Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells

Abstract

The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells.

Keywords: glucose metabolism; insulin secretion; oxidative stress; pancreatic β-cells; reactive oxygen species.

Figure 1

Mechanism of glucose-induced insulin secretion in β-cells. Insulin secretion from β-cells is regulated by intracellular glucose metabolism, and glucose-induced ATP production in mitochondria plays an essential role. Increased ATP levels in β-cells lead to the closure of K_ATP channels, followed by membrane depolarization and the subsequent activation of VDCCs. An elevation of intracellular Ca²⁺ levels triggers the exocytosis of insulin granules. The triggering pathway is critical for GSIS and is modulated by the signals of various GPCRs. In addition, ATP and other metabolites amplify downstream of Ca²⁺ influx in the triggering pathway (the amplifying pathway). Glu, glucose; GK, glucokinase; Pyr, pyruvate; ETC, electron transport chain; TP, the triggering pathway; AP, the amplifying pathway.

Figure 2

Involvement of c-Src in glucose-induced ROS generation in diabetic β-cells. In diabetic β-cells, acute ROS generation induced by glucose is upregulated, which is attributed to c-Src activation. GLP-1 signaling can suppress c-Src activation and ROS generation, resulting in restored ATP production. Glu, glucose; Pyr, pyruvate; ETC, electron transport chain.

Figure 3

HIF-1α regulates the change in glucose metabolism by ROS toxicity in diabetic β-cells. Under chronic oxidative stress, ROS inhibits PHD activity to activate HIF-1α. LDHA activation by HIF-1α causes excess lactate production from glucose. Glu, glucose; Pyr, pyruvate; Lac, lactate; ETC, electron transport chain; PR, proteasome.

Figure 4

Regulatory mechanism of gene expression by the Nrf2/Keap1 system. During normal physiological conditions, Nrf2 binds to Keap1 and is degraded through Cul3-mediated ubiquitination. During oxidative stress, Nrf2 is released from the binding of Keap1, translocated to the nucleus, and drives gene expression of antioxidant and NADPH-producing enzymes. Cul3, Cullin3; Ub, ubiquitin.