Molecular pathways and nutrigenomic review of insulin resistance development in gestational diabetes mellitus

Abstract

Gestational diabetes mellitus is a condition marked by raised blood sugar levels and insulin resistance that usually occurs during the second or third trimester of pregnancy. According to the World Health Organization, hyperglycemia affects 16.9% of pregnancies worldwide. Dietary changes are the primarily alternative treatment for gestational diabetes mellitus. This paper aims to perform an exhaustive overview of the interaction between diet, gene expression, and the metabolic pathways related to insulin resistance. The intake of foods rich in carbohydrates can influence the gene expression of glycolysis, as well as foods rich in fat, can disrupt the beta-oxidation and ketogenesis pathways. Furthermore, vitamins and minerals are related to inflammatory processes regulated by the TLR4/NF-κB and one carbon metabolic pathways. We indicate that diet regulated gene expression of PPARα, NOS, CREB3L3, IRS, and CPT I, altering cellular physiological mechanisms and thus increasing or decreasing the risk of gestational diabetes. The alteration of gene expression can cause inflammation, inhibition of fatty acid transport, or on the contrary help in the modulation of ketogenesis, improve insulin sensitivity, attenuate the effects of glucotoxicity, and others. Therefore, it is critical to comprehend the metabolic changes of pregnant women with gestational diabetes mellitus, to determine nutrients that help in the prevention and treatment of insulin resistance and its long-term consequences.

Keywords: gestational diabetes mellitus; insulin resistance; metabolic pathways; nutrients; nutrigenomic.

Figure 1

Pathways related to insulin resistance. (A,C) Glucose breaks down producing pyruvate, which serves to produce energy in the TCA. (B) Glucose biosynthesis occurs from oxaloacetate. (C–E) Carnitine carries fatty acids into the mitochondria to synthesize acetyl-CoA, which serves to generate energy in the TCA cycle or to form ketone bodies via ketogenesis. (F) TLR4 activation sets off a series of events that culminate in the activation of NF-B, which is responsible for the synthesis and release of proinflammatory cytokines, eventually leading to GDM. Upward arrows indicate an elevation, while downward arrows indicate a reduction. Different colors represent each cellular process. GLUT, Glucose Transporter; PC, Pyruvate carboxylase; PDH, Pyruvate dehydrogenase; PEP, Phosphoenolpyruvate; OAA, Oxaloacetate; LPS, lipopolysaccharide; TLR4, Toll-like receptor 4; IKK, IκB Kinase; NF-kB, Nuclear factor κB.

Figure 2

One-carbon metabolism. GLUT, Glucose Transporter; THF, Tetrahydrofolate; 5-10-MTHF, 5,10-methylenetetrahydrofolate; 5-MTHF, 5-methyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine.