the growth-promoting action of insulin in FaO cells but did not affect hormone-mediated increase in amino acid transport capacity or tyrosine aminotransferase induction in these cells.

                Author and article information

                BMJ Open Diabetes Res Care
                BMJ Open Diabetes Res Care
                BMJ Open Diabetes Research & Care
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                20 January 2020
                : 8
                : 1
                [1 ] departmentDepartment of Maternal and Child Health, School of Public Health , Peking University , Beijing, China
                [2 ] Tongzhou Maternal and Child Health Hospital , Beijing, China
                [3 ] departmentDepartment of Epidemiology and Biostatistics, School of Public Health , Peking University , Beijing, China
                Author notes
                [Correspondence to ] Professor Haijun Wang; whjun1@ 123456bjmu.edu.cn ; Dr Jue Liu; jueliu@ 123456bjmu.edu.cn
                © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81703240
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