Silencing of ANGPTL8 Alleviates Insulin Resistance in Trophoblast Cells.

Yu Bai,Le Zhang,Ling Li,Ping Li,Nana Wang,Bo Wu,Qiang Du

doi:10.3389/fendo.2021.635321

Abstract

This study aims to investigate the effect of angiopoietin like 8 (ANGPTL8) on gestational diabetes mellitus (GDM) and insulin resistance (IR). The GDM model was induced by high fat diet in mice, and IR was observed. The expression and secretion of ANGPTL8 were promoted in placenta of GDM mice. IR was induced in trophoblast cell HTR-8/SVneo by treatment of high concentration of insulin, and the expression levels of ANGPTL8 were increased. Silencing of ANGPTL8 alleviated IR and decreased glucose uptake in HTR-8/SVneo cells. However, the inflammation and oxidative stress in IR cells were not restrained by ANGPTL8 knockdown. In addition, c-Jun N-terminal kinase (JNK) signaling was activated by IR, which was inhibited by silencing of ANGPTL8. The effect of ANGPTL8 knockdown on IR was attenuated by JNK antagonist, and aggravated by JNK agonist, suggesting that ANGPTL8 affected IR by regulating JNK signaling. In conclusion, we demonstrated that the silencing of ANGPTL8 ameliorated IR by inhibiting JNK signaling in trophoblast cells. These findings may provide novel insights for diagnosis and treatment of GDM in clinic.

Highlights

Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy, defined as “the type of glucose intolerance that develops in the second and third trimester of pregnancy, resulting in hyperglycemia of variable severity” [1, 2]
The results showed that high fat diet (HFD) caused significant elevation of fasting blood and insulin levels and HOMA-insulin resistance (IR) index in pregnant mice (Figures 1D–F)
Insulin is synthesized and secreted in pancreatic b cells, which cooperates with glucagon to maintain plasma glucose homeostasis

Summary

Introduction

Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy, defined as “the type of glucose intolerance that develops in the second and third trimester of pregnancy, resulting in hyperglycemia of variable severity” [1, 2]. Women with GDM have an increasing risk factor to develop type 2 diabetes mellitus (T2DM) and cardiovascular disease after pregnancy, and their offspring are at increasing risk for the development of obesity and T2DM in later life [5]. Pancreatic b-cell secretory impairment and insulin resistance (IR) are pivotal during pathogenesis of GDM [1]. Pancreatic b-cell deterioration-induced IR and relative insulin deficiency are the primary metabolic changes in GDM. Gluconeogenesis is increased as a result of IR and ANGPTL8 Deteriorates Insulin Resistance insulin deficiency. IR and insulin deficiency are often considered as therapeutic targets for GDM

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Conclusion