Oxidative Stress, Intrauterine Growth Restriction, and Developmental Programming of Type 2 Diabetes

Abstract

Intrauterine growth restriction (IUGR) leads to reduced birth weight and the development of metabolic diseases such as Type 2 diabetes in adulthood. Mitochondria dysfunction and oxidative stress are commonly found in key tissues (pancreatic islets, liver, and skeletal muscle) of IUGR individuals. In this review, we explore the role of oxidative stress in IUGR-associated diabetes etiology.

FIGURE 1.

Pancreatic β-cell oxidative stress Insulin secretion in β-cells is coupled to glucose metabolism, leading to subsequent increase in the ATP-to-ADP ratio. Mitochondria are pivotal for producing ATP required for nutrient-induced insulin secretion. ATP binds and closes the ATP-sensitive K⁺ (K_ATP) channels. This depolarizes the plasma membrane, opening voltage-gated Ca⁺² channels with the influx of Ca⁺² stimulating secretion of insulin. NOX activation also contributes to insulin secretion, although the mechanism is unclear. These events observed in GSIS are depicted with black lines, and mechanisms by which oxidative stress is generated and contributes to altered GSIS are depicted with red lines and red Xs. ROS can damage mitochondrial components, including mtDNA and protein, which could result in reduced mitochondrial ATP production and increase mitochondrial-derived ROS. ROS consequently activates redox-responsive signaling pathway JNK, leading to nuclear exclusion of PDX-1, whereas activation of redox-regulated NF-κB upregulates pro-oxidant enzymes NOX-2 and iNOS. Both NF-κB and NRF2 increase gene expression of antioxidant defense genes. GSIS, glucose-stimulated insulin secretion; ROS, reactive oxygen species; TCA, tri-carboxylic acid cycle; Cyt C, cytochrome C; ATP, adenosine triphosphate; Glut2, glucose transporter type 2; NOX, NADPH oxidase; iNOS, inducible nitric oxide synthase; PDX-1, pancreatic and duodenal homeobox 1; JNK, c-Jun NH₂-terminal kinase; NRF2, nuclear factor (erythroid-derived 2)-like 2; NF-κB, nuclear factor kappa light-chain-enhancer of activated B cells.

FIGURE 2.

Skeletal muscle oxidative stress In skeletal muscle, insulin stimulates translocation and fusion of intracellular GLUT4-containing vesicles to the plasma membrane where it facilitates glucose uptake. Insulin mediates translocation via signal transduction involving IR and IRS tyrosine phosphorylation and PI3K activation. From here, signaling bifurcates activating Rac1 and AKT. Rac1 activation compartmentalizes insulin signaling and participates in GLUT4 translocation, whereas AKT activity leads to nNOS activation and AS160 inhibition, both participating in GLUT4 translocation. Also through unknown mechanisms, insulin stimulates ROS production from NOX, which contributes to signal transduction by locally and temporally decreasing PTP activity. Finally, calcium release from intracellular stores, mediated through PLC generation of IP3 and S-glutathionylation of RyRs, is required for translocation. These events observed in insulin-stimulated glucose uptake are depicted with black lines, and mechanisms by which oxidative stress contributes to altered GLUT4 translocation are depicted with red lines. Oxidative stress can activate serine/threonine protein kinases JNK or IKKβ that, respectively, inhibit IRS tyrosine phosphorylation and activate NF-κB. NF-κB activation is associated with modulation in cellular redox status and diminished insulin-mediated GLUT4 translocation. Oxidative stress also inhibits Rac1 activation and its downstream events. Finally, mitochondria-specific generation of oxidative stress abrogates insulin signaling. Disrupted insulin signaling led to insulin resistance and T2D. GLUT4, glucose transporter type 4 (SLC2A4); IRS, insulin receptor substrate; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP3, phosphatidylinositol (3-5)-trisphosphate; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; RyR, ryanodine receptor; Rac1, Ras-related C3 botulinum toxin substrate 1; GTP, guanosine triphosphate; AKT, protein kinase B; AS160, AKT substrate 160-KD (TBC1D4); nNOS, neuronal nitric oxide synthase; PTP, protein-tyrosine phosphatase.