The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review

Abstract

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring.

Keywords: FGF19 family; diabetes mellitus; fibroblast growth factors; gestational diabetes; metabolic disorders; pregnancy.

Figure 1

Metabolic effects of FGF19. Abbreviations: FGF19—fibroblast growth factor 19; FXR—farnesoid X receptor; FGFR4—fibroblast growth factor receptor 4; FGFR1—fibroblast growth factor receptor 1; β-Klotho—Klotho β-like protein; SHP—nuclear small heterodimer partner; CYP7A1—cholesterol 7 α hydroxylase; CREB—cAMP-response element-binding protein; PGC1α—peroxisome proliferator-activated receptor γ coactivator 1-α; GSK—glycogen synthase kinase; ↑—increased; ↓—decreased; AgRP—Agouti-related protein; NPY—neuropeptide Y; WAT—white adipose tissue.

Figure 2

Metabolic effects of FGF21. Abbreviations: FGF21—fibroblast growth factor 21; PPARα—peroxisomes proliferators-activated receptor α; FGFR1—fibroblast growth factor receptor 1; β Klotho—Klotho β-like protein; WAT—white adipose tissue; BAT—brown adipose tissue; UCP1—uncoupling protein 1.

Figure 3

Metabolic effects of FGF23. Abbreviations: FGF23—fibroblast growth factor; PTH—parathyroid hormone; PCT—proximal convoluted tubules; Cyp27b1—25-hydroxyvitamin D-1α-hydroxylase; Cyp24a1—24α-hydroxylase; NaPi-2a—sodium-dependent phosphate cotransporter 2A.