Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

Abstract

Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.

CD36 Signal Transduction in Metabolic Diseases: Novel Insights and Therapeutic Targeting

“…On the other hand, β-cells have a lower abundance of antioxidant defense enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) [ 124 , 125 , 126 ]. As such, the administration of antioxidant supplements can increase the defense capacity of islet cells to cope with oxidative stress [ 127 ].…”

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

“…Refs. (5,17,107,248)]. Type 2 diabetes etiology originates not only from the impaired molecular mechanisms of insulin secretion but also from low-grade inflammation causing insulin resistance and promoting b-cell oxidative stress, ER stress, and cell death.…”

“…We found that insulin secretion stimulated by branchedchain ketoacids (BCKAs) (194) and partly by fatty acids (FAs) (98,103) essentially relies on mitochondrial retrograde redox signaling. Due to the relatively low content of cytosolic glutathione (17,(135)(136)(137)270), the redox milieu of pancreatic b-cells promotes the signal spreading from mitochondria up to the targets within the plasma membrane, which can further switch-on Ca V opening and action potential firing, followed by IGV exocytosis. It is unknown whether the redox signal spreading is enabled by a H 2 O 2 diffusion or by a redox relay, for example, via peroxiredoxins, thioredoxins, or glutaredoxins, abundant in pancreatic b-cells (97,204).…”

“…In any case, b-cells appear to be a perfect redox system, ideally suited for redox signal conduction (105,274). Nevertheless, the redox state is highly compartmentalized (17,208).…”

Revisiting Regulators of Human β-cell Mass to Achieve β-cell–centric Approach Toward Type 2 Diabetes

“…One cause of glucose toxicity is chronic oxidative stress [ 9 , 10 ]. Glucose produces reactive oxygen species (ROS) through oxidative phosphorylation, and when the ROS concentration exceeds the physiological range as a result of hyperglycemia, it can cause tissue damage including β cells, which are especially susceptible to oxidative stress due to poor intrinsic antioxidant defenses [ 11 ]. Specifically, when β cells are attacked by ROS, mitochondrial dysfunction occurs and signaling that normally links glucose metabolism and insulin secretion is disrupted [ 12 , 13 ].…”