Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes

Abstract

Significance: Type 2 diabetes development involves multiple changes in β-cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relationships among the dysregulated metabolism, impaired β-cell “well-being,” biogenesis, or cross talk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity, and glucotoxicity cannot be separated from numerous other cell pathology events, such as the attempted compensation of β-cell for the increased insulin demand and dynamics of β-cell biogenesis and its “reversal” at dedifferentiation, that is, from the concomitantly decreasing islet β-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. Critical Issues: At prediabetes, the compensation responses of β-cells, attempting to delay the pathology progression—when exaggerated—set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various secretagogues including glucose, may lead to excretion of cytokines or chemokines by β-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. Future Directions: Should bring an understanding of the β-cell self-checking and related redox signaling, including the putative stress signal to periphery. Strategies to cure or prevent type 2 diabetes could be based on the substitution of the “wrong” signal by the “correct” self-checking signal.

Glucose-Stimulated Insulin Secretion Fundamentally Requires H2O2 Signaling by NADPH Oxidase 4

“…Insulin, which is released from pancreatic b-cells, controls the blood glucose level in healthy individuals, and insulin release is impaired in those with diabetes (1)(2)(3)(4). An understanding of the pathophysiology of the insulin release mechanism is indispensable for clinical innovation.…”

“…Thus, the elevation of the ATP-to-ADP ratio was thought to close K ATP channels without any additional requirement for parallel redox signaling. A rather weak antioxidant defense and low redox buffer capacity, but high thioredoxin and peroxiredoxin content (26), provide an ideal, delicate ROS homeostasis in b-cells, although this homeostasis might be disturbed by a relatively weak insult and may spread within the cytosol (2,27).…”

Redox Signaling from Mitochondria: Signal Propagation and Its Targets

“…Fatty acids were recognized as so-called insulin secretagogues [29,203,204]. The latter term is used for species stimulating secretion of insulin in pancreatic β-cells.…”

Centaurium erythraea extract reduces redox imbalance and improves insulin expression and secretion in pancreatic β-cells exposed to oxidative and nitrosative stress

“…Thus, H 2 O 2 acts as a signaling molecule in glucosestimulated insulin secretion (GSIS) in β-cells [4] while NO • is a physiological regulator of insulin secretion at lower concentrations [5]. High concentrations of ROS and RNS, resulting either from their overproduction or from the disruption of antioxidant protection, produce oxidative stress associated with damage and dysfunction of proteins, lipids and DNA [6]. To maintain redox homeostasis, the cell must ensure proper functioning of the endogenous antioxidant system.…”

“…Because of the relatively low expression and activity of antioxidant enzymes and redox buffers in comparison to other cell types, β-cells are more susceptible to oxidative stress [6,12]. As redox-homeostasis in β-cells can easily shift to a state of harmful oxidative stress, exogenously assisted lowering of excess ROS/ RNS levels and/or the improvement of endogenous antioxidant defenses can contribute to the preservation of structural and functional properties of β-cells in diabetes.…”