Pathogenesis of Gestational Diabetes

妊娠期糖尿病的发病机制

• 批准号: 10690347
• 负责人: Edwina Yeung
• 金额: $ 0.35万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10690347
• 关键词: Adipocytes; Adipose tissue; Biochemical Markers; Biological; Biological Markers; Carnitine; Clinical; Development; Diagnosis; Dietary Fats; Esterification; FABP4 gene; Fatty Acids; Fetal Growth; Fetal Macrosomia; First Pregnancy Trimester; Functional disorder; Gestational Diabetes; Goals; Gonadal Steroid Hormones; Hormones; Impairment; Individual; Insulin Resistance; Lead; Length; Light; Link; Lipids; Metabolism; Mitochondria; National Institute of Child Health and Human Development; Obesity; Pathogenesis; Pathway interactions; Plasma; Play; Polyunsaturated Fatty Acids; Pregnancy; Pregnancy Complications; Prevention; Primary Prevention; Process; Prolactin; Research; Risk; Risk Factors; Role; Saturated Fatty Acids; Second Pregnancy Trimester; Specimen; Time; Vitamin D; Vitamin D Deficiency; Woman; acylcarnitine; adipokines; base; cytokine; early pregnancy; effective intervention; fatty acid oxidation; fatty acid transport; glucose metabolism; hormone binding protein; improved; insulin secretion; lipidomics; mitochondrial dysfunction; modifiable risk; novel; precision nutrition; predictive modeling; prospective; risk stratification

Gestational diabetes is a common pregnancy complication. Although the precise underlying mechanism has yet to be identified, insulin resistance and inadequate insulin secretion to compensate for it play a central role in the pathophysiology of GDM. Excess adiposity is an important modifiable risk factor for the development of the condition. Mechanisms linking excess adiposity to elevated risk of GDM are not completely understood, but recent evidence points to the crucial role of specific hormones and cytokines (adipokines) secreted by the adipose tissue. The general goal of this project is for research on the pathogenesis of GDM. Under this research theme, the specific aim of this project is to prospectively investigate novel biochemical markers, for instance, biomarkers involved in adipocyte cytokine secretion and metabolism in association with subsequent risk of GDM and fetal overgrowth. This project utilizes bio-specimens collected 4 times throughout pregnancy from GDM cases and matched controls within the NICHD Fetal Growth Studies. In the past year multiple advances have been made to our understanding of the pathogenesis of GDM. Research on plasma fatty acids provides novel evidence for distinct associations of individual and subclasses of saturated fatty acids (SFAs) and poly-unsaturated fatty acids (PUFAs) varying by chain length, in relation to subsequent risk of GDM. For instance, it was demonstrated that primarily endogenously metabolized n-6 PUFAs including GLA, DGLA, and DTA in early to mid-pregnancy in the development of GDM. Several plasma acylcarnitine species are differentially associated with GDM risk by chain length. Carnitine plays a pivotal role in transporting fatty acids into the mitochondria for subsequent fatty acid oxidation (FAO). This process results in the esterification of carnitine to form acylcarnitine derivatives. Dysregulation of acylcarnitine derivatives may be indicative of impaired FAO and mitochondrial dysfunction, which in turn contributes to the pathogenesis of insulin resistance. In addition, based on non-targeted lipidomics profile of 420 metabolites, we observed that plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk. Taken together, these new findings shed light on the biological mechanisms that underlie prior findings on dietary fat and GDM risk and support the concept of precision nutrition for GDM prevention. Additionally, maternal vitamin D deficiency as early as the first trimester of pregnancy was associated with an elevated risk of GDM. The association was stronger for women who were persistently deficient through the second trimester. Assessment of vitamin D status in early pregnancy may be clinically important and valuable for improving risk stratification and developing effective interventions for the primary prevention of GDM. Furthermore, sex hormone binding protein, prolactin, and understudied adipokines including FABP4, chemerin, and sOB-R have been associated with GDM risk and may be involved in the pathophysiology of GDM, long before the diagnosis of GDM in the second half of pregnancy. Further research is needed to further elucidate the mechanisms in which these biomarkers are involved in GDM development. The lead PI, Dr. Cuilin Zhang, departed from the NICHD in 2021.

妊娠期糖尿病是一种常见的妊娠并发症。虽然确切的潜在机制尚未确定，但胰岛素抵抗和胰岛素分泌不足在GDM的病理生理中起着核心作用。过度肥胖是病情发展的一个重要的可改变的危险因素。过度肥胖与GDM风险升高之间的联系机制尚不完全清楚，但最近的证据表明，脂肪组织分泌的特定激素和细胞因子（脂肪因子）起着至关重要的作用。

项目成果

Plasma Phospholipid n-3/n-6 Polyunsaturated Fatty Acids and Desaturase Activities in Relation to Moderate-to-Vigorous Physical Activity through Pregnancy: A Longitudinal Study within the NICHD Fetal Growth Studies.

• DOI: 10.3390/nu12113544
• 发表时间: 2020-11-19
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Chen L;Zhu Y;Fei Z;Hinkle SN;Xia T;Liu X;Rahman ML;Li M;Wu J;Weir NL;Tsai MY;Zhang C
• 通讯作者: Zhang C

A Prospective Study of Leukocyte Telomere Length and Risk of Gestational Diabetes in a Multiracial Cohort.

多种族队列中白细胞端粒长度和妊娠糖尿病风险的前瞻性研究。

• DOI: 10.1097/ede.0000000000001081
• 发表时间: 2019
• 期刊: Epidemiology (Cambridge, Mass.)
• 作者: Lin,Yuan;Zhu,Yeyi;Wu,Jing;Hinkle,StefanieN;Rawal,Shristi;Han,Jiali;Weir,NatalieL;Tsai,MichaelY;Zhang,Cuilin
• 通讯作者: Zhang,Cuilin

Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort.

胰岛素样生长因子轴和妊娠糖尿病：多种族组中的一项纵向研究。

• DOI: 10.2337/db16-0514
• 发表时间: 2016-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Zhu Y;Mendola P;Albert PS;Bao W;Hinkle SN;Tsai MY;Zhang C
• 通讯作者: Zhang C

Brown Adipose Tissue, Adiposity, and Metabolic Profile in Preschool Children.

• DOI: 10.1210/clinem/dgab447
• 发表时间: 2021-09-27
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Tint MT;Michael N;Sadananthan SA;Huang JY;Khoo CM;Godfrey KM;Shek LP;Lek N;Tan KH;Yap F;Velan SS;Gluckman PD;Chong YS;Karnani N;Chan SY;Leow MK;Lee KJ;Lee YS;Hu HH;Zhang C;Fortier MV;Eriksson JG
• 通讯作者: Eriksson JG